Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:39])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:31]2[N:36]=[CH:35][C:34]([CH2:37][CH3:38])=[CH:33][N:32]=2)[CH2:19][C:20]2[CH:21]=[N:22][N:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:24]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:37]([C:34]1[CH:33]=[N:32][C:31]([N:18]([CH2:19][C:20]2[CH:21]=[N:22][N:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:24]=2)[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:39])=[O:5])[S:12][CH:13]=2)=[N:36][CH:35]=1)[CH3:38]
Reactant: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2cnn(-c3ccccc3)c2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)O)n2)Cc2cnn(-c3ccccc3)c2)nc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 76 %

Procedure:
2-{[4-(2-{(5-Ethylpyrimidin-2-yl)[(1-phenyl-1H-pyrazol-4-yl)methyl]amino}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (7.3 g) obtained in Example 326-1 was dissolved in dichloromethane (80 mL), trifluoroacetic acid (20 mL) was added, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution (at this time point, the object product had been extracted in the ethyl acetate layer). The ethyl acetate layer was washed with aqueous 10% citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (5.0 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19]Br>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=1
Reactant: CC(C)(C)c1cc(Br)ccc1N
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)c1cc(Br)ccc1N1CCCC1
Yield: 61.2 %

Procedure:
In a manner analogous to example 1 b, the process is carried out by a reaction of 10 g (44 mmol) of 4-bromo-2-tert-butylphenylamine with 3.8 g (96 mmol) of 60% sodium hydride and with 3.4 ml (96 mmol) of 1,4-dibromobutane. 7.6 g of 1-(4-bromo-2-tert-butylphenyl)-pyrrolidine are obtained in the form of an oil (yield=61%).
Reaction SMILES: N[C:2]1[S:3][C:4]([C:16]([O:18][CH3:19])=[O:17])=[C:5]([C:7]2[N:8]([CH2:12][CH2:13][O:14][CH3:15])[CH:9]=[CH:10][N:11]=2)[N:6]=1.[ClH:20].N([O-])=O.[Na+].NC(N)=O>C(O)(=O)C.O>[Cl:20][C:2]1[S:3][C:4]([C:16]([O:18][CH3:19])=[O:17])=[C:5]([C:7]2[N:8]([CH2:12][CH2:13][O:14][CH3:15])[CH:9]=[CH:10][N:11]=2)[N:6]=1
Reactant: Cl
Reactant: COCCn1ccnc1-c1nc(N)sc1C(=O)OC
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COCCn1ccnc1-c1nc(Cl)sc1C(=O)OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Methyl 2-amino-4-[1-(2-methoxyethyl)-1H-imidazol-2-yl]-1,3-thiazole-5-carboxylate (Intermediate 55; 0.55 g, 2.2 mmol) was suspended in glacial acetic acid (20 ml) and concentrated HCl (30 ml). The solution was cooled to 0° C. and a solution of sodium nitrite in water (15 ml) was added dropwise. After stirring at 0° C. for 10 min, the reaction was slowly warmed to room temperature and stirred for 1 hour. The reaction was followed by LCMS and once complete, a solution of urea (0.25 g) in water (10 ml) was added dropwise. After stirring at room temperature for 30 min, solvent was removed under reduced pressure. The residue was partitioned with sat. NaHCO3 (aq) and EtOAc. Extraction with EtOAc (×3), drying with MgSO4 and concentrating yielded an orange oil which was used without purification (0.20 g). MS (ES) (M+H)+: 302 for C11H12ClN3O3S; NMR: 3.34 (s, 3H), 3.62 (m, 2H), 3.81 (s, 3H), 4.22 (m, 2H), 7.24 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[C:7]([CH3:13])[C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:17])=O>CN(C=O)C.ClCCl>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[C:7]([CH3:13])[C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: Cc1c(F)c(F)cc(F)c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(F)c(F)cc(F)c1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A solution of 5.8 g (30.5 mmol) of 2,4,5-trifluoro-6-methylbenzoic acid, 4.7 g (37.0 mmol) of oxalyl chloride, and 100 ml of dichloromethane was treated with three drops of DMF. The reaction mixture was stirred at room temperature for two hours, then concentrated to give 6.3 g of the title compound as an oily solid. The product was used "as is" in the next step.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.C([O:15][C:16](=O)[CH2:17][CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[CH2:25][CH2:24][CH2:23][NH:22][C:21]=2[N:20]=1)C>C1COCC1>[CH3:4][O:3][P:2]([CH2:1][C:16](=[O:15])[CH2:17][CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[CH2:25][CH2:24][CH2:23][NH:22][C:21]=2[N:20]=1)(=[O:7])[O:5][CH3:6]
Reactant: COP(C)(=O)OC
Reactant: CCOC(=O)CCc1ccc2c(n1)NCCC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)CCc1ccc2c(n1)NCCC2)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of dimethyl methylphosphonate (1.9 mL, 17.08 mmol) in THF (20 mL) at −78° C. was added nBuLi (10.94 mL, 17.5 mmol). After 30 minutes, 2-9 (1 g , 4.27 mmol) in THF (5 mL) was added. After 1 hour, the reaction was quenched with saturated NH4Cl (10 mL) and warmed to ambient temperature. The mixture was diluted with ethyl acetate, washed with sat. NaHCO3, brine, and dried over MgSO4. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 70/25/5 CHCl3/EtOAc/MeOH) to give 2-10 as a yellow oil.
Reaction SMILES: [NH:1]([CH2:8][C:9]1([CH3:35])[CH:13]([C:14]([O:16]CC(Cl)(Cl)Cl)=[O:15])[N:12]2[C:22](=[O:34])[CH:23]([NH:24][C:25](=[O:33])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:11]2[S:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>CN(C)C=O.[Zn]>[NH:1]([CH2:8][C:9]1([CH3:35])[CH:13]([C:14]([OH:16])=[O:15])[N:12]2[C:22](=[O:34])[CH:23]([NH:24][C:25](=[O:33])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:11]2[S:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(CNc2ccccc2)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC1(CNc2ccccc2)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Reaction time: 6 h
Yield: 65.4 %

Procedure:
2,2,2-Trichloroethyl 2-anilinomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (1.00 g) was dissolved in dimethylformamide (5 ml). To this solution were added acetic acid (0.5 ml) and then zinc powder under cooling at -15° C and the mixture was stirred for 6 hours. After the reaction, zinc powder was filtered off and the filtrate was poured into ethyl acetate. The solution was washed 4 times with water and dried over magnesium sulfate. After drying, the solvent was distilled off and the residue was dissolved in a small amount of methanol and then pulverized by adding water to the solution. The powder was collected by filtration, washed with water and dried to give 2-anilinomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylic acid (0.50 g), mp. 120° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:7]=[CH:8][C:9]=1[NH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)([O-:3])=[O:2].[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([S:17]([NH2:20])(=[O:18])=[O:19])[CH:7]=[CH:8][C:9]=1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([S:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:29])=[O:28])[CH2:13][CH2:12]1)([O-:3])=[O:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NS(=O)(=O)c1ccc(NC2CCNCC2)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(NC2CCN(S(=O)(=O)c3ccccc3)CC2)c([N+](=O)[O-])c1

Procedure:
A mixture of EXAMPLE 157B (84 mg), benzenesulfonyl chloride (46 mg), and triethylamine (101 mg) in CH2Cl2 (2 mL) was stirred for 1 hours. The product was chromatographed on silica gel with 25% ethyl acetate/hexanes.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:17]3[CH2:16][N:15]([C:20]4[CH:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=4)[CH2:14][CH2:13][C:12]=3[N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:30][NH2:31]>>[CH3:30][NH:31][C:26]([C:23]1[CH:22]=[CH:21][C:20]([N:15]2[CH2:14][CH2:13][C:12]3[N:11]=[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:19]=[CH:18][C:17]=3[CH2:16]2)=[CH:25][N:24]=1)=[O:27]
Reactant: CN
Reactant: O=C(O)c1ccc(N2CCc3nc(OCCCN4CCCC4)ccc3C2)cn1
Agent: Cl
Product: CNC(=O)c1ccc(N2CCc3nc(OCCCN4CCCC4)ccc3C2)cn1
Yield: 35 %

Procedure:
The title compound was prepared from the product of example 62 and methylamine hydrochloride, using a similar method to that of example 64, as a yellow gum in 35% yield.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:15]1([CH3:24])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CC#N.O>[CH3:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH3:24])[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: Cc1cccc2cc(C=O)c(Cl)nc12
Reactant: Cc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1ccccc1-c1nc2c(C)cccc2cc1C=O

Procedure:
Prepared according to Procedure A using 2-chloro-8-methylquinoline-3-carbaldehyde (2.1 g, 10 mmol), o-tolylboronic acid (1.5 g, 1.1 eq), tetrakis(triphenyl-phosphine)palladium (575 mg, 0.05 eq), and sodium carbonate (5.5 g, 5 eq) in MeCN (75 mL) and water (25 mL). After purification, 8-methyl-2-o-tolylquinoline-3-carbaldehyde was obtained as white solid. 1H-NMR (CDCl3) 9.96 (s, 1H), 8.83 (s, 1H), 7.88 (d, J=7.8 Hz, 1H), 7.74 (d, J=6.3 Hz, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.36-7.46 (m, 4H), 2.84 (s, 3H), δ 2.30 (s, 3H). Mass Spectrum (ESI) m/e=262 (M+1).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][N:43]=[N+:44]=[N-:45])[C:21]=1[O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][N:31]=[N+:32]=[N-:33])[C:16]([O-:18])=[O:17])=[N+:2]=[N-:3].O.Cl>C1COCC1>[N:43]([CH2:42][CH2:41][O:40][CH2:39][CH2:38][O:37][CH2:36][CH2:35][O:34][C:20]1[CH:19]=[C:15]([CH:14]=[C:13]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])[C:21]=1[O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][N:31]=[N+:32]=[N-:33])[C:16]([OH:18])=[O:17])=[N+:44]=[N-:45]
Reactant: [N-]=[N+]=NCCOCCOCCOc1cc(C(=O)[O-])cc(OCCOCCOCCN=[N+]=[N-])c1OCCOCCOCCN=[N+]=[N-]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: [N-]=[N+]=NCCOCCOCCOc1cc(C(=O)O)cc(OCCOCCOCCN=[N+]=[N-])c1OCCOCCOCCN=[N+]=[N-]
Temperature: 25 °C
Yield: 136.1 %

Procedure:
To a solution in which the 3,4,5-tris(2-(2-(2-azidoethoxy)ethoxy)ethoxy)benzoate (2.18 g, 3.32 mmol) of Chemical Formula 11 was dissolved in THF, water-soluble LiOH (1 M) (9.96 mL, 9.96 mmol) was added at room temperature, and the mixture was heated under reflux for 4 hours. The post-reaction mixture was cooled to room temperature, and was acidified to pH 4 by adding 0.1 N HCl. This mixture was partitioned to distilled water (40 mL) and ethyl acetate (100 mL), the organic layer was separated, washed with saturated salted water (15 mL), dried with anhydrous sodium sulfate, then filtered, and the resulting filtrate was vacuum distilled to give 3,4,5-tris(2-(2-(2-azidoethoxy)ethoxy)ethoxy)benzoic acid (2.90 g, 98%). 1H NMR (500 MHz, CDCl3) δ 7.35 (s, 2H), 4.18-4.29 (m, 6H), 3.81-3.88 (m, 6H), 3.73 (m, 6H), 3.65-3.68 (m, 12H), 3.38 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 170.9, 152.4, 143.3, 124.0, 109.6, 72.5, 70.9 (3), 70.8 (3), 70.6, 70.1 (3), 69.8 (2), 68.9 (2), 50.7 (3).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=2)=[CH:11][C:10]=1[C:29]([CH3:32])([CH3:31])[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:33][C:34]1[C:35]([F:47])=[C:36]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[C:37](O)=[O:38]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH3:26])([CH3:28])[CH3:27])=[CH:21][CH:20]=2)[C:37](=[O:38])[C:36]2[CH:40]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:42]=[C:34]([Cl:33])[C:35]=2[F:47])=[CH:11][C:10]=1[C:29]([CH3:32])([CH3:31])[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(Cl)c1F
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(OCc3ccccc3)c(C(C)(C)C)c2)cc1
Product: CC(C)(C)c1ccc(CN(CCc2ccc(OCc3ccccc3)c(C(C)(C)C)c2)C(=O)c2cc(C(F)(F)F)cc(Cl)c2F)cc1

Procedure:
The title compound was prepared in analogy to Example 1, using [2-(4-benzyloxy-3-tert-butyl-phenyl)-ethyl]-(4-tert-butyl-benzyl)-amine (S9-C48) and 3-chloro-2-fluoro-5-(trifluoromethyl)benzoic acid. MS: 654.4 [ISP (M+H)+].
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:6]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]3[O:22][CH2:21][CH2:20][O:19]3)=[CH:14][CH:13]=1)=[N:7]2.[NH2:29][NH2:30]>O1CCOCC1>[O:22]1[CH2:21][CH2:20][O:19][CH:18]1[C:15]1[CH:16]=[CH:17][C:12]([C:6]2[C:5]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[N:11][C:2]=3[NH:29][NH2:30])[N:7]=2)=[CH:13][CH:14]=1
Reactant: Clc1nccc2nc(-c3ccc(C4OCCO4)cc3)c(-c3ccccc3)cc12
Reactant: NN
Solvent: C1COCCO1
Product: NNc1nccc2nc(-c3ccc(C4OCCO4)cc3)c(-c3ccccc3)cc12
Temperature: 100 °C

Procedure:
A suspension of 5-chloro-2-(4-[1,3]dioxolan-2-yl-phenyl)-3-phenyl-[1,6]naphthyridine (3-3, 5.2 g, 13.4 mmol) and anhydrous hydrazine (5 mL) in anhydrous 1,4-dioxane (15 mL) was heated at 100° C. in a microwave reactor for 5 min. The reaction mixture was cooled, concentrated and dried with toluene azotropically to give the title compound as a solid. LRMS m/z (M+1) Calcd: 385.2. Found 385.3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J19) (233 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (261 mg, 65%).
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1.N1CCCCC1>C(O)(=O)C>[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=[C:11]2[CH2:1][CH2:2][C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:9]2=[O:10])=[CH:14][CH:13]=1
Reactant: O=C1CCCc2ccccc21
Reactant: O=Cc1ccncc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: O=C1C(=Cc2ccncc2)CCc2ccccc21

Procedure:
A mixture of 73.0 grams (0.50 moles) of α-tetralone, 64.2 grams (0.60 moles) of 4-pyridinecarboxaldehyde, 10 grams of piperidine and 10 grams of acetic acid are heated at 80° for 19 hours. The resultant solid is crystallized from about 400 ml. of ethanol to give 2-(4-pyridylmethylene)- 1-tetralone; (m.p. 112°-114°C).
Reaction SMILES: [C:1]([C:7]1[CH:8]=[CH:9][C:10]([O:15][CH3:16])=[C:11]([CH:14]=1)[CH2:12][OH:13])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH-].[K+].[O-:19][Mn](=O)(=O)=O.[K+]>O1CCOCC1.O>[C:1]([C:7]1[CH:8]=[CH:9][C:10]([O:15][CH3:16])=[C:11]([CH:14]=1)[C:12]([OH:19])=[O:13])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1ccc(C(=O)C(C)(C)C)cc1CO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C(=O)C(C)(C)C)cc1C(=O)O
Temperature: 25 °C
Yield: 83.9 %

Procedure:
5-Pivaloyl-2-methoxy benzyl alcohol (1.19 g, 5.35 mmol) was dissolved in dioxane (20 ml). A solution of KOH (0.449 g, 8.025 mmol in water (5 ml) was added followed by KMnO4 (1.69 g, 10.7 mmol). The mixture was allowed to stir at room temperature over the weekend. The solution was filtered through Celite and extracted with ether. The aqueous phase was acidified with dil. HCl and extracted with ether (3×50 ml). The organic layer was dried over magnesium sulphate and concentrated in vacuo to afford the title compound as a white solid (1.06 g).
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10](O)[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:10]1[N:11]=[CH:12][N:13]=[C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:9]=1
Reactant: Oc1cc(Nc2ccccc2)ncn1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cc(Nc2ccccc2)ncn1
Temperature: 95 °C
Reaction time: 3 h

Procedure:
6-(Phenylamino)pyrimidin-4-ol (253 mg, 1.35 mmol) was dissolved in neat phosphorous oxychloride (5 mL) and stirred for 3 h at 95° C. then cooled to room temperature and concentrated. The residue was poured into an ice water slurry and extracted with dichloromethane. The extract was washed saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and the solvent evaporated to afford 6-chloro-N-phenylpyrimidine-4-amine (220 mg) which was used without further purification.
Reaction SMILES: [Na+].[C:2]1([S:8]([O-:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:12][C:13]#[N:14]>CN(C)C=O>[C:2]1([S:8]([CH2:12][C:13]#[N:14])(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCCl
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCS(=O)(=O)c1ccccc1
Temperature: 40 °C

Procedure:
Benzene sulfinic acid sodium salt, 49.2 g. (0.3 mole) was combined with 400 ml. of dimethyl formamide in a 1 liter flask. The mixture was stirred at 40°C. Chloroacetonitrile, 22.5 g. (0.3 mole) was added over a period of 5 minutes. The resulting mixture was stirred and heated at 40°-45°C. for 2 hours. The reaction mass was then poured into 600 ml. of water, and the solid insoluble product was collected by suction filtration and dried. There was obtained a yield of 29.8 g. of the title compound, m.p. 111°-112°C.
Reaction SMILES: [F:1]C1N=CC=CC=1C(O)=O.[C:11]([O:15][C:16](=[O:29])[NH:17][C:18]1[CH:19]=[N:20][C:21](C(F)(F)F)=[CH:22][C:23]=1[I:24])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16](=[O:29])[NH:17][C:18]1[C:19]([F:1])=[N:20][CH:21]=[CH:22][C:23]=1[I:24])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)c1cccnc1F
Reactant: CC(C)(C)OC(=O)Nc1cnc(C(F)(F)F)cc1I
Product: CC(C)(C)OC(=O)Nc1c(I)ccnc1F

Procedure:
The title product was prepared from 2-fluoronicotinic acid in the same manner as in the preparation of (4-iodo-6-trifluoromethylpyridin-3-yl)carbamic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([OH:18])=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:21]1([C:24](=[N:26]O)[NH2:25])[CH2:23][CH2:22]1>CN(C)C=O>[Br:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:18][N:26]=[C:24]([CH:21]4[CH2:23][CH2:22]4)[N:25]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NC(=NO)C1CC1
Reactant: CN1Cc2c(C(=O)O)ncn2-c2cccc(Br)c2C1=O
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3nc(C4CC4)no3)ncn2-c2cccc(Br)c2C1=O
Reaction time: 2 h

Procedure:
6.2 g (18 mmol) of 7-bromo-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid in 90 ml of N,N-dimethylformamide are stirred at 70° for 2.5 hours with 2.92 g (18 mmol) of N,N'-carbonyldiimidazole. 1.80 g (18 mmol) of cyclopropanecarboxamidoxime are subsequently added thereto and the mixture is stirred at 100° for a further 2 hours. The solution is evaporated, the residue is treated with 70 ml of acetic acid and the mixture is stirred at 120° for 5 hours. The reaction mixture is evaporated and the residue is partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic phase is dried over magnesium sulphate and evaporated. By chromatography on silica gel while eluting with ethyl acetate and recrystallization from acetonitrile there is obtained 7-bromo-4,5-dihydro-3-(3-cyclopropyl-1,2,4-oxadiazol-5yl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 187°-189°.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.O[N:37]1[C:41](=[O:42])[CH2:40][CH2:39][C:38]1=[O:43]>ClCCl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([O:20][N:37]1[C:41](=[O:42])[CH2:40][CH2:39][C:38]1=[O:43])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(ON1C(=O)CCC1=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 59.3 %

Procedure:
201 mg of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid was dissolved in dehydrated dichloromethane (3.6 mL), and 162 mg of N-methylmorpholin was added, followed by cooling to 0° C. 198.8 mg of isobutyl chloroformate was added to the mixture, followed by stirring for 10 minutes, and subsequently 167 mg of N-hydroxysuccinimide was added, followed by further stirring for 0.5 hours. The reaction mixture was washed with water and dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The resulting residue was applied to silica gel column chromatography (hexane/ethyl acetate=1/2) to afford 161 mg of the title compound as a colorless solid (yield 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[C:16]1(C)C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5]([O:7][CH3:16])=[O:6]
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Reactant: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)nc(Cl)c1
Reaction time: 4 h

Procedure:
2,6-Dichloroisonicotinic acid was (5 g, 26.04 mmol) was suspended in anhydrous toluene (75 ml). Thionyl chloride (19 ml, 260.4 mmol) was added and the mixture was heated to reflux for 4 h. The excess thionyl chloride was removed and solvent was removed in vacuo. Anhydrous MeOH (25 ml) was added and reaction was stirred for a further 4 h. Solvents were removed in vacuo to give a white colored solid which was dried under vacuum (4.8 g).
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5]CC)=[O:4].[OH-].[K+].O>CO>[CH3:1][C:2]([CH3:15])([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(Cc1ccccc1)C(=O)O

Procedure:
A solution of 1 g (20 mmol) of ethyl 2,2-dimethyl-3-phenylpropionate (stage 1) and 3.5 g (61 mmol) of potassium hydroxide in 15 ml of methanol was heated under reflux for 2 hours. Thereafter, 50 ml of water were added and the mixture was extracted twice with ether. The aqueous phase was acidified with concentrated hydrochloric acid and extracted again with ether, the organic phase was dried over magnesium sulfate and the solvent was stripped off in vacuo.