Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:38])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:34](=[CH:35][CH:36]=1)[O:33][C:12]1([CH2:16][CH2:15][N:14](C(=O)[C@H](C3C=CC4C(=CC=C(OC)C=4)C=3)C)[CH2:13]1)[CH2:11][C:10]2=[O:37].O>CC(O)=O>[CH3:2][O:3][C:4](=[O:38])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:34](=[CH:35][CH:36]=1)[O:33][C:12]1([CH2:16][CH2:15][NH:14][CH2:13]1)[CH2:11][C:10]2=[O:37]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)[C@@H](C)c3ccc4cc(OC)ccc4c3)C1)O2
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCNC1)O2
Temperature: 120 °C
Reaction time: 3 h
Yield: 39.5 %

Procedure:
HCl 20% aq. (5 ml, 30 mmol) was added to a suspension of (+)-(E)-3-[1′-[(S)-2-(6-methoxynaphthalen-2-yl)propanoyl]-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid methyl ester (926 mg, 1.85 mmol) in glacial AcOH (5 ml). The mixture was stirred in the microwave oven at 120° C. for 3 h. Water (5 ml) was added and the reaction mixture was extracted three times with DCM. The aqueous phase was evaporated under vacuum. MeOH (25 ml) and a catalytic amount of H2SO4 were added and the mixture was heated to 70° C. overnight. The solution was poured into water and NH3 was added to adjust the pH value to 9-10. The aqueous phase was extracted with DCM, dried over Na2SO4 and filtered. The solvent was evaporated to give (+)-(E)-3-[4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid methyl ester (210 mg) as a yellow oil (free base).
Reaction SMILES: [C:1]1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[N:18]12CCC[N:25]=[C:24]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2.CC1N=C(CO)C=CC=1>C1(C)C=CC=CC=1.CO.[OH-].[OH-].[Pd+2]>[CH3:1][C:24]1[N:25]=[C:20]([CH2:19][NH2:18])[CH:21]=[CH:22][CH:23]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: C1CCC2=NCCCN2CC1
Agent: [Pd+2]
Agent: Cc1cccc(CO)n1
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cccc(CN)n1
Reaction time: 8 h
Yield: 119.1 %

Procedure:
Diphenylphosphoryl azide (DPPA) (0.74 mL, 0.9 g, 3.4 mmol, 1.2 eq) and 1,8-Diazabicyclo(5.4.0)undec-7-ene (DBU) (0.508 mL, 0.52 g, 3.4 mmol, 1.2 eq) were added to a stirred solution of the (6-methylpyridin-2-yl)methanol (0.35 g, 2.8 mmol, 1 eq) in 7 mL anh. toluene under Ar. After stirring overnight, the solvent was removed in vacuo. Purification via flash chromatography yielded 0.47 g (3.2 mmol, 113% yield of the crude product. The crude was dissolved in 5 mL MeOH. Pd(OH)2 (20% by wt. on carbon, 0.040 g) was added, and the mixture was stirred vigorously under H2 overnight. The mixture was filtered through Celite, and the filter cake rinsed with MeOH. The solvent was removed in vacuo yielding 0.4948 g of crude (6-methylpyridin-2-yl)methanamine.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)(=[O:3])[NH2:2].C(Cl)(=O)C1C(=CC(=CC=1)C(Cl)=O)C(Cl)=[O:19].N.CC(C)=[O:33]>C(OCC)(=O)C.C(Cl)(Cl)Cl.ClCCl>[C:11]([C:6]1[CH:5]=[C:4]([C:1](=[O:3])[NH2:2])[CH:14]=[CH:13][C:7]=1[C:8]([OH:19])=[O:9])(=[O:12])[NH2:10].[C:8]([C:7]1[CH:13]=[CH:14][C:4]([C:1](=[O:3])[NH2:2])=[CH:5][C:6]=1[C:11]([OH:33])=[O:12])(=[O:9])[NH2:10]
Reactant: NC(=O)c1ccc2c(c1)C(=O)NC2=O
Reactant: CC(C)=O
Reactant: O=C(Cl)c1ccc(C(=O)Cl)c(C(=O)Cl)c1
Agent: N
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc(C(=O)O)c(C(N)=O)c1
Product: NC(=O)c1ccc(C(N)=O)c(C(=O)O)c1

Procedure:
In this step, 4-carbamoylphthalimide is prepared by reacting trimellitoyl chloride with ammonia and dehydrating the obtained product. Specifically, this reaction is conducted by reacting trimellitoyl chloride with aqueous ammonia either without any solvent or in a state dissolved in a solvent at a temperature ranging from about -15° C. to room temperature. The solvent to be used in this case is preferably acetone, dichloromethane, chloroform or ethyl acetate, though any organic solvent inert to the reaction may be used. The resulting reaction mixture is treated with an acid to give a mixture comprising 2,4-dicarbamoylbenzoic acid and 2,5-dicarbamoylbenzoic acid. This mixture is further treated in the absence or presence of a solvent for 0.5 to 24 hours to give the objective compound. This treatment is conducted at room temperature to about 200° C. The solvent to be used in this treatment is preferably N-methyl-2-pyrrolidinone, though any solvent inert to the reaction may be used.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C.[Br:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31]>CN(C)C=O.O>[Br:26][C:27]1[CH:28]=[C:29]([C:30]([NH:1][CH2:2][CH2:3][N:4]2[CH2:8][CH2:7][CH2:6][CH2:5]2)=[O:31])[CH:33]=[CH:34][CH:35]=1
Reactant: NCCN1CCCC1
Reactant: O=C(O)c1cccc(Br)c1
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCCN1CCCC1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.4 %

Procedure:
1-(2-Aminoethyl)pyrrolidine (4.34 g), diethyl cyanophosphate (5.57 ml) and triethylamine (10.4 ml) were added to a solution of 3-bromobenzoic acid (5.00 g) in N,N-dimethylformamide (DMF; 60 ml), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and then extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residues were crystallized from hexane to give the title compound (6.31 g).
Reaction SMILES: C1C2[C:15]3=[C:16]4[C:11](=CC=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[C:5]2[C:17](=[O:20])[C:18](=O)[C:3](=[C:4]23)C=1.[C:21]1([CH2:27][C:28]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=O)[CH:26]=[CH:25][CH:24]=[CH:23]C=1.[OH-].[K+].C(O)C.[C:42]1(C)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[C:31]1([C:30]2[C:3]3=[C:18]4[C:25]5=[C:24]6[C:23]7[C:15]([CH:4]=[C:26]5[C:21]3=[CH:27][CH:28]=2)=[CH:16][CH:11]=[CH:10][C:9]=7[CH:8]=[CH:7][C:6]6=[C:5]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:17]4=[O:20])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C1C(=O)c2cc3cccc4ccc5ccc1c2c5c43
Reactant: O=C(Cc1ccccc1)Cc1ccccc1
Reactant: Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=c1c(-c2ccccc2)c2ccc3cccc4cc5c6ccc(-c7ccccc7)c6c1c5c2c34
Temperature: 50 °C

Procedure:
Next, 3 g (11 mmol) of cyclopenta[cd]pyrene-3,4-dione and 2.3 g (11 mmol) of 1,3-diphenylacetone were added to 300 mL of an ethanol/toluene (10/1) solution. Under stirring, 52 mL of 6 N aqueous potassium hydroxide was added dropwise thereto. After the completion of the dropwise addition, the mixture was heated to 50° C., stirred for 1 hour, and cooled. The resulting precipitate was filtered, washed with water, ethanol, and isopropyl alcohol, in that order, and dried by heating under reduced pressure to give 2.85 g of 9,11-diphenyl-10H-pentaleno[1,2,3-cd]pyren-10-one as a black solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N+:3]=1[O-:9].[NH2:10][CH2:11][CH2:12][CH2:13][OH:14].C([O-])(O)=O.[Na+].C(O)(CC)(C)C>C(Cl)Cl>[OH:14][CH2:13][CH2:12][CH2:11][NH:10][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N+:3]=1[O-:9]
Reactant: Cc1cc[n+]([O-])c(Cl)c1
Reactant: NCCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)(C)O
Solvent: ClCCl
Product: Cc1cc[n+]([O-])c(NCCCO)c1
Reaction time: 16 h
Yield: 87.7 %

Procedure:
A mixture of 2-chloro-4-methylpyridine-N-oxide (12.1 g, 0.068 mole) (Brown, E. V. J. Amer. Chem. Soc. 1957, 79, 3565), 3-amino-1-propanol (10.33 mL, 0.14 mole), NaHCO3 (28 g, 0.34 mole), and tert-amyl alcohol (70 mL) was heated to reflux. After 16 hr, the reaction was cooled, diluted with CH2Cl2 (300 mL), and suction filtered to remove insoluble materials. The filtrate was concentrated and reconcentrated from toluene to leave a yellow oil. Recrystallization from CH2Cl2/Et2O gave the title compound (10.87 g, 88%) as a yellow solid: TLC (15% MeOH/CH2Cl2) Rf 0.44; 1H NMR (400, CDCl3) δ 7.92 (d, J=6.7, 1 H), 7.28 (br t, 1 H), 6.43 (s, 1 H), 6.33 (dd, J=6.6, 2.1 Hz, 1 H), 3.73 (t, J=5.7 Hz, 2 H), 3.47 (q, H=6.3 Hz, 2 H), 2.29 (s, 3 H), 1.82-1.88 (m, 2 H); MS (ES) m/e 183 (M+H)+.
Reaction SMILES: [O-]CC.[Na+].[Na].[CH3:6][O:7][C:8]1[C:13]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:22][C:23]#[N:24].[C:25](=O)([O:29]CC)[O:26][CH2:27][CH3:28]>C1(C)C=CC=CC=1.C(O)C>[C:23]([CH:22]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[C:8]=1[O:7][CH3:6])[C:25]([O:26][CH2:27][CH3:28])=[O:29])#[N:24]
Reactant: CCOC(=O)OCC
Reactant: COc1c(CC#N)cccc1Oc1ccccc1C
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)c1cccc(Oc2ccccc2C)c1OC
Yield: 96.5 %

Procedure:
A mixture of sodium ethoxide prepared from ethanol (20 ml) and sodium metal (480 mg), 2-[2-methoxy-3-(o-tolyloxy)phenyl]acetonitrile (5 g) and diethyl carbonate (9.4 g) in toluene (50 ml) was treated in a similar manner to that of Example 10-(4) to give oily ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]acetate (6.2 g).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:14][C:15]1[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:14][C:15]1[C:20]([O:21][C:2]2[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: Cc1ncccc1O
Reactant: N#Cc1ccc(C(F)(F)F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncccc1Oc1cc(C(F)(F)F)ccc1C#N
Temperature: 50 °C
Yield: 93.4 %

Procedure:
A mixture of 2-fluoro-4-(trifluoromethyl)benzonitrile (0.19 g, 1.0 mmol), 2-methylpyridin-3-ol (0.11 g, 1.0 mmol), and cesium carbonate (0.33 g, 1.0 mmol) in anhydrous DMF (5 mL) was heated at 50° C. for 16 h. The reaction was diluted with water and extracted with EtOAc. The combined extracts were washed with water, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (0%-30% EtOAc-hexanes) to obtain 2-(2-methylpyridin-3-yloxy)-4-(trifluoromethyl)benzonitrile (0.26 g, 94% yield). 1H NMR (400 MHz, CDCl3) δ 8.50 (dd, J=4.7, 1.4 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.44 (dd, J=8.1, 0.7 Hz, 1H), 7.35 (dd, J=8.1, 1.4 Hz, 1H), 7.28-7.25 (m, 1H), 6.87 (s, 1H), 2.50 (s, 3H) ppm.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:6][C@@H:7]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)=[N+:2]=[N-:3].[Li+].[CH3:23][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[N:1]([CH2:4][C@@H:5]([N:14]([CH3:23])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:6][C@@H:7]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])C[C@@H]1CCCCOC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@H](CN=[N+]=[N-])C[C@@H]1CCCCOC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (S)-1-azido-3-((S)-oxepan-3-yl)propan-2-ylcarbamate (83 mg, 0.28 mmol) in anhydrous THF (5 mL) at −78° C. was added 1.0 M LHMDS solution in THF (1.1 mL, 1.12 mmol), then stirred at this temperature for 30 min. To this mixture was added MeI (237 mg, 104 μL, 1.67 mmol), then the temperature was allowed to warm to 0° C., and stand for 12 h and −20° C. The reaction mixture was quenched with saturated aq. NH4Cl, extracted with EtOAc (30 mL), the separated organic phase was washed with H2O (2×10 mL), brine, and dried over Na2SO4, and filtered. The filtrate was concentrated, the resulting slurry was purified through flash chromatography on silica gel (eluted with gradient system, 0-30% EtOAc in hexane) to afford tert-butyl (S)-1-azido-3-((S)-oxepan-3-yl)propan-2-yl(methyl)carbamate. MS ESI +ve m/z 321 (M+Na).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=3)=[CH:17][C:16]=2[NH2:31])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([C:35]1[C:36]([N:42]=[CH:43][N:44]([CH3:46])C)=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=1)#N.C(OC(=O)NC1C=CC=C(SC2C=CC(C(=O)NC3C=CC=C(Br)C=3)=CC=2N)C=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=3)=[CH:17][C:16]=2[NH:31][C:46]2[C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[N:37][C:36]=3[N:42]=[CH:43][N:44]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc(C(=O)Nc3cccc(Br)c3)cc2N)c1
Agent: CC(C)(C)OC(=O)Nc1cccc(Sc2ccc(C(=O)Nc3cccc(Br)c3)cc2N)c1
Product: Cc1ccc2c(Nc3cc(C(=O)Nc4cccc(Br)c4)ccc3Oc3cccc(NC(=O)OC(C)(C)C)c3)ncnc2n1
Yield: 44 %

Procedure:
The product of Example 107B was reacted with the product from Example 9B using the procedure from Example 95D substituting the product from Example 107B for the product from Example 95C and substituting the product from Example 9B for the product from Example 8E to provide the crude product was purified by HPLC with NH4OH to provide the title compound (28 mg, 44%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.45 (s, 9 H), 2.66 (s, 3 H), 6.61 (d, J=8.09 Hz, 1 H), 7.04 (d, J=8.46 Hz, 1 H), 7.11-7.23 (m, 2 H), 7.25-7.39 (m, 3 H), 7.51 (d, J=8.46 Hz, 1 H), 7.71-7.80 (m, 1 H), 7.91 (dd, J=8.46, 2.21 Hz, 1 H), 8.09-8.12 (m, 1 H), 8.20 (d, J=1.84 Hz, 1 H), 8.60 (s, 1 H), 8.73 (d, J=8.46 Hz, 1 H), 9.44 (s, 1 H), 10.02 (s, 1 H), 10.36 (s, 1 H); MS (ESI+) m/z 641/643 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl-:11].[Al+3].[Cl-].[Cl-].[CH2:15]([O:17][C:18]([C:20]1[C:24]([CH2:25][CH3:26])=[CH:23][N:22]([CH3:27])[C:21]=1[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:19])[CH3:16]>ClCCCl>[Cl:11][C:3]1[CH:2]=[CH:10][CH:9]=[C:5]([CH:4]=1)[C:6]([C:23]1[N:22]([CH3:27])[C:21]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:20]([C:18]([O:17][CH2:15][CH3:16])=[O:19])[C:24]=1[CH2:25][CH3:26])=[O:7]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(CC)cn1C
Reactant: [Cl-]
Agent: [Al+3]
Solvent: ClCCCl
Product: CCOC(=O)Cc1c(C(=O)OCC)c(CC)c(C(=O)c2cccc(Cl)c2)n1C
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A solution of 13.8 g. (0.0788 mole) of p-chlorobenzoyl chloride and 10.5 g. (0.0788 mole) of aluminum chloride in 120 ml. of 1,2-dichloroethane is added to a refluxing solution of 21.8 g. (0.0788 mole) of ethyl 3-ethoxycarbonyl-4-ethyl-1-methylpyrrole-2-acetate. The mixture is heated under reflux for 10 hours and stirred at room temperature for an additional 10 hours. It is then poured into ice-hydrochloric acid. The organic layer is separated, and the aqueous layer washed with 1,2-dichloroethane. The combined organics are washed successively with water, N,N-dimethylaminopropylamine, dilute HCl and brine. The solution is then dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo. The residual red oily residue crystallizes on standing. It is recrystallized twice from methanol to give ethyl (5-chlorobenzoyl)-3-ethoxycarbonyl-4-ethyl-1-methyl-pyrrole-2-acetate as a white solid, m.p. 72-74° C.
Reaction SMILES: Cl.Cl[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([CH:9]=[O:10])=[N:5]1.[F:11][C:12]([F:21])([F:20])[CH2:13][CH2:14][CH:15]([C:18]#[N:19])[C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:9]([C:6]1[CH:7]=[CH:8][N:4]([CH2:3][C:15]([CH2:14][CH2:13][C:12]([F:11])([F:20])[F:21])([C:16]#[N:17])[C:18]#[N:19])[N:5]=1)=[O:10]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: O=Cc1ccn(CCl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1ccc(C=O)n1
Yield: 2.1 %

Procedure:
1.57 g of 1-chloromethyl-3-formylpyrazole hydrochloride and 1.52 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 30 ml of N,N-dimethylformamide. 2.76 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for 5 hours. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.05 g of [(3-formyl-1H-pyrazole-1-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (8), hereinafter) shown by below formula.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:25][C:26]1([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)[CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:12][CH:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=3)[CH2:14]2)=[C:6]([CH:10]=1)[C:7]([NH:25][C:26]1([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)[CH2:28][CH2:27]1)=[O:9]
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(Oc2ccc(F)c(F)c2)C1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Oc4ccc(F)c(F)c4)C3)CC2)cc1
Yield: 38.2 %

Procedure:
The title compound (D155) (50 mg) was prepared according to the experimental procedure described in Description 144 starting from 5-chloro-2-(3-(3,4-difluorophenoxy)azetidin-1-yl)nicotinic acid (D109) (87 mg, 0.255 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (58.14 mg, 0.255 mmol).
Reaction SMILES: O.CO.Cl.COC1C=CC=CC=1C[NH:10][C@H:11]1[CH2:16][CH2:15][CH2:14][NH:13][C@H:12]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[C].[Pd].C(O)C>[NH2:10][C@H:11]1[CH2:16][CH2:15][CH2:14][NH:13][C@H:12]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccccc1CN[C@H]1CCCN[C@H]1c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: O
Product: N[C@H]1CCCN[C@H]1c1ccccc1
Reaction time: 24 h

Procedure:
In a bottle were placed 31 g of 10% palladium-carbon, 50 mL of water, 300 mL of methanol, 450 mL of ethanol, 20 mL of concentrated aqueous hydrochloric acid and 15 g (0.04 mole) of the hydrochloride salt of (2S,3S)-3-(2-methoxybenzyl)amino-2-phenylpiperdine. The mixture was shaken under hydrogen (40 p.s.i.) for 1 day and filtered through a pad of diatomaceous earth. The pad was rinsed with 2N aqueous hydrochloric acid (HCl), water, ethanol and water and concentrated with a rotary evaporator. Water was added to the residue and the mixture was made basic using 4N aqueous sodium hydroxide (NaOH). The mixture was extracted with four portions of dichloromethane, and the extracts were dried over magnesium sulfate (MgSO4) and concentrated to obtain 2.23 g of the title compound. The aqueous fraction was concentrated to dryness and triturated with chloroform. Concentration of the chloroform solution afforded an additional 4.15 g of title compound. The product obtained in this manner had spectral properties identical to those of the product of Example 1.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:13][C:14]([NH:16]C(OCC)=O)=S)=[N:4][C:5]([C:8]([O:10][CH2:11]C)=[O:9])=[CH:6][CH:7]=1.Cl.NO.C([N:28](C(C)C)CC)(C)C>CO>[CH3:11][O:10][C:8]([C:5]1[N:4]2[N:28]=[C:14]([NH2:16])[N:13]=[C:3]2[C:2]([Br:1])=[CH:7][CH:6]=1)=[O:9]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1nc(C(=O)OCC)ccc1Br
Agent: Cl
Agent: NO
Solvent: CO
Product: COC(=O)c1ccc(Br)c2nc(N)nn12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of N-(3-bromo-6-ethoxycarbonyl-pyridin-2-yl)-N′-ethoxycarbonyl-thiourea (2 g, 5.52 mmol) in dry methanol (10 mL) were added hydroxylamine hydrochloride (1.92 g, 27.62 mmol) and diisopropyl ethylamine (2.98 mL, 16.57 mmol) under an argon atmosphere and stirred at room temperature for 4 hours. The solid was filtered and methanol (40 mL) was added to residue. The reaction mixture was heated to reflux for 12 hours. The solvent was evaporated and the title compound was obtained as off white solid (800 mg, 53%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3([CH2:18][NH2:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](O)=[O:26])#[N:21]>>[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([NH:19][CH2:18][C:12]1([C:9]2[S:10][CH:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)=[O:26])#[N:21]
Reactant: NCC1(c2nc(-c3ccccc3)cs2)CCOCC1
Reactant: N#Cc1cccc(C(=O)O)c1
Product: N#Cc1cccc(C(=O)NCC2(c3nc(-c4ccccc4)cs3)CCOCC2)c1
Yield: 89 %

Procedure:
This compound was synthesized from (4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-cyanobenzoic acid as described in example 8 step 6 (6.6 g, yield 89%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.11-8.10 (m, 1H), 8.02-7.99 (dt, J=7.9 Hz, 1.5 Hz, 1H), 7.91-7.88 (m, 2H), 7.78-7.74 (dt, J=7.7 Hz, 1.3 Hz, 1H), 7.71-7.68 (m, 1H), 7.53-7.46 (m, 3H), 7.42-7.36 (m, 1H), 3.97-3.90 (m, 2H), 3.85-3.83 (d, J=5.7 Hz, 2H), 3.77-3.69 (m, 2H), 2.35-2.29 (m, 2H), 2.07-1.98 (m, 2H). MS (ESI) m/z: Calculated for C23H21N3O2S: 403.14. found: 402.2 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[C:21]=1[Cl:22].[CH2:23]([N:25]=[C:26]=[O:27])[CH3:24]>>[Cl:22][C:21]1[C:6]2[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])=[N:8][CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:5]=2[CH:4]=[CH:3][C:2]=1[NH:1][C:26]([NH:25][CH2:23][CH3:24])=[O:27]
Reactant: CCN=C=O
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2c1ccc(N)c2Cl
Product: CCNC(=O)Nc1ccc2c(c1Cl)C(c1ccccc1F)=NCC(=O)N2C

Procedure:
5 g (0.016 M) of 7-amino-6-chloro-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one are heated at reflux with 15 ml of ethylisocyanate under nitrogen for 7 hours. The mixture is poured on to methanol/ice-water and extracted with methylene chloride. The organic phase is separated, dried with sodium sulphate, filtered and concentrated. The residue is purified on a 300 g silica gel column using ethyl acetate as the eluting agent and crystallised from ethyl acetate/ether. There is obtained 1-[6-chloro-5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-ethylurea which melts at 155°-160° C. with decomposition.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:9]1([CH2:14][CH2:13][N:12](C)[CH2:11][CH2:10]1)[NH:8][CH2:7][C:6]2=[O:21].CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.[Cl:38]C(OC(Cl)C)=O>ClC(Cl)C>[ClH:38].[ClH:38].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:9]1([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[NH:8][CH2:7][C:6]2=[O:21]
Reactant: COc1cc2c(cc1OC)C1(CCN(C)CC1)NCC2=O
Reactant: CC(Cl)OC(=O)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: CC(Cl)Cl
Product: COc1cc2c(cc1OC)C1(CCNCC1)NCC2=O
Product: Cl

Procedure:
To a solution of 6,7-dimethoxy-1'-methylspiro[1,2,3,4-tetrahydroisoquinoline-1,4'-piperidin]-4-one (Helv. Chem. Acta., 58, Fasc. 1, Nr. 8 (1975)) (1.0 g) and N,N,N',N'-tetramethyl-1,8-napthalenediamine (1.9 g) in dichloroethane at 0° C. under nitrogen was added 1-chloroethyl chloroformate (9.5 ml) and the mixture stirred at reflux for 1 hr. The reaction was cooled, passed thru silica and the product eluted with 10% ethyl acetate in methylene chloride. After evaporation, methanol was added and the mixture refluxed for 1 hr. Upon evaporation the foam was crystallized from ethanol/ether to give 0.6 g of the title compound as dihydrochloride salt.