Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1F.[NH2:17][C:18]1[C:19]([CH3:24])=[CH:20][CH:21]=[CH:22][CH:23]=1>C(OCC)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24]
Reactant: Cc1ccccc1N
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1F
Solvent: CCOCC
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1Nc1ccccc1C
Temperature: 25 °C
Reaction time: 36 h
Yield: 68 %

Procedure:
4-Amino-2,3-difluoro-5-nitro-benzoic acid methyl ester 4 (12.0 g, 51.7 mmol) is suspended in xylenes (60 mL) and ortho-toluidine is added (55.2 mL, 518 mmol). The reaction mixture is heated to reflux with stirring under a nitrogen atmosphere. After 36 hours, the reaction mixture is cooled to room temperature, diluted with diethyl ether and washed with 10% aqueous HCl solution. The aqueous washing are extracted with diethyl ether. The combined organic extracts are concentrated under reduced pressure. The residue is dissolved in methylene chloride and filtered through silica gel in a fritted funnel, rising with methylene chloride. Three fractions are recovered. The first (2 liter) is nearly clean by HPLC. The second (1 liter) and third (1 liter) fraction are only partially pure. The first fraction is concentrated under reduced pressure and triturated with diethyl ether to give 11.2 g (68%) of clean desired product as a bright yellow solid: MS APCI (−) m/z 318 (M−1) detected.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[C:8]1[CH:14]=[C:15]([O:18][CH2:19][C@@H:20]([N:25]3[C:33](=[O:34])[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26]3=[O:35])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:16]=[CH:17][C:7]2=1.C1C(=O)N([Br:43])C(=O)C1>C(#N)C>[Br:43][C:16]1[C:15]([O:18][CH2:19][C@@H:20]([N:25]2[C:26](=[O:35])[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]2=[O:34])[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:14][C:8]2[N:9]([CH3:13])[C:10](=[O:12])[C:11]3[C:6]([C:7]=2[CH:17]=1)=[CH:5][CH:4]=[N:3][C:2]=3[CH3:1]
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)N3C(=O)c4ccccc4C3=O)ccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)N3C(=O)c4ccccc4C3=O)c(Br)cc21
Temperature: 80 °C
Yield: 88.2 %

Procedure:
To a solution of (S)-2-(1-((4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)isoindoline-1,3-dione (1 g, 1.917 mmol) in acetonitrile (20 mL) was added NBS (0.341 g, 1.917 mmol) and the solution heated to 80° C. overnight to afford (S)-2-(1-((9-bromo-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)isoindoline-1,3-dione (1.2 g, 1.69 mmol, 88% crude yield) as brown solid. The material was carried forward without further purification. LC/MS (ESI) m/e 548.0 [(M+H)+, calcd for C28H27BrN3O4 548.1; LC/MS retention time (method D): tR=0.76 min.
Reaction SMILES: [C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)(Cl)Cl>[C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][O:21][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:18][CH:19]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)C(=CNc1ccc(CO)cc1)C(=O)OCC
Reactant: O=C(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCC(=O)C(=CNc1ccc(COC(=O)c2ccccc2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
A solution of ethyl 2-butyryl-3-(4-hydroxymethylphenylamino)acrylate (49.5 g, 0.17 mol) and pyridine (50 ml) in chloroform (250 ml) was stirred at 0°-5° (ice-bath). Benzoyl chloride (22 ml, 0.19 mol) in chloroform (250 ml) was added dropwise keeping the reaction temperature below 10° C. Cooling was removed and the mixture was stirred overnight at room temperature. The mixture was washed with 2M HCl, sodium hydrogen carbonate solution and brine, dried (anhyd. MgSO4), filtered and evaporated to an oil which crystallized on standing. The product was slurried with petroleum ether, filtered off and washed with petroleum ether to give ethyl 2-butyryl-3-(4-benzoyloxymethylphenylamino)acrylate as white crystals (61.8 g, 92%), m.p. 73°-5° C.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C@@H:12]1[CH2:17][CH2:18][CH:19]([OH:32])[C:20]1[O:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])=[CH:23][CH:24]=1)C.[OH-].[Na+].Cl.C(OCC)(=O)C>CO>[OH:32][CH:19]([C:20]1[O:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])=[CH:23][CH:24]=1)[CH2:18][CH2:17][C@H:12]1[CH2:13][CH2:14][C:15](=[O:16])[N:11]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:33])=[O:3]
Reactant: CCOC(=O)CCCCCCN1C(=O)CC[C@@H]1CCC(O)c1ccc(-c2ccccc2C)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1ccc(C(O)CC[C@H]2CCC(=O)N2CCCCCCC(=O)O)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
The ester (54 mg) was dissolved in methanol (3 mL) and treated with 5 M aqueous solution of sodium hydroxide (0.5 mL) and stirred at ambient temperature for 1 hour. 7-{(S)-2-[3-hydroxy-3-(5-o-tolyl-furan-2-yl)-propyl]-5-oxo-pyrrolidin-1-yl}-heptanoic acid (54) (71) (45 mg, 0.10 mmol) resulted upon treatment with 1 M aqueous hydrochloric acid and extraction with ethyl acetate: MS: 428 [(M+H)+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]=[C:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:2].[N+:13]([CH3:16])([O-:15])=[O:14].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1([CH2:16][N+:13]([O-:15])=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)C=C1CCCCC1
Reactant: C[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC1(C[N+](=O)[O-])CCCCC1

Procedure:
14.8 g (0.088 mol) of the cyclohexylideneacetic acid ethyl ester produced according to 1.1 were dissolved in 50 ml of tetrahydrofuran, 7.11 ml (0.132 mol) of nitromethane and 88 ml of tetrabutylammonium fluoride (1 molar in tetrahydrofuran) were added under a nitrogen atmosphere and refluxed for 20 hours. After cooling, the mixture was diluted with 50 ml of water and extracted three times with dieethyl ether. The organic phase was washed with 10 wt. % aqueous potassium hydrogensulfate solution and then washed with water, dried over magnesium sulfate and evaporated. (1-Nitromethylcyclohexyl)acetic acid ethyl ester was obtained as an orange-yellow oily liquid. The yield amounted to 19.8 g (98% of theoretical).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:15].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:15])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc2cc(F)ccc2n1CCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2cc(F)ccc2n1CCCOS(C)(=O)=O
Temperature: 25 °C

Procedure:
To a stirred, cold mixture (-25° C.) of 1-(3-hydroxy-propyl)-2-methyl-5-fluoro-1H -benzimidazole (1.99 gm), triethylamine (1.47 ml) and methylenechloride (40 ml) is dropwise added a solution of methanesulfonylchloride (0.96 ml) in 15 ml CH2Cl2. After complete addition, the mixture is warmed to ambient temperature, extracted with water (2×20 ml), dried over Na2SO4 and concentrated to a thick brown oil consisting of crude 1-(3-methanesulfonyloxy-propyl)-2-methyl-5-fluoro-1H -benzimidazole.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2=[CH:9][S:10][CH:11]=[C:4]2[S:3]1(=[O:13])=[O:12].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1.C(N(CC)CC)C.Cl>CS(C)=O>[OH:8][C:7]1[N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[C:4]2[C:5](=[CH:9][S:10][CH:11]=2)[C:6]=1[C:22](=[O:23])[NH:21][C:18]1[CH:19]=[CH:20][C:15]([Br:14])=[CH:16][CH:17]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: CN1C(=O)Cc2cscc2S1(=O)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1C(O)=C(C(=O)Nc2ccc(Br)cc2)c2cscc2S1(=O)=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
4 g (18.4 mmol) of 3,4-dihydro-2-methyl-3-oxo-2H-thieno[3,4-e]-1,2-thiazine 1,1-dioxide are stirred at room temperature under nitrogen for 24 hours with 3.6 g (18.4 mmol) of p-bromophenylisocyanate and 1.86 g (18.4 mmol) of triethylamine in 40 ml of absolute dimethylsulfoxide. Thereafter, the mixture is poured into 150 ml of 2-N hydrochloric acid and 100 g of ice and stirred for 20 minutes. The separated precipitate is filtered off under suction and washed neutral with water. The precipitate is taken up in 500 ml of methylene chloride, the turbid solution is dried over sodium sulfate, stirred with 1 g of active carbon and filtered. The filtrate is extracted with four 250 ml portions of semi-saturated sodium carbonate solution, each of the aqueous phases being re-extracted with a small amount of methylene chloride. The combined aqueous phases are acidified to pH 1 with concentrated hydrochloric acid. The separated product is extracted with three 300 ml portions of methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated. The residual oil is covered with 5 ml of ethanol, the product separating out after standing for several days. The crystals are filtered off under suction, digested with a small amount of ethanol and dried. There is obtained 3-hydroxy-2-methyl-4-(4-bromophenylcarbamoyl)-2H-thieno[3,4-e]-1,2-thiazine 1,1-dioxide of melting point 138°-140° C.
Reaction SMILES: [Li]CCCC.[C:6]1([CH3:20])[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19].CON(C)[C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]1)=[O:25]>C1COCC1>[C:35]([O:34][C:32]([N:28]1[CH2:29][CH2:30][CH2:31][C@@H:26]([C:24](=[O:25])[C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[CH3:20])[C:14]=2[F:19])[CH2:27]1)=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Cc1ccccc1Oc1ccccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccccc1Oc1cccc(C(=O)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 2.0 mL of 2.0 M n-BuLi (2.0 mL, 4.0 mmol) was added dropwise to a solution of 1-(o-tolyloxy)-2-fluorobenzene (0.7009 g, 3.5 mmol) in THF (15 mL); the internal temperature was maintained below −70° C. during the addition. A pale, yellow slurry resulted. Confirmation of proton abstraction was confirmed by quenching an aliquot on solid 12. A solution of (R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate (1.1159 g, 4.1 mmol) in THF (15 mL) was added dropwise. The reaction was permitted to warm to rt and stirred at for 12 h. The reaction was quenched at 0° C. with satd aq NH4Cl and extracted with Et2O. The Et2O extracts were washed with aq NH4Cl and brine and dried over Na2SO4. Removal of the solvent left crude (3R)-1-tert-butoxycarbonyl-3-(2-fluoro-3-(o-tolyloxy)benzoyl)piperidine (1.79 g, ˜80% pure, quantitative) which was used directly without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[CH3:32][O:33][C:34]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[CH:36][C:35]=1[OH:49]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C@@H:18]2[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28])[CH2:20][CH2:19]2)=[CH:3][C:2]([C:38]2[CH:37]=[CH:36][C:35]([OH:49])=[C:34]([O:33][CH3:32])[CH:39]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c3c2)ccc1O

Procedure:
Following general procedure F, tert-butyl cis-4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]cyclohexylcarbamate (40 mg, 0.082 mmol) was reacted with 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (31 mg, 0.124 mmol) to afford the crude product (43 mg) as a yellow solid: ESI MS m/z 532 [C31H37N3O5+H]+.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:16])[CH2:12][C:13]([CH3:15])=[O:14])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:17]Br>C(O)(=O)C>[C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:16])[CH2:12][C:13]([CH2:15][Br:17])=[O:14])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrBr
Reactant: CC(=O)CC(=O)Nc1nnc(C(C)(C)C)s1
Solvent: CC(=O)O
Product: CC(C)(C)c1nnc(NC(=O)CC(=O)CBr)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.6 %

Procedure:
A reaction flask was charged with 14.3 g (0.059 mole) of N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)acetoacetamide dissolved in 230 ml of acetic acid. With efficient stirring, there was added dropwise 9.4 g (0.059 mole) of bromine dissolved in 55 ml of acetic acid while controlling the temperature at 20°-25°. The reaction solution was allowed to stir overnight at ambient temperature. On the following morning a sample of the precipitated solids was withdrawn. By N.M.R. analysis, the material was determined to be the corresponding 2-bromoacetoacetamide, m.p. 128°-30°. The reaction mixture was heated at 75°-80° for twelve hours. The solution was cooled to 20° and the precipitated solid was collected on a vacuum filter. After washing the filter cake with water, the material was stirred with aqueous sodium bicarbonate. The product was isolated and dried. There was obtained 8.8 g (46.6%) of authentic N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-4-bromoacetoacetamide, m.p. 144°-46°. N.M.R. (CDCl3) ∂ 1.4 [C(CH3)3 ], 4.4 (CH2), 6.3 (CH, enol).
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].[C:9]([CH2:11][C@@H:12]([OH:21])[CH2:13][C:14](OCCCC)=[O:15])#[N:10].C([N-]C(C)C)(C)C.[Li+].Cl>O1CCCC1.C(OCC)(=O)C>[C:9]([CH2:11][C@@H:12]([OH:21])[CH2:13][C:14](=[O:15])[CH2:2][C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3])#[N:10]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCCCOC(=O)C[C@H](O)CC#N
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)C[C@H](O)CC#N
Reaction time: 1.5 h

Procedure:
To a stirred -50° C. solution of tertiary-butyl acetate (60 mL, 0.44 mol), (R)-4-cyano-3-hydroxybutyric acid, n-butyl ester (20 g, 0.11 mol) and 150 mL tetrahydrofuran is added lithium diisopropylamide (300 mL of 1.5 M) in tetrahydrofuran over 15 minutes and the mixture is stirred at -45° C. to -50° C. for 90 minutes. To this solution is added 700 mL of 5% aqueous hydrochloric acid solution along with 300 mL of ethyl acetate. The aqueous layer is separated and the remaining top layer washed with aqueous sodium chloride solution. The organic layer is then concentrated in vacuo to afford crude (5R)-1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxo-hexanoate which is not isolated, and is carried on to (4R-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl -1,3-dioxane-4-acetate as described in Example 2. TLC: Rf =0.15 (1:1 ethyl acetate: hexanes) on a Kieselgel 60 F254 0.254 mm silica thin layer plate.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([CH2:35][CH2:36][CH3:37])[N:11]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[NH:34][N:33]=[N:32][N:31]=4)=[CH:20][CH:19]=3)[C:12]=2[C:13]([O:15]C)=[O:14])[C:4]([CH3:7])=[CH:5][CH:6]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([CH2:35][CH2:36][CH3:37])[N:11]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[NH:31][N:32]=[N:33][N:34]=4)=[CH:20][CH:19]=3)[C:12]=2[C:13]([OH:15])=[O:14])[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: CCCc1nc(-n2c(C)ccc2C)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1nc(-n2c(C)ccc2C)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A mixture of methyl 4-(2,5-dimethyl-1H-pyrrol-1-yl)-2-propyl-1-[(2'-(1H-tetrazol-5-yl)biphen-4-yl)methyl]-1H-imidazole-5-carboxylate 9 (Example 70) in methanol (5 mL) containing 5 mL of 2.5N NaOH was heated under reflux for 3 hours. The reaction mixture was cooled, acidified with 10% citric acid to pH 4, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4 and the solvent removed under reduced pressure. The acid was further purified by flash chromatography on silica gel eluting with 5% methanol in ethyl acetate to furnish 0.2 g for the title compound 4-(2,5-dimethyl-1H-pyrrol-1-yl)-2-propyl-1-[(2'-(1H-tetrazol-5-yl)biphen-4-yl)methyl]-1H-imidazole-5-carboxylic acid. MS (FAB, thioglycerol) 482 (M+).
Reaction SMILES: [F:1][C:2]1[CH:24]=[N:23][CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1O)[C:12]([F:18])([F:17])[O:11][C:10]2([F:20])[F:19])=[O:5].O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[F:20][C:10]1([F:19])[C:9]2[C:13](=[CH:14][C:15]3[O:5][C:4]([C:3]4[CH:21]=[CH:22][N:23]=[CH:24][C:2]=4[F:1])=[N:6][C:7]=3[CH:8]=2)[C:12]([F:17])([F:18])[O:11]1
Reactant: O=C(Nc1cc2c(cc1O)C(F)(F)OC2(F)F)c1ccncc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Fc1cnccc1-c1nc2cc3c(cc2o1)C(F)(F)OC3(F)F
Reaction time: 1 h
Yield: 78.8 %

Procedure:
To a mixture of 1.46 g of 3-fluoro-N-(1,1,3,3-tetrafluoro-6-hydroxy-1,3-dihydroisobenzofuran-5-yl)isonicotinamide, 10 ml of tetrahydrofuran and 2.02 g of triphenylphosphine, 0.90 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature, and the reaction mixture was stirred for one hour. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.09 g of 5,5,7,7-tetrafluoro-2-(3-fluoropyridin-4-yl)-5,7-dihydro-furo[3′,4′:4,5]benzo[1,2-d]oxazole (hereinafter, referred to as “active compound 87”).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][S:5]([NH:8][C:9]1[C:10](=[O:20])[N:11]([CH2:16][C:17](O)=[O:18])[C:12]([CH3:15])=[CH:13][CH:14]=1)(=[O:7])=[O:6].Cl.Cl.[N:28]1[NH:29][CH:30]=[C:31]2[C:36]=1[CH2:35][CH2:34][CH:33]([CH2:37][NH2:38])[CH2:32]2>>[Cl:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][S:5]([NH:8][C:9]1[C:10](=[O:20])[N:11]([CH2:16][C:17]([NH:38][CH2:37][CH:33]2[CH2:34][CH2:35][C:36]3[C:31](=[CH:30][NH:29][N:28]=3)[CH2:32]2)=[O:18])[C:12]([CH3:15])=[CH:13][CH:14]=1)(=[O:7])=[O:6]
Reactant: Cc1ccc(NS(=O)(=O)Cc2ccc(F)cc2Cl)c(=O)n1CC(=O)O
Reactant: NCC1CCc2n[nH]cc2C1
Agent: Cl
Product: Cc1ccc(NS(=O)(=O)Cc2ccc(F)cc2Cl)c(=O)n1CC(=O)NCC1CCc2n[nH]cc2C1

Procedure:
The title compound was prepared from 2-[3-{[(2-chloro-4-fluorobenzyl)sulfonyl]amino}-6-methyl-2-oxo-1(2H)pyridinyl]acetic acid and 4,5,6,7-tetrahydro-2H-indazol-5-ylmethanamine dihydrochloride using the procedure of EXAMPLE 1 (STEP 6), and was obtained as a white solid compound.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:36]=[CH:35][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([C@@H:20]3[CH2:24][CH2:23][CH2:22][N:21]3[S:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:54][C:55]1[CH:60]=[CH:59][C:58]([O:61][CH2:62][CH:63]2[CH2:65][O:64]2)=[CH:57][CH:56]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[F:34][C:31]1[CH:30]=[CH:29][C:28]([S:25]([N:21]2[CH2:22][CH2:23][CH2:24][C@H:20]2[C:18]([N:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:10]3[CH:35]=[CH:36][C:7]([CH2:6][CH2:5][NH:4][CH2:65][C@H:63]([OH:64])[CH2:62][O:61][C:58]4[CH:59]=[CH:60][C:55]([OH:54])=[CH:56][CH:57]=4)=[CH:8][CH:9]=3)[CH2:13][CH2:14]2)=[O:19])(=[O:26])=[O:27])=[CH:33][CH:32]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1ccc(NC2CCN(C(=O)[C@@H]3CCCN3S(=O)(=O)c3ccc(F)cc3)CC2)cc1
Solvent: O=CO
Product: O=C([C@@H]1CCCN1S(=O)(=O)c1ccc(F)cc1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 21.8 %

Procedure:
{4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}{(2S)-1-[(4-fluorophenyl)sulfonyl]-pyrrolidinyl}methanone formate (0.30 g, 0.574 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.232 g, 0.574 mmol) according to Procedure G to give the title compound (0.11 g, 0.125 mmol).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH3:19])[N:13]=2)[CH:3]=1.[NH2:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>CN1CCCC1=O>[C:30]([O:29][C:28](=[O:34])[NH:27][C@H:22]1[CH2:23][CH2:24][CH2:25][CH2:26][C@H:21]1[NH:20][C:2]1[N:7]=[N:6][C:5]([C:8](=[O:9])[NH2:10])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH3:19])[N:13]=2)[CH:3]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: CCc1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Solvent: CN1CCCC1=O
Product: CCc1cccc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)n1
Temperature: 150 °C
Reaction time: 16 h
Yield: 46.7 %

Procedure:
6-Chloro-4-(6-ethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide (218 mg, 0.785 mmol), and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (336 mg, 1.57 mmol) were dissolved in N-methylpyrrolidinone (4 mL) and heated at 150° C. for 40 h. Additional tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (168 mg, 0.78 mmol) was added and the heating continued for 16 h more. The reaction mixture was cooled and concentrated in vacuo, then diluted with water, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. Purification by chromatography (silica, 0 to 5% methanol in dichloromethane) gave {(1S,2R)-2-[6-carbamoyl-5-(6-ethyl-pyridin-2-ylamino)-pyridazin-3-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (167 mg, 46%) as a light brown amorphous residue. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 11.44 (s, 1H) 8.47 (s, 1H) 7.97-8.03 (m, 1H) 7.52 (t, J=7.6 Hz, 1H) 7.22-7.26 (m, 1H) 6.78 (d, J=7.2 Hz, 1H) 6.70 (d, J=7.9 Hz, 1H) 5.38-5.43 (m, 1H) 4.92-5.00 (m, 1H) 3.97-4.08 (m, 2H) 2.80 (q, J=7.6 Hz, 2H) 1.58-1.96 (m, 8H) 1.41 (s, 9H) 1.31-1.39 (m, 3H); LCMS (EI/CI) m/z: 456 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH2:7][C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:37]=[CH:36][C:30]([O:31][CH2:32][C:33](O)=[O:34])=[CH:29][CH:28]=1>>[NH2:23][C:12]1[N:13]=[C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:33](=[O:34])[CH2:32][O:31][C:30]3[CH:36]=[CH:37][C:27]([Cl:26])=[CH:28][CH:29]=3)[CH2:21][CH2:22]2)[C:15]2[N:16]=[C:8]([CH2:7][CH2:6][C:5]3[CH:24]=[CH:25][C:2]([Br:1])=[CH:3][CH:4]=3)[S:9][C:10]=2[N:11]=1
Reactant: O=C(O)COc1ccc(Cl)cc1
Reactant: Nc1nc(N2CCNCC2)c2nc(CCc3ccc(Br)cc3)sc2n1
Product: Nc1nc(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)c2nc(CCc3ccc(Br)cc3)sc2n1
Yield: 29 %

Procedure:
This compound was prepared from 2-(4-bromophenethyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-chlorophenoxyacetic acid in a yield of 29%, according to the procedure for the synthesis of example 50.