Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[C:17]([Cl:24])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:15][CH3:16])=[C:9]([S:11](Cl)(=[O:13])=[O:12])[CH:10]=1.C(N(CC)CC)C.[CH:32]1([NH2:35])[CH2:34][CH2:33]1.Cl>C(Cl)Cl.O>[CH:32]1([NH:35][S:11]([C:9]2[CH:10]=[C:5]([O:4][C:3]3[C:2]([Cl:1])=[CH:20][C:19]([N+:21]([O-:23])=[O:22])=[CH:18][C:17]=3[Cl:24])[CH:6]=[CH:7][C:8]=2[O:15][CH3:16])(=[O:13])=[O:12])[CH2:34][CH2:33]1
Reactant: NC1CC1
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1S(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1S(=O)(=O)NC1CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 68.4 %

Procedure:
To a cooled solution of 5-(2,6-dichloro-4-nitro-phenoxy)-2-methoxy-benzenesulfonyl chloride (920 mg, 2.2 mmol) in CH2Cl2 (25 mL) at 0° C. was added triethylamine (470 μL, 3.4 mmol) and cyclopropylamine (170 μL, 2.5 mol). The resulting mixture was stirred at 0° C. for 5 min, then at RT for 6 h. Water (30 mL) and 1N HCl (1 mL) was added and the solution was extracted with EtOAc (3×50 mL). The combined EtOAc extracts were dried and concentrated. The product was purified by chromatography to give the title compound of Step B (652 mg). MS (APCI) Calc.: 432.0, Found: 430.9 (M−1).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].CN(C)C=O.Cl.[NH2:21][CH:22]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:23]([O:25][CH3:26])=[O:24].CCN(C(C)C)C(C)C>O>[F:33][C:30]1[CH:29]=[CH:28][C:27]([CH:22]([NH:21][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[C:23]([O:25][CH3:26])=[O:24])=[CH:32][CH:31]=1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: COC(=O)C(N)c1ccc(F)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(C(=O)OC)c2ccc(F)cc2)c([N+](=O)[O-])c1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round-bottom flask, was placed methyl 4-fluoro-3-nitrobenzoate (15.4 g, 77.78 mmol, 1.00 equiv), N,N-dimethylformamide (100 mL), methyl 2-amino-2-(4-fluorophenyl)acetate hydrochloride (20.4 g, 93.15 mmol, 1.20 equiv), and DIEA (50.2 g, 389.15 mmol, 5.00 equiv). The reaction was stirred overnight at 35° C. in an oil bath. The resulting solution was diluted with 500 ml of H2O and the resulting solids were collected by filtration. This resulted in 15 g (53%) of methyl 4-(1-(4-fluorophenyl)-2-methoxy-2-oxoethylamino)-3-nitrobenzoate as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=O)[NH:8][C:7]2=O)([O-:3])=[O:2].P(Cl)(Cl)([Cl:18])=O.[CH:21]([N:24](C(C)C)C=O)([CH3:23])[CH3:22].C(N)(C)C>O>[Cl:18][C:9]1[N:8]=[C:7]([NH:24][CH:21]([CH3:23])[CH3:22])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)N(C=O)C(C)C
Reactant: O=c1[nH]c(=O)c2cc([N+](=O)[O-])ccc2[nH]1
Solvent: O
Solvent: CC(C)N
Product: CC(C)Nc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
To 1.00 g (4.83 mmol) of 6-nitroquinazoline-2,4 (1H,3H)-dione were added 32.90 g (0.22 mol) of phosphorus oxychloride and 0.70 ml (4.83 mmol) of diisopropylformamide, and the resulting mixture was subjected to heating under reflux for 24 hours. After phosphorus oxychloride was removed in vacuo, the mixture was dissolved in 15 ml of acetonitrile, followed by addition of 2.49 ml (29.11 mmol) of isopropylamine under ice cooling and stirring under ice cooling for 30 minutes. To the reaction solution was added water, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 870 mg (yield: 67.5%) of the title compound.
Reaction SMILES: Br.[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]=[C:8]([C:11]3[N:12]4[CH2:19][CH2:18][N:17]=[C:13]4[S:14][C:15]=3Br)[CH:9]=[CH:10][C:3]1=2.C([Mg]Cl)C.CN(C)[CH:26]=[O:27]>O1CCCC1>[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]=[C:8]([C:11]3[N:12]4[CH2:19][CH2:18][N:17]=[C:13]4[S:14][C:15]=3[CH:26]=[O:27])[CH:9]=[CH:10][C:3]1=2
Reactant: BrC1=C(c2ccc3sccc3c2)N2CCN=C2S1
Reactant: CN(C)C=O
Agent: Br
Agent: CC[Mg]Cl
Solvent: C1CCOC1
Product: O=CC1=C(c2ccc3sccc3c2)N2CCN=C2S1
Reaction time: 0.33 h

Procedure:
3-(Benzo[b]thiophen-5-yl)-2-bromo-5,6-dihydroimidazo[2,1-b]thiazole hydrobromide (1.9 g) was added in portions under nitrogen at 0-5° C. to a stirred solution of ethylmagnesium chloride (2M solution in ether; 6.8 ml) in tetrahydrofuran (30 ml), then the mixture was stirred at this temperature for 20 minutes. Dimethylformamide (1.5 ml) was added at <15° C., the mixture was stirred at <15° C. for 20 minutes and at ambient temperature for 1 hour, then it was quenched by the addition of saturated aqueous ammonium chloride solution (10 ml) and water (5 ml). Ethyl acetate (30 ml) was added, the mixture was stirred at ambient temperature for 18 hours, then the organic layer was separated and further product was isolated from the aqueous layer by extraction into ethyl acetate (2×15 ml). The combined ethyl acetate solutions were washed with water (2×30 ml) and saturated aqueous sodium chloride solution (35 ml), then they were dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using a 9:1 mixture of ethyl acetate and methanol as eluant. Appropriate fractions were combined and the solvents were removed in vacuo to give 3-(benzo[b]thiophen-5-yl)-5,6-dihydroimidazo[2,1-b]thiazole-2-carboxaldehyde (0.7 g) as a yellow solid, m.p. 146° C.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[H][H]>O1CCCC1.[Pd]>[F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: O=C(O)C=Cc1ccc(F)cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(F)cc1F
Temperature: 100 °C
Yield: 98.1 %

Procedure:
105 g of 2,4-difluorocinnamic acid from Example 5 were dissolved in 450 ml of tetrahydrofuran and reacted with 5 g of palladium on active carbon with stirring at 100° C. and a hydrogen pressure of 50 bar. After a constant pressure had been achieved, the mixture was cooled to room temperature, the pressure was released, the palladium catalyst was filtered off and the solvent was removed by distillation. After drying in vacuo, 104.1 g of 3-(2,4-difluorophenyl)-propionic acid (98% of theory; melting point: 100-102° C.) were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[OH:25][C:26]1([CH2:50][CH2:51][CH2:52][OH:53])[CH2:31][C:30]2[CH:32]=[CH:33][C:34]([O:36][CH:37]([CH2:39][CH2:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH3:38])=[CH:35][C:29]=2[O:28][C:27]1([CH3:49])[CH3:48].C(N(CC)CC)C.[C:61](OC(=O)C)(=[O:63])[CH3:62]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[C:61]([O:25][C:26]1([CH2:50][CH2:51][CH2:52][OH:53])[CH2:31][C:30]2[CH:32]=[CH:33][C:34]([O:36][CH:37]([CH2:39][CH2:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH3:38])=[CH:35][C:29]=2[O:28][C:27]1([CH3:48])[CH3:49])(=[O:63])[CH3:62]
Reactant: CC(CCCc1ccccc1)Oc1ccc2c(c1)OC(C)(C)C(O)(CCCO)C2
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC1(CCCO)Cc2ccc(OC(C)CCCc3ccccc3)cc2OC1(C)C
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 29.4 %

Procedure:
To a solution of 3.177 g (7.96 mmole) dl-5-hydroxy-3-(3-hydroxypropyl)-2,2-dimethyl-7-(5-phenyl-2-pentyloxy)-3,4-dihydro-2H-benzopyran in 40 ml methylene chloride, under a nitrogen atmosphere, was added 805 mg (7.96 mmole) triethylamine, the mixture stirred for 15 minutes and cooled to 10° C. At this temperature, 970 mg (7.79 mmole) 4-dimethylaminopyridine in 3 ml methylene chloride followed by 813 mg (7.96 mmole) acetic anhydride was added and the resulting mixture stirred at 0°-5° C. for one hour. After allowing the mixture to warm to room temperature, it was extracted three times with 30 ml portions methylene chloride. The extracts were washed with saturated sodium bicarbonate solution, dried (MgSO4) and evaporated to obtain 4.158 g of crude oil. The crude product was purified by column chromatography on silica gel eluting with ethyl ether/methylene chloride 3:97 (v/v) for 7 fractions and 1:9 (v/v) for 43 fractions. Fractions 18-27 contained the diacetate. Fractions 28-45 containing desired monoacetate were combined and evaporated to afford 1.823 g of the title compound. 1H-NMR(CDCl3)ppm(delta): 2.20 (s, 3H), 3.50 (t, 2H), 6.20 (m, 2H), 7.10 (s, 5H).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:23]1([C:33](Cl)=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:33]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)=[O:34])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])=[CH:6][CH:7]=1
Reactant: NC(Cc1ccccc1C(F)(F)F)C(O)c1ccc(F)cc1
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccccc1C(F)(F)F)C(O)c1ccc(F)cc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(2-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in ethyl acetate (15 ml) were added 1-naphthoyl chloride (282 ml, 1.87 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (536 mg, 80%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[Cl:8].C(O)(=[O:12])C>>[Cl:8][C:7]1[C:2](=[O:12])[NH:3][N:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Clc1cc(Cl)c(Cl)nn1
Reactant: CC(=O)O
Product: O=c1[nH]nc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
3,4,6-Trichloro-pyridazine (34.39 g, 187.5 mmol) in 100 mL acetic acid was heated at reflux for three hours. The resulting mixture was cooled to room temperature and filtered. The filtrate was diluted with ethylacetate. This was washed three times with water, washed with brine, dried over anhydrous MgSO4, concentrated in vacuo, and purified by flash chromatography (30% ethylacetate/hexanes) to yield 4,6-Dichloro-2H-pyridazin-3-one (6.143 g, 37.23 mmol). MS (ESI) 165.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][CH:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[C:3]=1[C:19]([OH:21])=O.[F:22][C:23]1[CH:24]=[C:25]([NH:30][C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([NH2:40])[CH:38]=3)[NH:33][N:32]=2)[CH:26]=[C:27]([F:29])[CH:28]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:22][C:23]1[CH:24]=[C:25]([NH:30][C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([NH:40][C:19]([C:3]4[CH:4]([C:9]5[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:11][CH:10]=5)[NH:5][C:6](=[O:8])[NH:7][C:2]=4[CH3:1])=[O:21])[CH:38]=3)[NH:33][N:32]=2)[CH:26]=[C:27]([F:29])[CH:28]=1
Reactant: CC1=C(C(=O)O)C(c2ccc(C(F)(F)F)cc2)NC(=O)N1
Reactant: Nc1ccc2[nH]nc(Nc3cc(F)cc(F)c3)c2c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Nc4cc(F)cc(F)c4)c3c2)C(c2ccc(C(F)(F)F)cc2)NC(=O)N1

Procedure:
The titled compound was prepared following the procedure of Example 175 using 6-Methyl-2-oxo-4-(4-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, N3-(3,5-difluoro-phenyl)-1H-indazole-3,5-diamine, PyBroP and diisopropylethylamine in methylene chloride. MS (ESI) m/z=543 [M+H]+.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:32][CH3:33])[C:25]([O:27]C(C)(C)C)=[O:26])[C:5]1=[O:34])[CH:2]=[CH2:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@H:24]([CH2:32][CH3:33])[C:25]([OH:27])=[O:26])[C:5]1=[O:34])[CH:2]=[CH2:3]
Reactant: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CC)C(=O)O)C1=O
Reaction time: 3 h

Procedure:
To a solution of 320 mg (0.64 mmol) of tert-butyl (2S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanoate (Example 1, Step G) in DCM (3184 μL) was added trifluoroacetic acid (2453 μL, 31.8 mmol) at 0° C. After being stirred at 25 C for 3 h, solvents were removed under reduced pressure and the residual TFA was removed by azeotroping with toluene under reduced pressure 3-times to provide the title compound as a pale yellow foam which was used in the subsequent reaction without further purification.
Reaction SMILES: [OH-:1].[K+].[CH2:3]([C:5]1[N:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[C:11]2[C:6]=1[CH:7]=[C:8](C(N)=O)[C:9](=[O:54])[N:10]2[CH2:17][C:18]1[CH:23]=[CH:22][C:21](C2C=CC=CC=2C2N=NN(C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)N=2)=[CH:20][CH:19]=1)[CH3:4].C[CH2:59][O:60]CC>C(O)C>[CH2:3]([C:5]1[N:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:54])[N:10]2[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:59]([OH:60])=[O:1])=[CH:22][CH:23]=1)[CH3:4]
Reactant: CCOCC
Reactant: [OH-]
Reactant: CCc1cc2c(cc(C(N)=O)c(=O)n2Cc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(CC)n1
Agent: [K+]
Solvent: CCO
Product: CCc1cc2c(ccc(=O)n2Cc2ccc(C(=O)O)cc2)c(CC)n1

Procedure:
Potassium hydroxide (0.112 g) was added to a solution of methyl 4-[(5,7-diethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-1-yl)-methyl]benzoate (A) (0.35 g) in ethanol (10 ml) and the mixture was heated at reflux for 90 minutes. Volatile material was removed by evaporation and the residue was dissolved in a minimum of water which was then acidified with acetic acid. Ether was added to the mixture and the solid which crystallised was collected by filtration. Further solid was obtained by adding petroleum ether to the ether phase of the filtrate. The combined solids were recrystallised from ethyl acetate/petroleum ether to give 4-[(5,7-diethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-1-yl)methyl]benzoic acid (0.175 g), as a solid, m.p. 143°-146° C.; NMR (CDCl3): 1.21(t, 3H), 1.35(t, 3H), 2.79(q, 2H), 3.12(q, 2H), 5.56(s, 2H), 6.77(s, 1H), 6.80(d, 1H), 7.30(d, 2H), 7.81(d, 1H), 8.05(d, 2H); mass spectrum (CI. ammonia): 337 (M+H)+ ; microanalysis, found: C, 71.3; H, 6.3; N, 7.9%; C20H20N2O3 requires: C, 71.4; H, 6.0; N, 8.3%.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([CH3:13])[C:9]2=O)=[CH:5][CH:4]=1)#[N:2].Br[CH2:15][C:16]([O:18][CH3:19])=[O:17].C1C=CC=CC=1.II.C(O)(=[O:30])C>C(O)C.CCOCC>[OH:30][CH:7]1[C:6]2[C:10](=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[C:9]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:8]1[CH3:13]
Reactant: COC(=O)CBr
Reactant: CC1Cc2ccc(C#N)cc2C1=O
Reactant: CC(=O)O
Agent: II
Solvent: CCO
Solvent: c1ccccc1
Solvent: CCOCC
Product: COC(=O)CC1=C(C)C(O)c2ccc(C#N)cc21
Reaction time: 3 h

Procedure:
A solution of 13.0 g. of 6-cyano-2-methylindanone and 19.3 g. of methyl bromoacetate in 45 ml. benzene is added over a period of 5 minutes to 21 g. of zinc amalgam (prepared according to Org. Syn. Coll., Vol. 3) in 110 ml. benzene and 40 ml. dry ether. A few crystals of iodine are added to start the reaction, and the reaction mixture is maintained at reflux temperature (ca. 65°) with external heating. At 3 hour intervals two batches of 10 g. zinc amalgam and 10 g. bromoester are added and the mixture is then refluxed for 8 hours. After addition of 30 ml. of ethanol and 150 ml. of acetic acid, the mixture is poured into 700 ml. of 1:1 aqueous acetic acid. The organic layer is separated, and the aqueous layer is extracted twice with ether. The combined organic layers are washed thoroughly with water, ammonium hydroxide and water. Drying over sodium sulfate, evaporation of solvent in vacuo followed by pumping at 80° (bath temp.) (1-2 mm.) gives crude methyl (1-hydroxy-2-methyl-5-cyano-indenyl)acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][C:14]2[CH:19]([C:20]([OH:22])=[O:21])[N:18]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:17]3[S:16][CH:15]=2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[Cl:42][C:43]([Cl:47])([Cl:46])[CH2:44]O.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[Cl:42][C:43]([Cl:47])([Cl:46])[CH2:44][O:21][C:20]([CH:19]1[N:18]2[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:17]2[S:16][CH:15]=[C:14]1[CH2:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:22]
Reactant: OCC(Cl)(Cl)Cl
Reactant: COc1ccc(CC2=CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N3C2C(=O)O)c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(CC2=CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N3C2C(=O)OCC(Cl)(Cl)Cl)c2ccccc12

Procedure:
A solution of 10.9 g of 3-(4-methoxy-1-naphthylmethyl)-7β-phenylacetylamino-ceph-2-em-4ξ-carboxylic acid in 300 ml of methylene chloride is treated with 1.80 ml of pyridine, then successively with 2.50 ml of 2,2,2-trichloroethanol in 20 ml of methylene chloride and 4.95 g of dicyclohexylcarbodiimide in 40 ml of methylene chloride. The addition of the reagents is carried out at room temperature and while stirring. The reaction mixture is stirred for 20 hours at room temperature, freed from dicyclohexylurea by means of filtration and the filtrate is evaporated under reduced pressure. The residue is taken up in ethyl acetate and mixed with an aqueous dipotassium hydrogen phosphate buffer solution (pH 7.5). The aqueous portion is separated, washed several times with ethyl acetate and the pH adjusted to 2.5 with 20% aqueous phosphoric acid. After repeated extraction with ethyl acetate, the organic extracts from the aqueous phase having pH 2.5 are combined, washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated under reduced pressure. The residue is chromatographed on 450 g of silica gel, elution being carried out with methylene chloride containing 5% of methyl acetate, fractions of 500 ml being taken. The residue of the fractions 12-13 is crystallised from ethyl acetate and yields the 3-(4-methoxy-1-naphthylmethyl)-7β-phenylacetylamino-ceph-2-em-4ξ-carboxylic acid 2,2,2-trichloroethylester, which melts at 145-147°; [α]D20 = + 271° ± 1° (c = 0,918 in chloroform); ultraviolet absorption spectrum (in methanol): λmax = 210 mμ (ε = 67000), 232 mμ (ε = 41200), 298 mμ (ε = 9990) and 322 mμ (ε = 4960); infrared absorption spectrum (in mineral oil): characteristic bands at 2,90μ, 5,62μ, 5,68μ, 6,02μ, 6,27μ and 6,60μ; thin-layer chromatogram (silica gel): Rf = 0.27 (system: toluene/ethyl acetate 4:1) and Rf = 0.38 (system: toluene/acetone 9:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:11]=2[CH:12]=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH2:22]([NH2:24])[CH3:23]>>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:11]=2[CH2:12][NH:24][CH2:22][CH3:23])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: CCN
Reactant: COc1ncc(Br)cc1-c1ccc(C(F)(F)F)cc1C=O
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cc(Br)cnc1OC

Procedure:
2-(5-Bromo-2-methoxy-pyridin-3-yl)-5-trifluoromethyl-benzaldehyde and ethylamine (2M in THF) as described in Example 3, Step 3 to provide [2-(5-bromo-2-methoxy-pyridin-3-yl)-5-trifluoromethyl-benzyl]-ethyl-amine.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH:18]4[CH2:19][CH2:20][CH:14]3[CH2:15][O:16][CH2:17]4)[N:10]=[C:9]([C:21]3[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.ClC(Cl)(O[C:32](=[O:38])OC(Cl)(Cl)Cl)Cl.[F:40][C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=1>>[F:40][C:41]1[CH:47]=[CH:46][C:44]([NH:45][C:32]([NH:25][C:24]2[CH:26]=[CH:27][C:21]([C:9]3[N:8]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:12]=[C:11]([N:13]4[CH:14]5[CH2:20][CH2:19][CH:18]4[CH2:17][O:16][CH2:15]5)[N:10]=3)=[CH:22][CH:23]=2)=[O:38])=[CH:43][CH:42]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3C4CCC3COC4)n2)cc1
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3C4CCC3COC4)n2)cc1
Yield: 48.8 %

Procedure:
Following the procedure described in example 34, reaction of 4-[4-morpholin-4-yl-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1,3,5-triazin-2-yl]aniline (22 mg, 0.06 mmol) (22 mg, 0.06 mmol, triphosgene (18 mg, 0.06 mmol) and 4-fluoroaniline (20 mg, 0.18 mmol) gave the title compound as off-white solid (14.8 mg, 49% yield). MS (ESI) m/z 506.5.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[S:6]C(C(NC(CC2C=CC=CC=2)=O)C(O)=O)[NH:4][CH:3]1[C:21]([OH:23])=[O:22].COC1C=CC=C(N)C=1.C1(C)C=CC=CC=1.C(O)(=O)C>O>[NH2:4][C@@H:3]([C:21]([OH:23])=[O:22])[C:2]([SH:6])([CH3:24])[CH3:1]
Reactant: CC1(C)SC(C(NC(=O)Cc2ccccc2)C(=O)O)NC1C(=O)O
Agent: COc1cccc(N)c1
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(S)[C@@H](N)C(=O)O
Reaction time: 4 h

Procedure:
3.52 g (0.01 mole) of benzylpenicilloic acid, 3.70 g (0.03 mole) of m-anisidine and 20 ml of toluene were added to a solution of 3.60 g (0.06mole) of acetic acid in 30 ml of water. The mixture was heated under reflux, with stirring, for 4 hours in a nitrogen atmosphere. The reaction mixture was then treated as described in Example 9 to give D-penicillamine as colorless crystals: yield 1.07 g (71.8%), m.p. 201°-202° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:8]([C:10]1[CH:31]=[CH:30][C:13]2[N:14]([CH3:29])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=3[O:27][CH3:28])=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:39].C(O)C.C(=O)([O-])[O-].[NH4+:47].[NH4+]>ClCCl.C(O)C>[ClH:39].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:8]([C:10]1[CH:31]=[CH:30][C:13]2[N:14]([CH3:29])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:47])[NH2:26])=[CH:21][C:20]=3[O:27][CH3:28])=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1OC)n2C)c1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1OC)n2C)c1ccccn1
Yield: 67 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyano-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 67% of theory, C28H31N7O4 (529.6) Rf value: 0.16 (silica gel; dichloromethane/ethanol=4:1) EKA mass spectrum: (M+H)+ =530