Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([C:14]([OH:16])=[O:15])=[C:9]([OH:17])[CH:8]=[CH:7]2)(=[NH:3])[NH2:2].CS([O-])(=O)=O.N1C=CC=CC=1.Cl.[NH2:30][N:31]=[CH:32][NH:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>O>[NH2:30][N:31]=[CH:32][NH:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([O:17][C:9]2[CH:8]=[CH:7][C:6]3[C:11](=[CH:12][CH:13]=[C:4]([C:1](=[NH:2])[NH2:3])[CH:5]=3)[C:10]=2[C:14]([OH:16])=[O:15])=[O:39])=[CH:36][CH:35]=1
Reactant: NN=CNc1ccc(C(=O)Cl)cc1
Reactant: N=C(N)c1ccc2c(C(=O)O)c(O)ccc2c1
Agent: CS(=O)(=O)[O-]
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: N=C(N)c1ccc2c(C(=O)O)c(OC(=O)c3ccc(NC=NN)cc3)ccc2c1
Reaction time: 2 h
Yield: 77.9 %

Procedure:
To 930 mg of 6-amidino-1-carboxy-2-naphthol.methanesulfonate were added 10 ml of anhydrous pyridine and then 667.5 mg of 4-aminoiminomethylaminobenzoic acid chloride.hydrochloride, followed by stirring for 2 hours under cooling with ice and then 48 hours under cooling with water. The precipitate was collected by filtration and washed with a small amount of pyridine. To the collected precipitated were added 20 ml of warm DMF and then 0.6 ml of methanesulfonic acid. The resulting solution was added dropwise to 600 ml of ether, followed by stirring for 1 hour under cooling with ice. The supernatant liquid was decanted, and 20 ml of methanol was added to the residue. This solution was added dropwise to 450 ml of acetone, followed by stirring for 15 minutes under cooling with ice. Then, the precipitate was collected by filtration and washed with a small amount of acetone to obtain 869 mg of the desired product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14]CC)=[O:13])[CH:7]=[CH:8][CH:9]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[C:6]([CH2:10][CH:11]([O:17][CH:18]([CH3:19])[CH3:20])[C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=2)=[O:30])=[CH:24][CH:23]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C(Cc1cccc(CCO)c1)OC(C)C
Product: CC(C)OC(Cc1cccc(CCOC(=O)Nc2ccc(Cl)cc2)c1)C(=O)O

Procedure:
Using ethyl 3-[3-(2-hydroxyethyl)phenyl]-2-isopropoxypropanoate and 4-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[C:5]([CH:16]2[CH2:18][CH2:17]2)=[CH:4][N:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1>C(Cl)Cl.CO>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[C:5]([CH:16]3[CH2:18][CH2:17]3)=[CH:4][N:3]=[C:2]([NH:31][C:30]3[CH:29]=[CH:28][C:27]([CH2:26][N:23]4[CH2:22][CH2:21][N:20]([CH3:19])[CH2:25][CH2:24]4)=[CH:33][CH:32]=3)[N:7]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: Fc1ccc(-c2nc(Cl)ncc2C2CC2)cc1Cl
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(Nc3ncc(C4CC4)c(-c4ccc(F)c(Cl)c4)n3)cc2)CC1
Yield: 51 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-chloro-4-(3-chloro-4-fluorophenyl)-5-cyclopropylpyrimidine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 51% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.22 (s, 1H), 7.90 (dd, 1H, J=7.0, 2.0 Hz), 7.72 (m, 1H), 7.55 (d, 2H, J=8.6 Hz), 7.22 (d, 1H, J=8.6 Hz), 7.09 (d, 2H, J=8.6 Hz), 3.45 (s, 2H), 2.43 (bs, 8H), 2.26 (s, 3H), 1.86 (m, 1H), 0.92 (m, 2H), 0.63 (m, 2H); MS (ESI): 452.3 [M+H]+, 226.9 [M+2H]2+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9](OC3CCOCC3)[C:10]=2[N:11]=1.[CH3:19][C:20]1[C:24]([NH2:25])=[C:23]([CH3:26])[O:22][N:21]=1.C([O-])(=O)C.[Na+]>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:25][C:24]3[C:20]([CH3:19])=[N:21][O:22][C:23]=3[CH3:26])[C:10]=2[N:11]=1
Reactant: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Reactant: Cc1noc(C)c1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1noc(C)c1Nc1ncnc2ccc(Cl)nc12
Yield: 59.5 %

Procedure:
A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.100 g, 0.500 mmol), 3,5-dimethylisoxazol-4-amine (0.140 g, 1.250 mmol) and sodium acetate (0.123 g, 1.50 mmol) in 5 ml of solvent (THF:H2O=1:1) was refluxed for 1 hour. The reaction mixture was diluted with EtOAc. The organics were washed with brine, dried over Na2SO4, filtered and concentrated. The crued was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to get N-(6-chloropyrido[3,2-d]pyrimidin-4-yl)-3,5-dimethylisoxazol-4-amine (0.082 g, 59%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.24 (3H, s), 2.40 (3H, s), 7.74 (1H, d, J=8.8 Hz), 7.93 (1H, brs), 8.16 ((1H, d, J=8.8 Hz), 8.69 (1H, s).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:67])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47](OS(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH:46]([O:63][CH2:64][CH2:65][CH3:66])[CH2:45]2)[CH:7]([CH3:68])[CH2:6][CH2:5][C:4]1=[O:69])[CH3:2].[N-:70]=[N+:71]=[N-:72].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:67])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:70]=[N+:71]=[N-:72])[CH:46]([O:63][CH2:64][CH2:65][CH3:66])[CH2:45]2)[CH:7]([CH3:68])[CH2:6][CH2:5][C:4]1=[O:69])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1OS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1N=[N+]=[N-]
Temperature: 70 °C
Yield: 55.9 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-(o-nitrophenylsulfonyloxy)-3"-propyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (111 mg) in N,N-dimethyl formamide (1.1 ml) was added an excess of sodium azide (32 mg) and the mixture heated to 70° C. After 5.5 hours the reaction was cooled to room temperature, diluted with ethyl acetate, extracted from half-saturated ammonium chloride, and washed with brine. The combined organics were dried over sodium sulfate and purified by flash chromatography on silica gel (ethyl acetate: hexane (1:2)+1% methanol) to give the title compound (52 mg).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:15][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[C:9]=2[CH:8]=[N:7]1)C.[BH4-].[Na+].Cl>CO>[CH2:19]([O:18][C:16](=[O:17])[NH:15][C@@H:10]1[CH2:11][CH2:12][CH2:13][C:14]2[N:6]([CH2:5][CH2:4][OH:3])[N:7]=[CH:8][C:9]1=2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2NC(=O)OCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(N[C@@H]1CCCc2c1cnn2CCO)OCc1ccccc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a solution of ((R)-4-benzyloxycarbonylamino-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (2.00 g, 5.60 mmol) in methanol (150 mL) was added sodium borohydride (1.61 g, 39.5 mmol). The mixture was stirred at 70° C. for 2 hours. After being cooled to room temperature, the reaction mixture was acidified to pH 7 with 5N hydrochloric acid, and then concentrated to remove methanol. The resulting mixture was extracted with dichloromethane (20 mL). After filtering out any insoluble materials from the organic layer, the filtrate was concentrated in vacuo to give [(R)-1-(2-hydroxy-ethyl)-4,5,6,7-tetrahydro-1H-indazol-4-yl]-carbamic acid benzyl ester (1.68 g, 95%) as a white solid. MS calcd. for C17H21N3O3 315, obsd. (ESI+) [(M+H)+] 316.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[C:13]([F:15])[C:12]([CH3:16])=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][C:10]2=O)(=[O:3])[CH3:2].[H][H]>[C].[Pd].CO>[C:1]([NH:4][C:5]1[CH:14]=[C:13]([F:15])[C:12]([CH3:16])=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(F)c(C)c2c1CCCC2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1cc(F)c(C)c2c1CCCC2
Temperature: 50 °C
Reaction time: 18 h
Yield: 80.8 %

Procedure:
In a 50-ml autoclave, 1.0 g of 5-acetylamino-7 -fluoro-8-methyl-l-tetralone and 10 ml of methanol were charged. To the resulting mixture, 0.5 g of 10% palladium-carbon was added. The hydrogen pressure was increased to 40 kg/cm2 at room temperature, under which the resulting mixture was stirred at 50° C. for 18 hours. After the completion of the reaction, the reaction mixture was filtered. The catalyst so obtained was washed with chloroform and then the filtrate was concentrated under reduced pressure. To the residue, isopropyl ether was added. The crystals so precipitated were collected by filtration, followed by drying under reduced pressure, whereby 0.76 g of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:22]=1[C:9]1([CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)[N:8]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[C:7]2=[S:32].[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:22]=1[C:9]1([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[N:8]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[C:7]2=[S:32].[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]
Reactant: COc1ccc(CN2C(=S)c3cccc(Cl)c3C23CCN(C(=O)OC(C)(C)C)CC3)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN2C(=S)c3cccc(Cl)c3C23CCNCC3)cc1
Reaction time: 0.5 h

Procedure:
Tert-butyl 7-chloro-2-(4-methoxybenzyl)-3-thioxospiro[isoindoline-1,4′-piperidine]-1′-carboxylate (52 mg, 0.11 mmol) was dissolved in neat TFA (−2 mL): After 0.5 h LC-MS showed removal of the boc group. The mixture was evaporated to afford crude 7-chloro-2-(4-methoxybenzyl)spiro[isoindoline-1,4′-piperidine]-3-thione as its TFA salt which was used without purification.
Reaction SMILES: [H-].[Na+].CI.[CH2:5]([S:7][C:8]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:9]=1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=1)=[O:11])[CH3:6].[CH2:31]1COCC1>O>[CH2:5]([S:7][C:8]1[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=[CH:23][C:9]=1[C:10]([N:12]([CH3:31])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][N:14]=1)=[O:11])[CH3:6]
Reactant: C1CCOC1
Reactant: CCSc1cc(C(F)(F)F)ccc1C(=O)Nc1ccc(C(F)(F)F)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCSc1cc(C(F)(F)F)ccc1C(=O)N(C)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.12 g of 60% sodium hydride (oil-based) and 0.56 g of methyl iodide were added to a mixture of 0.78 g of 2-ethylsulfanyl-4-trifluoromethyl-N-(5-trifluoromethyl-pyri din-2-yl)-benzamide and 5 mL of THF, and the mixture was stirred at room temperature for 2 hours. 1 g of methyl iodide was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. 1 g of methyl iodide was further added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.59 g of 2-ethylsulfanyl-N-methyl-4-trifluoromethyl-N-(5-trifluoromethyl-pyridin-2-yl)-benzamide (hereinafter, referred to as Compound of Present Invention 2).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[N:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[N:10]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>O1CCOCC1.[Ni]>[NH2:1][C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[N:10]=[C:11]([CH3:16])[CH:12]=[C:13]([CH3:15])[N:14]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: Cc1cc(C)nc(Oc2ccc([N+](=O)[O-])cc2)n1
Agent: [Ni]
Solvent: C1COCCO1
Product: Cc1cc(C)nc(Oc2ccc(N)cc2)n1
Yield: 94.8 %

Procedure:
24.5 g (0.1 mole) of 2-(4-nitro-phenoxy)-4,6-dimethyl-pyrimidine were dissolved in 150 ml of dioxane and subjected to exhaustive hydrogenation with hydrogen in the presence of Raney nickel under a pressure of 50 bar at a temperature between 20° and 50° C. The catalyst was then filtered off with suction and the filtrate was evaporated under reduced pressure. 20.4 g (95% of theory) of 2-(4-amino-phenoxy)-4,6-dimethylpyrimidine were obtained in the form of a solid substance.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH3:10][N:11]1[C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]([CH3:19])=[N:12]1>>[CH3:10][N:11]1[C:15]([C:16]([OH:18])=[O:17])=[C:14]([N+:6]([O-:9])=[O:7])[C:13]([CH3:19])=[N:12]1
Reactant: Cc1cc(C(=O)O)n(C)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1nn(C)c(C(=O)O)c1[N+](=O)[O-]

Procedure:
One-hundred twelve g concentrated sulfuric acid is added to 42 ml 90% nitric acid at 70°-80° C., 39 g of 1,3-dimethylpyrazole-5-carboxylic acid is added in portions over one hour such that the temperature does not go over 90° C. After 2.5 hours the reaction mixture is cooled and poured over ice. The resulting percipitate was filtered, dried, and recrystallized in ethanol, mp 141°-142° C.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[C:29]([F:36])[CH:30]=[CH:31][CH:32]=2)[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[C:29]([F:36])[CH:30]=[CH:31][CH:32]=5)[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Fc1cccc2ccc(Cl)nc12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ccc5cccc(F)c5n4)cc3CC[C@@H]12
Yield: 50.5 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-8-fluoroquinoline (84 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 78 mg (50%) of the title compound as an amorphous foam. FDMS: m/e=406. α[D]589 =+63.29 (c=0.56, chloroform).
Reaction SMILES: FC(F)(F)C(O)=O.[SH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1.O[CH:20]([C:27]1[C:32]([O:33][CH3:34])=[CH:31][C:30]([O:35][CH3:36])=[CH:29][C:28]=1[O:37][CH3:38])[CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>>[CH3:38][O:37][C:28]1[CH:29]=[C:30]([O:35][CH3:36])[CH:31]=[C:32]([O:33][CH3:34])[C:27]=1[CH:20]([S:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=1)[CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: COc1cc(OC)c(C(O)Cn2ccnc2)c(OC)c1
Reactant: COC(=O)c1ccc(S)cc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2c(OC)cc(OC)cc2OC)cc1
Reaction time: 2 h
Yield: 94.3 %

Procedure:
13.5 ml of trifluoroacetic acid were added, whilst ice-cooling, to a mixture of 940 mg of methyl 4-mercaptobenzoate and 1.04 g of 1-[2-hydroxy-2-(2,4,6-trimethoxyphenyl)ethyl]imidazole, and the resulting mixture was stirred at a temperature between 0° and 5° C. for 2 hours. The reaction mixture was then treated and purified in a similar manner to that described in Example 13 to give 1.51 g of the title compound as a colorless oil.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N+:27]([C:30]1[CH:66]=[CH:65][C:33]([CH2:34][O:35][C:36]([N:38]2[CH2:42][CH2:41][C@H:40]([S:43][C:44]3[N:45]=[CH:46][N:47]4[CH:51]=[C:50]([Sn](CCCC)(CCCC)CCCC)[S:49][C:48]=34)[CH2:39]2)=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])=[C:8]([C:50]3[S:49][C:48]4=[C:44]([S:43][C@H:40]5[CH2:41][CH2:42][N:38]([C:36]([O:35][CH2:34][C:33]6[CH:65]=[CH:66][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=6)=[O:37])[CH2:39]5)[N:45]=[CH:46][N:47]4[CH:51]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(S[C@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(S[C@H]5CCN(C(=O)OCc6ccc([N+](=O)[O-])cc6)C5)c4s3)[C@H](C)[C@H]12
Yield: 46 %

Procedure:
The procedure of Example 1a) was repeated, except that 143 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 287 mg of 7-[(3S)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-yl]thio-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds. Thus, 136 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[(3S)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-yl]thioimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[CH:24]=[CH:23][C:19]3[O:20][CH2:21][O:22][C:18]=3[CH:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:20]1[C:19]2[CH:23]=[CH:24][C:16]([C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:15])=[CH:17][C:18]=2[O:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc3c(c2)OCO3)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)OCO2)C1CCNCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90 %

Procedure:
To a solution of 4-(benzo[1,3]dioxole-5-carbonyl)-piperidine-1-carboxylic acid tert-butyl ester (0.50 g, 1.5 mmol) in 10 mL of DCM, was added 2 mL of TFA. The reaction mixture was stirred at ambient temperature for 2.5 hours, then solvent was removed by reduced pressure to yield the title product (0.35 g, 1.35 mmol). MS (ESI) m/z 234.9 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.11 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.CC(C)([O-])C.[K+].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1[CH3:26].Cl>CS(C)=O.O>[CH3:1][O:2][C:3]1[C:4](=[O:9])[N:5]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=2[CH3:26])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc[nH]c1=O
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cccn(-c2ccc([N+](=O)[O-])cc2C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
28.5 g (228 mol) of 3-methoxypyridin-2(1H)-one are dissolved in 850 ml of dimethyl sulphoxide, and 31 g (273 mmol) of potassium tert-butoxide are added at RT. The suspension is stirred at RT for 30 min, and 35 g (228 mmol) of 1-fluoro-2-methyl-4-nitrobenzene are then added, and the reaction solution is heated at 80° C. for 20 h. The solution is then carefully diluted with 1 l of water and adjusted to pH 1-2 using 1N hydrochloric acid. The solution is extracted repeatedly with dichloromethane. The combined organic extracts are washed with water and saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated under reduced pressure. The solid obtained is washed with a little tert-butyl methyl ether, filtered off and dried under reduced pressure. This gives 42.8 g (72% of theory) of the desired compound.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O:24]1[CH2:29][CH2:28][N:27]([C:30](Cl)=[O:31])[CH2:26][CH2:25]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH:22][C:30]([N:27]1[CH2:28][CH2:29][O:24][CH2:25][CH2:26]1)=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: O=C(Cl)N1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CNC(=O)N1CCOCC1)OCc1ccccc1

Procedure:
Analogously to Example 7b), 7.69 g (22.8 mmol) of glycine-benzyl ester 4-toluenesulfonate and 2.8 g (19 mmol) of (morpholinocarbonyl)chloride in 118 ml of methylene chloride and 9 ml (53 mmol) of N-ethyldiisopropylamine are reacted for 18 h. The title compound is obtained in pure form after extraction with methylene chloride and digestion with hexane: tRet (I)=11.6 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH2:22]([O:29][CH2:30][CH2:31][CH2:32][CH2:33]O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OCCCCOCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(OCCCCOCc2ccccc2)c1

Procedure:
Mitsunobu reaction of phenol 58 with 4-benzyloxybutanol gave 2-(3-(3-(4-(benzyloxy)butoxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (0.830 g, 54%): 1H NMR (400 MHz, CDCl3) δ 7.81-7.85 (m, 2H), 7.70-7.74 (m, 2H), 7.28-7.35 (m, 5H), 7.10-7.16 (m, 1H), 6.77 (d, J=8.2 Hz, 1H), 6.73 (s, 1H), 6.65 (dd, J=7.6, 2.4 Hz, 1H), 4.52 (s, 2H), 3.94 (t, J=6.0 Hz, 2H), 3.74 (t, J=7.2 Hz, 2H), 3.55 (t, J=6.4 Hz, 2H), 2.63 (t, J=7.6 Hz, 2H), 2.00-2.08 (m, 2H), 1.82-1.90 (m, 2H), 1.76-1.81 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:6]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[N:5]=[C:4]([NH2:19])[N:3]=1.[CH2:20]([OH:23])[CH:21]=[CH2:22]>>[CH2:20]([O:23][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:6]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[N:5]=[C:4]([NH2:19])[N:3]=1)[CH:21]=[CH2:22]
Reactant: Nc1nc(Cl)c(-c2ccncc2)c(-c2ccco2)n1
Reactant: C=CCO
Product: C=CCOc1nc(N)nc(-c2ccco2)c1-c1ccncc1

Procedure:
The title compound was synthesized in a similar manner to Example 3 using 4-chloro-6-(2-furyl)-5-(4-pyridyl)-2-pyrimidinylamine and allyl alcohol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]([CH3:19])[CH:12]=1)=[C:5]2[CH3:20].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]([CH3:19])[CH:12]=1)=[C:5]2[CH3:20])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cc(-c2[nH]c3ccc(O)cc3c2C)cc(C)c1O
Reactant: BrCc1ccccc1
Product: Cc1cc(-c2[nH]c3ccc(OCc4ccccc4)cc3c2C)cc(C)c1O

Procedure:
5-Hydroxy-2-(4-hydroxy-3,5-dimethylphenyl)-3-methylindole and benzyl bromide were treated in the same way as in Example 35 to obtain 5-benzyloxy-2-(4-hydroxy-3,5-dimethylphenyl)-3-methylindole.