Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8]C=1C#N)([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:16].[O:20]1[CH2:25][CH2:24]OCC1>>[CH:1]([C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:24]=1[C:25]([OH:20])=[O:16])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc([N+](=O)[O-])ccc1C#N
Reactant: O=S(=O)(O)O
Reactant: C1COCCO1
Product: CC(C)c1cc([N+](=O)[O-])ccc1C(=O)O
Yield: 52 %

Procedure:
2-Isopropyl-4-nitro-benzonitrile (0.4 g, 2.10 mmol) was dissolved in dioxane (10 mL) and 80% sulfuric acid (10 mL) was added. The mixture was heated at reflux for 2 days then dioxane was evaporated under reduced pressure. The residue was basified with dilute sodium hydroxide solution and washed with ethyl acetate. The aqueous layer was then acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was separated, washed with water and brine, dried over sodium sulfate and concentrated to yield 2-isopropyl-4-nitro-benzoic acid (0.23 g, 52%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH2:15][CH2:16][CH:17]=O)=[CH:13][C:12]([CH2:19][CH2:20][CH3:21])=[N:11]2)=[CH:6][CH:5]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][N:34]([CH2:17][CH2:16][CH2:15][C:14]2[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:23])([F:22])[F:1])=[CH:5][CH:6]=3)[N:11]=[C:12]([CH2:19][CH2:20][CH3:21])[CH:13]=2)[CH2:33][CH2:32]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCCc1cc(CCC=O)n(-c2ccc(OC(F)(F)F)cc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccc(OC(F)(F)F)cc2)n1

Procedure:
100 mg (80.6%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-(4-trifluoromethoxyphenyl)-3-propyl-1H-pyrazol-5-yl)propanal (82.5 mg, 0.253 mmol), 1-(2-fluorophenyl)piperazine (60 mL, 0.379 mmol), and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[C:12]([Cl:17])[N:11]=1.O>O1CCCC1>[Cl:9][C:10]1[N:11]=[C:12]([Cl:17])[CH:13]=[C:14]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)[N:15]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: Cc1ccc(N)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(Nc2cc(Cl)nc(Cl)n2)cc1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
6.4 g of p-toluidine was dissolved in 50 ml of tetrahydrofuran, and 5.5 g of 2,4,6-trichloropyrimidine was dropwise added thereto with stirring at room temperature. After being stirred for 1 hour, 200 ml of water was added to the reaction mixture. The crystal thus precipitated was taken out by filtration and dried to obtain 6.6 g of 2,4-dichloro-6-p-toluidinopyrimidine, which had a m.p. of 162° to 166° C. Next, 2.4 g of phenol and 8.6 g of potassium carbonate were dispersed in 30 ml of N,N'-dimethylimidazolin-2-one, and 2.54 g of the previously prepared 2,4-dichloro-6-p-toluidinopyrimidine was added thereto with stirring and then heated at 150° C. for 2 hours. After the reaction solution was cooled, 100 ml of ethyl acetate was added thereto. The solution was then washed with water and extracted. The resulting ethyl acetate extract was concentrated, and methanol was added to the residue for crystallization. Accordingly, 3.4 g of the intended Coupler (12) was obtained, which had a m.p. of 151° to 152° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:49])[CH2:7][N:8]([C:18](=[O:48])[C@H:19]([CH3:47])[NH:20][C@H:21]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][N:29](C(OCC2C=CC=CC=2)=O)[CH2:28][CH2:27]1)[CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2]>CO.[C].[Pd]>[C:1]([O:5][C:6](=[O:49])[CH2:7][N:8]([C:18](=[O:48])[C@H:19]([CH3:47])[NH:20][C@H:21]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]1)[CH:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)[C@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](C)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)[C@H](CCCCC1CCNCC1)N[C@@H](C)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.5 %

Procedure:
In 20 ml of methanol is dissolved 0.4 g of N-[N-[(S)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanyl]-N-(indan-2-yl)glycine tert-butyl ester, and a catalytic reduction is carried out at ambient temperature and under atmospheric pressure using 10% palladium-carbon (50% wet, 0.4 g) as a catalyst. After stirring at room temperature for 4 hours, the catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure to give 0.3 g of N-[N-[(S)-5-(4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanyl]-N-(indan-2-yl)glycine tert-butyl ester as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[N:9]=2)=[CH:4][CH:3]=1.[OH:17][C:18]([CH3:33])([CH3:32])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[O:30][CH3:31]>CO.O.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][N:11]([C:24]3[CH:25]=[CH:26][C:21]([O:20][CH2:19][C:18]([OH:17])([CH3:33])[CH3:32])=[C:22]([O:30][CH3:31])[CH:23]=3)[C:10](=[O:14])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1nc(COc2ccc(Cl)cc2)cc[nH]1
Reactant: COc1cc(B(O)O)ccc1OCC(C)(C)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: O
Product: COc1cc(-n2ccc(COc3ccc(Cl)cc3)nc2=O)ccc1OCC(C)(C)O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a mixture of 4-((4-chlorophenoxy)methyl)pyrimidin-2(1H)-one Part C (0.2 g, 0.845 mmol), 4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenylboronic acid Part D of Procedure 4 (0.304 g, 1.268 mmol), and copper (II) acetate monohydrate (0.169 g, 0.845 mmol) in MeOH (45 mL) and H2O (11 mL) was added N,N,N′N′-tetramethylethylenediamine (0.26 mL, 1.690 mmol). After stirring at RT for 45 minutes in the presence of air, the mixture was extracted with CH2Cl2 (200 mL). The organic phase was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica gel/100:0 to 0:100 hexanes-ethyl acetate to 95:5 CH2Cl2/MeOH gradient). The product thus obtained was re-purified using prep HPLC (Phen Luna Axia C18 5μ 10:90 to 90:10 MeOH/H2O) to afford the desired product 4-((4-chlorophenoxy)methyl)-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-2(1H)-one C-1 (16.9 mg, 0.036 mmol, 4.32% yield) as a yellow solid. 100 mg of starting material 4-((4-chlorophenoxy)methyl)pyrimidin-2(1H)-one was also recovered. LC/MS 431 (M+H)+, tR 0.81 min (method 5); 1H NMR (400 MHz, Chloroform-D) δ 7.73 (1H, d, J=6.78 Hz), 7.28-7.31 (2H, m), 6.94-7.03 (2H, m), 6.86-6.94 (3H, m), 6.66 (1H, d, J=7.03 Hz), 5.02 (2H, s), 3.87 (3H, s), 3.86 (2H, s), 1.36 (6H, s).
Reaction SMILES: O1C(C2C=C3C(=CC=2)NC(=O)C3)=CN=C1.COC(OC)(N(C)C)C.[CH3:25][N:26]([CH3:44])[C:27](=[C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38]3[O:42][CH:41]=[N:40][CH:39]=3)[CH:36]=2)[NH:31][C:30]1=[O:43])[CH3:28].[S:45]([NH2:55])(=[O:54])([C:47]1[CH:52]=[CH:51][C:50]([NH2:53])=[CH:49][CH:48]=1)=[O:46]>>[CH3:44][N:26]([CH3:25])[C:27](=[C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38]3[O:42][CH:41]=[N:40][CH:39]=3)[CH:36]=2)[NH:31][C:30]1=[O:43])[CH3:28].[O:42]1[C:38]([C:35]2[CH:36]=[C:37]3[C:32](=[CH:33][CH:34]=2)[NH:31][C:30](=[O:43])[C:29]3=[C:27]([NH:53][C:50]2[CH:49]=[CH:48][C:47]([S:45]([NH2:55])(=[O:54])=[O:46])=[CH:52][CH:51]=2)[CH3:28])=[CH:39][N:40]=[CH:41]1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: CC(=C1C(=O)Nc2ccc(-c3cnco3)cc21)N(C)C
Agent: COC(C)(OC)N(C)C
Agent: O=C1Cc2cc(-c3cnco3)ccc2N1
Product: CC(Nc1ccc(S(N)(=O)=O)cc1)=C1C(=O)Nc2ccc(-c3cnco3)cc21

Procedure:
3-(1-Dimethylaminoethylidene)-5-(oxazol-5-yl)-1,3-dihydroindol-2-one was prepared from 5-(oxazol-5-yl)-1,3-dihydroindol-2-one and N,N-dimethylacetamide dimethyl acetal according to Procedure H. Condensation of 3-(1-dimethylaminoethylidene)-5-(oxazol-5-yl)-1,3-dihydroindol-2-one and sulfanilamide according to Procedure J provided the title compound: mp>250° C.; 1H NMR (DMSO-d6): δ2.51 (s, 0.8H, DMSO), 2.61 (s, 3H), 6.97 (d, J=8.2 Hz, 1H), 7.37 (s, 2H), 7.40 (dd, J=8.0, 1.5 Hz, 1H), 7.45 (d, J=8.8 Hz, 2H), 7.56 (s, 1H), 7.66 (d, J=1.2 Hz,1H), 7.83 (d, J=8.5 Hz, 2H), 8.34 (s, 1H), 10.85 (s, 1H), 12.33 (s, 1H); APCI−MS m/z 395 (M−H)−. Anal. Calcd for C19H16N4O4S.0.1C2H6OS.0.6H2O: C, 55.56; H, 4.32; N, 13.50; S, 8.50. Found: C, 55.53; H, 4.32; N, 13.27; S, 8.58.
Reaction SMILES: C(N(CC)C(C)C)(C)C.F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].[O:20]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21]1>C(O)CCC>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:25][CH:22]1[CH2:23][CH2:24][O:20][CH2:21]1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: NC1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: O=[N+]([O-])c1ccccc1NC1CCOC1
Temperature: 180 °C
Reaction time: 0.33 h

Procedure:
N,N-Diisopropylethylamine (3.2 mL, 18.4 mmol) was added to a solution of 1-fluoro-2-nitrobenzene (0.484 mL, 4.6 mmol) and (±)-tetrahydrofuran-3-amine (400 mg, 4.6 mmol) in n-butanol (10 mL) and the mixture heated to 180° C. in a microwave reactor. After 20 min, the reaction was allowed to cool to ambient temperature and concentrated. Purification by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, gave the title compound. MS: m/z=209 (M+1).
Reaction SMILES: C[C:2]1[CH:6]=[C:5](C)[N:4]([C:8](=[NH:20])[NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16](Cl)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[N:3]=1.[CH3:21]S(O)(=O)=O.N1C=C[CH:29]=[C:28](CN)[CH:27]=1>>[NH2:20][C:8]([NH:4][CH2:5][C:6]1[CH:2]=[N:3][CH:27]=[CH:28][CH:29]=1)=[N:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:21])=[CH:17][CH:18]=1)(=[O:11])=[O:12]
Reactant: NCc1cccnc1
Reactant: Cc1cc(C)n(C(=N)NS(=O)(=O)c2ccc(Cl)cc2)n1
Reactant: CS(=O)(=O)O
Product: Cc1ccc(S(=O)(=O)N=C(N)NCc2cccnc2)cc1

Procedure:
The compound of Example 23 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-chlorobenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of 3-picolylamine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 304.37; found mol. wt. (M+H) 305.3; 609.2 (Dimer)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:18][O:19][C:20]([C:22]1[S:26][C:25]2[C:27]([NH2:31])=[CH:28][CH:29]=[CH:30][C:24]=2[CH:23]=1)=[O:21]>C(Cl)Cl.CN(C)C1C=CN=CC=1.CCOC(C)=O>[CH3:18][O:19][C:20]([C:22]1[S:26][C:25]2[C:27]([NH:31][C:6]([C:5]3[CH:4]=[N:3][C:2]([Cl:1])=[CH:10][CH:9]=3)=[O:8])=[CH:28][CH:29]=[CH:30][C:24]=2[CH:23]=1)=[O:21]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: COC(=O)c1cc2cccc(N)c2s1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2cccc(NC(=O)c3ccc(Cl)nc3)c2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
To a solution of 6-chloronicotinic acid (1.5 eq) and triethylamine (2.0 eq) in CH2Cl2 (5 mL) was added BopCl (2.0 eq). After 15 min, 7-amino-benzo[b]thiophene-2-carboxylic acid methyl ester (87 mg) in CH2Cl2 and 4-dimethylaminopyridine (DMAP) (1.0 eq) were added to the reaction solution above. The reaction was stirred at room temperature 12 h. The reaction was then diluted with EtOAc, and washed with NaHCO3 solution and brine. The organics were dried over MgSO4, filtered and concentrated to give a crude material which was purified by flash chromatography on silica gel (20%-50% EtOAc/hexane) to provide 100 mg (68%) of the desired 7-[(6-chloro-pyridine-3-carbonyl)-amino]-benzo[b]thiophene-2-carboxylic acid methyl ester as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1.ClC1C=C(C=CC=1)C(OO)=[O:23]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:10]3=[N+:11]([O-:23])[CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1c2ccc(Cl)cc2CCc2cccnc21
Solvent: ClCCl
Product: O=C1c2ccc(Cl)cc2CCc2ccc[n+]([O-])c21
Temperature: 0 °C

Procedure:
To a mixture of 25.1 grams (0.103 mole) of 8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one in 175 ml of dry CH2Cl2 at 0° C. under an argon atmosphere was added dropwise over 70 minutes a solution of 24.12 grams of 3-chloroperoxy-benzoic acid in 150 ml of CH2Cl2. After the addition the solution was stirred for ½ hour after which the ice bath was removed. After two days the reaction was poured into 1.0 N aqueous NaOH and extracted with CH2Cl2. The organic portions were combined, washed once with water, dried over MgSO4, filtered and concentrated in vacuo. The resultant product was triturated with isopropyl ether and filtered to provide 25.8 grams (96%) yield of the title compound.
Reaction SMILES: [C:1](=[O:7])([O:5][CH3:6])[O:2][CH2:3]Cl.[F:8][C:9]([S:12][CH2:13][C:14]([NH:16][CH:17]1[C:35](=[O:36])[N:19]2[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH:24]([S:26][C:27]3[NH:31][N:30]=[N:29][N:28]=3)[CH3:25])[CH2:22][S:23][C@H:18]12)=[O:15])([F:11])[F:10].[Na]>CN(C=O)C>[F:8][C:9]([S:12][CH2:13][C:14]([NH:16][CH:17]1[C:35](=[O:36])[N:19]2[C:20]([C:32]([O:34][CH2:3][O:2][C:1]([O:5][CH3:6])=[O:7])=[O:33])=[C:21]([CH:24]([S:26][C:27]3[NH:28][N:29]=[N:30][N:31]=3)[CH3:25])[CH2:22][S:23][C@H:18]12)=[O:15])([F:11])[F:10]
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)CSC(F)(F)F)[C@H]2SC1
Reactant: COC(=O)OCCl
Agent: [Na]
Solvent: CN(C)C=O
Product: COC(=O)OCOC(=O)C1=C(C(C)Sc2nnn[nH]2)CS[C@@H]2C(NC(=O)CSC(F)(F)F)C(=O)N12

Procedure:
Chloromethyl methyl carbonate (0.02 mol) is reacted with sodium 7-trifluoromethylmercaptoacetamido-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (0.01 mol) in DMF for 20 hours. On work up as described in Example 1, methoxycarbonyloxymethyl 7-trifluoromethylmercaptoacetamido-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylate is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[O:9]1[CH2:13][CH2:12][NH:11][C:10]1=[O:14]>>[Br:8][C:4]1[N:3]=[C:2]([N:11]2[CH2:12][CH2:13][O:9][C:10]2=[O:14])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1NCCO1
Reactant: Brc1cccc(Br)n1
Product: O=C1OCCN1c1cccc(Br)n1

Procedure:
Prepared according to the procedure described in Example 139, Step 1, using 2,6-dibromo-pyridine and oxazolidin-2-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[C:19]([CH3:23])[C:20]([CH3:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[C:24](Cl)(=[O:26])[CH3:25].C(OCC)(=O)C.C(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][C:24](=[O:26])[CH3:25])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[C:19]([CH3:23])[C:20]([CH3:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc([C@@H]2Sc3cc(C)c(C)cc3NC(=O)[C@@H]2O)cc1
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc([C@@H]2Sc3cc(C)c(C)cc3NC(=O)[C@@H]2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
226 mg of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-7,8-dimethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are suspended in 2 ml of pyridine, and 59 mg of acetyl chloride are added thereto under ice-cooling. The mixture is stirred at room temperature for 2 hours. After the reaction is completed, ethyl acetate-chloroform (1:1) is added to the reaction mixture. The mixture is washed with 10% hydrochlric acid and water, successively. Then, the mixture is dried and evaporated under reduced pressure to remove solvent. 219 mg of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-7,8-dimethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH2:17][C:18]3([CH2:21][O:22][CH3:23])[CH2:20][CH2:19]3)[C:13]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)=[C:12]([O:31][CH2:32][CH3:33])[CH:11]=2)=[CH:4][N:3]=1.O>C(O)C.C(O)(=O)C.O=[Pt]=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([O:31][CH2:32][CH3:33])[C:13]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)=[C:14]([O:16][CH2:17][C:18]([CH3:19])([CH3:20])[CH2:21][O:22][CH3:23])[CH:15]=2)=[CH:4][N:3]=1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC2(COC)CC2)c1-c1ccc(O)cc1
Agent: O=[Pt]=O
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC(C)(C)COC)c1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
4′-(2,4-Diamino-pyrimidin-5-ylmethyl)-2′-ethoxy-6′-(1-methoxymethyl-cydopropylmethoxy)-biphenyl-4-ol (235 mg; 0.52 mmol) is hydrogenated in ethanol/acetic acid conc./water (4/1/0.1) (10 ml) over PtO2 (6×35 mg) at 100° C. The reaction mixture is cooled to room temperature, the catalyst is filtered off with suction and the filtrate is concentrated. The residue is stirred in water, the pH is adjusted to pH 9 by addition of NH4OH conc., stirring is continued for 30 minutes and the mixture is filtered with suction. The grey crude product is then chromatographed over silica gel (20 g) with methylene chloride/methanol/NH4OH conc. (19/1/0.05). 104 mg (44%) 4′-(2,4-diamino-pyrimidin-5-ylmethyl)-6′-ethoxy-2′-(3-methoxy-2,2-dimethyl-propoxy)-biphenyl-4-ol are obtained as a colourless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:34])([CH3:33])[C:13](=[O:32])[N:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([C:24]4[CH:29]=[C:28]([OH:30])[CH:27]=[CH:26][C:25]=4[CH3:31])=[O:23])[CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:34])([CH3:33])[C:13](=[O:32])[N:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([C:24]4[CH:29]=[C:28]([CH:27]=[CH:26][C:25]=4[CH3:31])[O:30][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[O:23])[CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(O)ccc4C)CC3)C(=O)C2(C)C)cc1OC
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C)c(C(=O)N2CCC(N3N=C(c4ccc(OC)c(OC)c4)C(C)(C)C3=O)CC2)c1
Temperature: 50 °C

Procedure:
0.5 g of 5-(3,4-dimethoxyphenyl)-2-{1-[(5-hydroxy-2-methylphenyl)carbonyl]piperidin-4-yl}-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound described in example 85) and 0.3 g potassium carbonate are suspended in 20 ml of DMF. 0.2 ml of ethyl bromoacetate is added and the reaction mixture is heated to 50° C. under a blanket of nitrogen for about 16 h until the reaction is completed according to TLC analysis. The solvent is evaporated under reduced pressure, and the remaining residue is taken up in EA. The organic phase is washed twice with water and brine, dried over MgSO4, and the solvent is removed under reduced pressure. Purification of the resulting crude product by crystallization from diethyl ether yields the title compound.
Reaction SMILES: Br[CH:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[C:11]([O:24][CH3:25])[C:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[CH:13][C:4]=2[CH:3]1O.[C:27]1(=[O:33])[NH:32][CH2:31][CH2:30][CH2:29][CH2:28]1.[H-].[Na+].CS(C)=[O:38]>>[CH3:8][C:7]1([CH3:9])[O:6][C:5]2[CH:10]=[C:11]([O:24][CH3:25])[C:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:15])=[O:16])=[CH:13][C:4]=2[C@@H:3]([N:32]2[CH2:31][CH2:30][CH2:29][CH2:28][C:27]2=[O:33])[C@@H:2]1[OH:38]
Reactant: CS(C)=O
Reactant: O=C1CCCCN1
Reactant: COc1cc2c(cc1S(=O)(=O)c1ccc(C)cc1)C(O)C(Br)C(C)(C)O2
Agent: [H-]
Agent: [Na+]
Product: COc1cc2c(cc1S(=O)(=O)c1ccc(C)cc1)[C@@H](N1CCCCC1=O)[C@H](O)C(C)(C)O2
Temperature: 40 °C
Reaction time: 5 h

Procedure:
5 g (0.011 mol) of 3-bromo-3,4-dihydro-2,2-dimethyl-7-methoxy-6-(p-tolylsulfonyl)-2H-benzo [b]pyran-4ol are dissolved in 32 ml of dimethyl sulfoxide, 4.9 g of valerolactam (0.0526 mol) and 0.8 g (0.033 mol) of NaH, 80 % suspension in oil, are added and the mixture is stirred for 5 hours at 40° C., poured on ice water and filtered with suction. The residue is boiled up several times with methanol. White crystals of melting point 261-63° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]#N)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-:14].[K+].C(O)C[OH:18].Cl>CCOC(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([OH:18])=[O:14])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: [OH-]
Reactant: N#CC1(c2ccc(Br)cc2)CCC1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)C1(c2ccc(Br)cc2)CCC1
Temperature: 25 °C

Procedure:
1-(4-bromophenyl)cyclobutanecarbonitrile (1-2c,12.04 g, 51.0 mmol), potassium hydroxide (11.44 g, 204 mmol) and ethylene glycol (50 mL, 897 mmol) were heated to reflux for 4 h. The reaction mixture was cooled to room temperature, then diluted with EtOAc and water. The aqueous layer was acidified with 1 M HCl, then was extracted into EtOAc. The organic layer was dried over Na2SO4, filtered and reduced in vacuo to give 7-1 as a tan oil.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]#[N:34])=[CH:23][CH:22]=2)[C:7]2[N:8]([C:10]([CH3:19])=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:39]=[N+:40]=[N-:41])(C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[NH:41][N:40]=[N:39][N:34]=3)=[CH:25][CH:26]=2)[C:7]2[N:8]([C:10]([CH3:19])=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCCCc1nn2c(C)c(-c3ccccc3)nc2n1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCc1nn2c(C)c(-c3ccccc3)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 38.8 %

Procedure:
A mixture of 95.0 mg (0.213 mmol) of 2-butyl-3-[(2'-cyanobiphenyl-4-yl)methyl]-6-methyl-5-phenyl-3H-imidazo[1,2-b][1,2,4]triazole (from Step F), 158 mg (0.769 mmol) of trimethyltin azide, and 2.0 ml of toluene was stirred at reflux under N2 for 24 hours. The mixture was concentrated in vacuo, and the residue was treated with 3 ml of dry MeOH and 1.0 g of silica gel. The resulting mixture was stirred at room temperature in a stoppered flask overnight. The solvent was removed by rotary evaporation in vacuo to give a dry powder, which was added as a slurry in CH2Cl2 to the top of a column of silica gel (26×2.5 cm) packed in CH2Cl2. Gradient elution of the column with 1.5% MeOH in CH2Cl2 and concentration of the product fractions yielded 40.4 mg (37%) of the title compound as a yellow gum, which, upon trituration with ether, was transformed to a tan solid (28 mg, 25%), mp 207°-208° C.; homogeneous by TLC in 90:10:0.1 CH2Cl2 -MeOH-AcOH.