Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.Cl.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[S:28][CH2:27][CH2:26][NH:25][CH2:24]2)[CH:18]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:25]2[CH2:26][CH2:27][S:28][CH:23]([C:19]3[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=3)[CH2:24]2)=[O:15])=[CH:6][CH:7]=1
Reactant: c1cncc(C2CNCCS2)c1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Agent: Cl
Product: Cc1ccc(-c2oncc2C(=O)N2CCSC(c3cccnc3)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 2-pyridin-3-yl thiomorpholine hydrochloride (13 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (11.5 mg). Calcd for C20H19N3O2S: 365.1198, found 365.1200.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)=[CH:10][CH:9]=1)[CH3:2].[CH2:20]([O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[CH2:21][CH:22]=[CH2:23].C(N(CC)CC)C>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][N:6]([S:31]([C:28]1[CH:27]=[CH:26][C:25]([O:24][CH2:20][CH2:21][CH:22]=[CH2:23])=[CH:30][CH:29]=1)(=[O:33])=[O:32])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)CNCc1ccc(-n2cncn2)cc1
Reactant: C=CCCOc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C=CCCOc1ccc(S(=O)(=O)N(CC(=O)OCC)Cc2ccc(-n3cncn3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2 g (7.683 mmol) of (4-[1,2,4] triazol-1-yl-benzylamino)-acetic acid ethyl ester in 15 ml of dioxane and 15 ml of H 20, 2.3 g (9.22 mmol) of 4-but-3-enyloxy-benzenesulfonyl chloride and 1.3 ml (9.22 mmol) of triethyl amine are successively added at 0–5° C. After being stirred for 18 h at r.t., the reaction mixture is diluted with H 20 and extracted with AcOEt. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give the title compound. 1H-NMR (400 MHz, CDCl3): 1.17 (t, 3H, J=7.04 Hz), 2.55–2.65 (m, 2H), 3.95 (s, 2H), 4.07 (t, 2H, J=7.04 Hz), 4.09 (t, 2H, J=6.56 Hz), 4.53 (s, 2H), 5.10–5.25 (m, 2H), 5.85–5.95 (m, 1H), 6.99 (d, 2H, J=8.04 Hz), 7.44 (d, 2H, J=7.56 Hz), 7.64 (d, 2H, J=8.04 Hz), 7.82 (d, 2H, J=7.56 Hz), 8.11 (s, 1H), 8.55 (s, 1H).
Reaction SMILES: [Br-].[CH3:2]OC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:30][C:31]1[CH:32]=[C:33]([C@H:37]2[CH2:42][CH2:41][C@H:40]([CH:43]=O)[CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1.O>C1COCC1.C1(C)C=CC=CC=1>[F:30][C:31]1[CH:32]=[C:33]([C@H:37]2[CH2:42][CH2:41][C@H:40]([CH:43]=[CH2:2])[CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C[C@H]1CC[C@H](c2cccc(F)c2)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: C=C[C@H]1CC[C@H](c2cccc(F)c2)CC1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
Well-dried methoxymethyltriphenylphosphonium bromide (26.0 g) and THF (200 ml) were mixed under a nitrogen atmosphere, and cooled to −30° C. Then, potassium t-butoxide (t-BuOK; 8.2 g) was put in thereto in twice in the temperature range of −30° C. to 20° C. After the mixture had been stirred at −20° C. for 30 minutes, the compound (37) (10.0 g) dissolved in THF (50 ml) was added dropwise thereto in the temperature range of −30° C. to −20° C. After the reaction mixture had been stirred at −10° C. for 30 minutes, it was poured into a mixture of water (200 ml) and toluene (200 ml), and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and an extractive operation was carried out. The organic phase obtained was fractionated, washed with water, and then dried over anhydrous magnesium sulfate. The solution obtained was concentrated under reduced pressure, and the residue obtained was purified with a fractional operation by means of column chromatography using toluene as the eluent and silica gel as the stationary phase powder. The eluent obtained was concentrated under reduced pressure, giving 9.0 g of 1-(3-fluorophenyl)-trans-4-ethenylcyclohexane (38). The yield based on the compound (37) was 90.9%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:35])([CH2:29][N:30]1[CH:34]=[N:33][CH:32]=[N:31]1)[C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[CH:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[C:13]1=[O:28])[CH3:11].[C:36](=[O:44])([O:40][CH:41]([CH3:43])[CH3:42])[O:37][CH2:38][Cl:39].C(#N)C>C(OC(C)C)(C)C>[Cl-:39].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:35])([C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH:27]=[CH:26][N:25]=[N:24]3)=[CH:21][CH:22]=2)[C:13]1=[O:28])[CH3:11])[CH2:29][NH+:30]1[CH2:34][N:33]([CH2:38][O:37][C:36]([O:40][CH:41]([CH3:43])[CH3:42])=[O:44])[CH:32]=[N:31]1
Reactant: CC(C)OC(=O)OCCl
Reactant: C[C@@H](N1CCN(c2ccc(-n3ccnn3)cc2)C1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: CC#N
Solvent: CC(C)OC(C)C
Product: CC(C)OC(=O)OCN1C=N[NH+](C[C@](O)(c2ccc(F)cc2F)[C@@H](C)N2CCN(c3ccc(-n4ccnn4)cc3)C2=O)C1
Product: [Cl-]
Temperature: 100 °C
Reaction time: 25 h
Yield: 2.7 %

Procedure:
A mixture of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1,2,3-triazol-1-yl)phenyl]-2-imidazolidinone(o.5 g), chloromethyl isopropyl carbonate (3.2 g) and acetonitrile (1 ml) was stirred for 25 hours at 100° C. After having been cooled, the mixture was diluted with diisopropyl ether (10 ml), and the resulting powder was collected by filtration and subjected to the silica gel column chromatography (eluent: ethyl acetate→acetone→acetone/ethanol=10/1→acetone/ethanol=5/1). Solvent was distilled off under reduced pressure, and residue was subjected to crystallization from ethyl acetate. The crystals were dissolved in water (10 ml). The aqueous solution was lyophilized to give 1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1,2,3-triazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-4-[(isopropoxycarbonyloxy)methyl]-1H-1,2,4-triazolium chloride (Compound 9, 0.18 g) as a white powder.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:7])[CH2:4][O:5][CH3:6].[C:8](Cl)(=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)C(C)C)(C)C.CN(C=O)C>C1COCC1.CN(C)C1C=CN=CC=1>[OH:7][CH:3]([CH2:4][O:5][CH3:6])[CH2:2][NH:1][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COCC(O)CN
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCC(O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5.0 g (47.6 mmol) of rac-1-amino-3-methoxypropan-2-ol were initially charged in THF (158 ml), and 7.36 ml (52.3 mmol) of benzyl chlorocarbonate, 24.85 ml (142.7 mmol) of N,N-diisopropyl ethyl amine and 1.16 g (9.5 mmol) of 4-dimethylaminopyridine were added. The reaction mixture was stirred at RT for 16 h. 3.7 ml (26.2 mmol) of benzyl chlorocarbonate and then 15 ml of DMF were added, and the reaction solution was stirred at RT overnight. The mixture was concentrated and diluted with ethyl acetate. The mixture was then washed with water, saturated aqueous sodium bicarbonate solution and with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate, filtered off and concentrated. The aqueous phase was concentrated, the residue was taken up in ethyl acetate, the mixture was washed with saturated aqueous sodium bicarbonate solution and with saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered off and concentrated. Both fractions were combined and purified by silica gel chromatography (dichloromethane/methanol gradient: from 100:0 to 10:1). This gave 12.16 g (81% of theory, purity 76%) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:14]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl:26]Cl>ClC1C=CC=CC=1.[Fe]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[Cl:1][C:16]1[CH:15]=[C:14]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:19]=[CH:18][CH:17]=1.[Cl:26][C:6]1[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:5]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: ClCl
Agent: [Fe]
Agent: Clc1ccc(-c2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: Clc1ccccc1
Product: Clc1cccc(-c2ccccc2)c1
Product: Clc1ccccc1-c1ccccc1

Procedure:
It would be desirable to be able to prepare 4-chlorobiphenyl in a single step from biphenyl and chlorine. According to U.S. Pat. No. 1,890,427, this is possible by chlorination of biphenyl in chlorobenzene in the presence of metallic iron as catalyst. However, this gives a mixture comprising 4-chlorobiphenyl, 3-chlorobiphenyl, 2-chlorobiphenyl and unreacted biphenyl. The separation of this mixture is very complicated. For separating off one isomer, the reference describes crystallization from noneutectic mixtures above the freezing point of the eutectic. This means that separation of the entire mixture makes it necessary to carry out a complicated sequence of distillation and crystallization steps. Czech. Chem. Prum., 30(10), 529-32 (1980) confirms this. To achieve purities of greater than 99%, the latter reference describes the following steps to be carried out in succession for the separation of mixtures comprising 2-, 3- and 4-chlorobiphenyl: 1. distillation, 2. crystallization of the fractions from the distillation and 3. recrystallization of the fractions from the crystallization from ethanol.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C>Cl.NCCCCCCCCCCCC(OCC)=O>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: CCOC(=O)CCCCCCCCCCCN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCCCCCCCCNc1c([N+](=O)[O-])cnc2ccccc12
Reaction time: 6 h
Yield: 100.3 %

Procedure:
4-Chloro-3-nitroquinoline (15.52 g, 74.40 mmol) was treated with ethyl 12-aminododecanoate hydrochloride (25.0 g, 89.3 mmol) in the presence of potassium carbonate (10.28 g, 74.38 mmol) and triethylamine (25.9 mL, 186 mmol) according to a modification of the method described in Part A of Example 15. After the reaction was stirred for six hours, an analysis by TLC indicated the presence of starting material, and additional ethyl 12-aminododecanate hydrochloride (1.0 g, 3.6 mmol) was added. The reaction was stirred overnight and subjected to the work-up procedure to provide 31.0 g of ethyl 12-(3-nitroquinolin-4-ylamino)dodecanoate.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([OH:11])[C:6]([Cl:10])=[CH:7][C:8]=1[F:9].[CH2:12](Br)[C:13]#[CH:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:10][C:6]1[C:5]([O:11][CH2:14][C:13]#[CH:12])=[CH:4][C:3]([NH2:2])=[C:8]([F:9])[CH:7]=1
Reactant: C#CCBr
Reactant: Nc1cc(O)c(Cl)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1cc(N)c(F)cc1Cl

Procedure:
Using the procedure of Example 1, Step A and employing 50.0 g (252.45 mmol) of 3-amino-6-chloro-4-fluorophenol hydrochloride, 80% propargyl bromide (60.07 g, 504.9 mmol), and potassium carbonate (69.8 g, 504.9 mmol) in acetonitrile (200 mL), the title compound was obtained as a yellow solid (16.2 g), m.p. 62°-64° C. IR (nujol, era-1), NH2 (3298.0), triple bond (2117.6). 1H NMR was consistent with the structure.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8](=[O:15])[NH:7]2)([O-:3])=[O:2].[H-].[Na+].[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]Br)[CH:22]=1>CN(C)C=O>[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:10]2[C:11]3[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=3)[NH:7][C:8](=[O:15])[C:9]2=[O:14])[CH:22]=1
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2[nH]c1=O
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2c(=O)c(=O)[nH]c3cc([N+](=O)[O-])ccc32)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.9 %

Procedure:
Under an N2 stream and exclusion of moisture, 1.03 g (5 millimoles) of 6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline is combined with 50 ml of dimethylformamide at room temperature. To this mixture is added 330 mg (11 mmol) of sodium hydride (80% strength) in 3 portions. The mixture is then stirred for one hour at room temperature. To this mixture is added dropwise 1.26 g (5.5 mmol) of 3-bromomethyl-benzoic acid methyl ester in 5 ml of dimethylformamide, and the mixture is further stirred for 3½ hours. After concentration, the residue is distributed in acetic water/ethyl acetate. The organic phase is separated, dried, filtered and concentrated. The residue is chromatographed over silica gel with dichloromethan:ethanol=95:5, thus obtaining, besides 211 mg of 3-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl-methyl)benzoic acid methyl ester, which is not further purified, also 222 mg of 3-(7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl) benzoic acid methyl ester, mp: 265-267° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([OH:33])[CH2:11][N:12]1[C:20]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])=[C:19]2[C:14]([N:15]([CH3:32])[C:16](=[O:31])[N:17]([CH3:30])[C:18]2=[O:29])=[CH:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:37][C:38]([N:40]([O:42][CH3:43])[CH3:41])=[O:39]>C1COCC1>[Si:1]([O:8][CH2:9][CH:10]([O:33][CH2:37][C:38]([N:40]([O:42][CH3:43])[CH3:41])=[O:39])[CH2:11][N:12]1[C:20]([C:21]2[CH:28]=[CH:27][CH:26]=[C:23]([C:24]#[N:25])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH3:32])[C:16](=[O:31])[N:17]([CH3:30])[C:18]2=[O:29])=[CH:13]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(CC(O)CO[Si](C)(C)C(C)(C)C)cc2n(C)c1=O
Reactant: CON(C)C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CON(C)C(=O)COC(CO[Si](C)(C)C(C)(C)C)Cn1cc2c(c1-c1cccc(C#N)c1)c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 3-(6-(3-((tert-Butyldimethylsilyl)oxy)-2-hydroxypropyl)-1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (Example 9a, step 1) (280 mg, 0.597 mmol) in THF (5975 μL) was added sodium hydride (60% in mineral oil) (71.7 mg, 1.792 mmol) at 0° C. The resulting red solution was warmed to room temperature and stirred for 20 minutes, before being cooled to 0° C. 2-Bromo-N-methoxy-N-methylacetamide (Example 13, step 1) (141 mg, 0.777 mmol) was then added dropwise over 5 minutes. The reaction mixture was warmed to room temperature over 3 hours and then cooled to 0° C. and quenched with saturated aqueous ammonium chloride solution (5 mL). DCM (10 mL) was added to the biphasic solution. The aqueous phase was separated and extracted with DCM (3×10 mL); the combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to afford a yellow oil. The oil was purified using Teledyne ISCO (12 g, SiO2) eluting with 0-65% EtOAc/hexanes to afford the title compound as an amorphous white solid.
Reaction SMILES: C(Cl)([Cl:3])=O.[CH3:5][N:6]([CH3:13])[CH2:7][CH2:8][S:9]([O-])(=[O:11])=[O:10].[Na+].CN(C=O)C>C(Cl)Cl>[CH3:5][N:6]([CH3:13])[CH2:7][CH2:8][S:9]([Cl:3])(=[O:11])=[O:10]
Reactant: CN(C)CCS(=O)(=O)[O-]
Reactant: O=C(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)CCS(=O)(=O)Cl

Procedure:
Phosgene (12 ml, 1M in toluene) was added to a solution of the subtitle product of step i) in DCM (20 ml) and DMF (2.5 ml) and stirred for 3 h before concentrating in vacuo to afford the subtitle compound as an oil that was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[CH3:37][O:38][CH2:39][CH2:40][N:41]([CH2:51][CH2:52][O:53][CH3:54])[C:42](=[O:50])[CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:47]3[CH2:48][CH2:49][N:44]([CH2:43][C:42]([N:41]([CH2:40][CH2:39][O:38][CH3:37])[CH2:51][CH2:52][O:53][CH3:54])=[O:50])[CH2:45][CH2:46]3)=[O:21])[C:10]([C:23]3[CH:28]=[C:27]([C:29]([C:32]#[N:33])([CH3:30])[CH3:31])[CH:26]=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: COCCN(CCOC)C(=O)CN1CCNCC1
Reactant: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1ccc(C(C)(C)C#N)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(CCOC)CCOC)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N,N-bis-(2-methoxy-ethyl)-acetamide was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12e) and N,N-bis-(2-methoxy-ethyl)-2-piperazin-1-yl-acetamide (example 16) in an analogous manner as described in example 25. LR-MS: 763.4 [(M+H)+]
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4].[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C:21]1[N:22]=[CH:23][S:24][CH:25]=1.C([Li])CCC.[NH:31]1[CH:35]=[N:34][CH:33]=[N:32]1.[H-].[Na+]>>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3]([C:23]1[S:24][CH:25]=[C:21]([C:15]2[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=2[F:13])[N:22]=1)([OH:4])[CH2:2][N:31]1[CH:35]=[N:34][CH:33]=[N:32]1
Reactant: O=C(CCl)c1ccc(F)cc1F
Reactant: c1nc[nH]n1
Reactant: Fc1ccc(-c2cscn2)c(F)c1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Product: OC(Cn1cncn1)(c1nc(-c2ccc(F)cc2F)cs1)c1ccc(F)cc1F

Procedure:
2-Chloro-2',4'-difluoroacetophenone is added to 4-(2,4-difluorophenyl)thiazole in the presence of n-butyllithium. After subjecting the reaction product to a post treatment, 1,2,4-triazole and sodium hydride are added thereto to obtain 1-(2,4-difluorophenyl)-1-(4-(2,4-difluorophenyl)thiazol-2-yl)-2-(1H-1,2,4-triazol-1-yl)ethanol.
Reaction SMILES: ClC1C([C:12]2[C:13](F)=[CH:14][C:15]3[O:20][CH2:19][C:18](=[O:21])[NH:17][C:16]=3[CH:22]=2)=NN(C)C=1C(F)(F)F.C([O-])([O-])=O.[K+].[K+].C(Br)C#C>CC(C)=O.O>[O:20]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:22][C:16]=2[NH:17][C:18](=[O:21])[CH2:19]1
Reactant: Cn1nc(-c2cc3c(cc2F)OCC(=O)N3)c(Cl)c1C(F)(F)F
Agent: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C1COc2ccccc2N1
Temperature: 40 °C
Reaction time: 6 h
Yield: 231.5 %

Procedure:
At 25° C., 3.0 g (8.6 mmole) of the product of step A, 1.22 g (6.0 mmole) K2CO3 and 0.79 mL (8.8 mmole) 80% propargyl bromide were slurried in 50 mL acetone. The reaction was stirred at 40° C. for 6 hours. The reaction was cooled, diluted with 100 mL cold water, and extracted four times with ethyl acetate. The ethyl acetate extracts were washed with brine, dried over anhydrous MgSO4, and stripped in vacuo. The residue was recrystallized from methylcyclohexane to give 2.97 g (89%) of 2H-1,4-benzoxazin-3(4H)-one, 6-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-7-fluoro-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one as a beige solid, mp 142°-143° C.
Reaction SMILES: O.NN.[Cl:4][C:5]1[N:10]=[CH:9][C:8]([CH2:11][N:12]2C(=O)C3=CC=CC=C3C2=O)=[CH:7][CH:6]=1.O>CCO>[Cl:4][C:5]1[N:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(Cl)nc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1ccc(Cl)nc1
Yield: 70.1 %

Procedure:
Hydrazine hydrate (1.7 ml) was added to a refluxing solution of 6.5 g (2.4×10−2 mole) of N-(6-chloro-3-pyridylmethyl)phthalimide in 100 ml of EtOH, and the mixture was further refluxed for 1 hour. After addition of 20 ml of water, the ethanol was distilled off under reduced pressure. Concentrated hydrochloric acid (25 ml) was added to the residue and the mixture was refluxed for 1 hour. After cooling, the reaction mixture was neutralized with NaOH and the aqueous layer was saturated with NaCl and extracted with Et2O. The extract was dried over Na2SO4 and the solvent was distilled off to give 2.4 g of the title compound as a yellow oil.
Reaction SMILES: C(N(CC)CCCl)C.FC1C=CC=CC=1C1C2C=C([N+]([O-])=O)C=CC=2N(C)C(=O)C(C)(C)N=1.[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]1[C:47]2[CH:48]=[C:49]([N+:52]([O-:54])=[O:53])[CH:50]=[CH:51][C:46]=2[N:45](CCN(CC)CC)[C:44](=[O:62])[C:43]([CH3:64])([CH3:63])[N:42]=1>CCOCC.CCCCCC>[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]1[C:47]2[CH:48]=[C:49]([N+:52]([O-:54])=[O:53])[CH:50]=[CH:51][C:46]=2[NH:45][C:44](=[O:62])[C:43]([CH3:64])([CH3:63])[N:42]=1
Reactant: CCN(CC)CCN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc21
Agent: CCN(CC)CCCl
Agent: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc21
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1(C)N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2NC1=O

Procedure:
From 25 g (0.073 mol) of 5-(o-chlorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one and 2-diethylaminoethyl chloride there is obtained, in analogy to the details in paragraph (c) of Example 1, with a reaction period of 60 hours, 5-(o-chlorophenyl)-1,3-dihyro-1-(2-diethylaminoethyl)-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 109° (ether/n-hexane).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5](O)=O.[NH2:8][C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=1.Cl.N>>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[NH:8][C:9]2[C:14]([N:15]=1)=[CH:13][CH:12]=[CH:11][N:10]=2
Reactant: Nc1cccnc1N
Reactant: O=C(O)CCCO
Agent: Cl
Agent: N
Product: OCCCc1nc2cccnc2[nH]1
Temperature: 150 °C
Reaction time: 4 h
Yield: 66.4 %

Procedure:
0.83 g of 4-hydroxybutyric acid (prepared as described in Preparation 32) was added to 0.77 g of 2,3-diaminopyridine, and the resulting mixture was stirred at 150° C. for 4 hours. At the end of this time, the reaction mixture was treated with 3 N aqueous hydrochloric acid and subsequently made alkaline by the addition of aqueous ammonia. The aqueous mixture was evaporated to dryness under reduced pressure, and then the resulting residue was purified by column chromatography through silica gel, using a 5:1 by volume mixture of ethyl acetate and methanol as the eluent. The product was crystallized by trituration with ethyl acetate, to give 0.83 g of the title compound, melting at 151-153° C.