Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH:13]([F:15])[CH2:12][N:11]3[N:16]=[C:17]([NH2:19])[N:18]=[C:10]23)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[N:25]=[C:24]([N:26]2[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]2)[S:23][N:22]=1.[BH4-].[Na+].C(O)C>ClC(Cl)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH:13]([F:15])[CH2:12][N:11]3[N:16]=[C:17]([NH:19][CH:29]4[CH2:28][CH2:27][N:26]([C:24]5[S:23][N:22]=[C:21]([CH3:20])[N:25]=5)[CH2:31][CH2:30]4)[N:18]=[C:10]23)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Nc1nc2n(n1)CC(F)CC2c1ccc(F)c(F)c1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCO
Solvent: CC(Cl)Cl
Product: Cc1nsc(N2CCC(Nc3nc4n(n3)CC(F)CC4c3ccc(F)c(F)c3)CC2)n1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
A solution of 8-(3,4-difluorophenyl)-6-fluoro-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine (74 mg, 276 μmol), 1-(3-methyl-1,2,4-thiadiazol-5-yl)piperidin-4-one (82 mg, 414 μmol) and titanium(IV) isopropoxide (240 mg, 253 μL, 828 μmol) dissolved in dichloroethane (6 mL) was heated to 85° C. for 12 hours. Further 1-(3-methyl-1,2,4-thiadiazol-5-yl)piperidin-4-one (54 mg, 276 μmol) was added and stirred at 85° C. for another two hours. The reaction mixture was cooled to 50° C., sodium borohydride (41.7 mg, 1.1 mmol) and ethanol (3 mL) were added and stirred at 50° C. for one hour. The solvent was evaporated, the residue extracted with 2 N Na2CO3 solution and ethyl acetate. The organic layers were combined, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, 70 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane) and then by preparative HPLC. The title compound was obtained as light green foam (37.1 mg, 30%).
Reaction SMILES: Br[C:2]([CH3:17])([CH3:16])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[OH:15])=[O:4].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:16][C:2]1([CH3:17])[C:3](=[O:4])[NH:5][C:6]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=2[O:15]1
Reactant: CC(C)(Br)C(=O)Nc1cc([N+](=O)[O-])ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2NC1=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
2-Bromo-N-(2-hydroxy-5-nitro-phenyl)-2-methyl-propionamide was mixed with K2CO3 in 20 mL of DMF and stirred overnight at 50° C. The reaction mixture was poured into ice H2O. The precipitate was collected by filtration and washed with H2O. The crude compound was recrystallized from EtOH.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:32]=[CH:31][C:9]([O:10][C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4([C:28]#[N:29])[CH2:27][CH2:26]4)[CH:20]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:8][CH:7]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:7]2[CH:8]=[C:9]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]5([C:28]#[N:29])[CH2:26][CH2:27]5)[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc(N)cc4)c3)c2)CC1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(N)sc5c4)c3)c2)CC1
Yield: 69.3 %

Procedure:
Using potassium thiocyanate (5.52 g, 56.8 mmol), acetic acid (380 mL), N-[3-(4-aminophenoxy)phenyl]-3-(1-cyanocyclopropyl)benzamide (5.25 g), and bromine (3.15 g, 19.7 mmol) as starting materials, and in the same manner as in Example A12(iv), the title compound (4.2 g, total of 2 steps 78%) was obtained as a yellow amorphous substance. The obtained compound was used in the next reaction without a further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:3]=1.Cl.Cl[C:21]1C=CC(C(O)=O)=C(NC2C=CC(OC)=CC=2)C=1.S(OC)(OC)(=O)=O.ClC1C=CC(C(OC)=O)=C(NC2C=CC(OC)=CC=2)C=1.B(Br)(Br)Br>CO>[CH3:21][C:3]1[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[C:5]([CH:9]=[CH:10][C:2]=1[Cl:1])[C:6]([OH:8])=[O:7]
Reactant: COc1ccc(Nc2cc(Cl)ccc2C(=O)O)cc1
Reactant: O=C(O)c1ccc(Cl)cc1Nc1ccc(O)cc1
Agent: BrB(Br)Br
Agent: COC(=O)c1ccc(Cl)cc1Nc1ccc(OC)cc1
Agent: Cl
Solvent: COS(=O)(=O)OC
Solvent: CO
Product: Cc1c(Cl)ccc(C(=O)O)c1Nc1ccc(O)cc1

Procedure:
[I; R=4-Cl, R' and R"=H, Alk=CH3, OH at 4-position] is obtainable by esterification of 4-chloro-2-(4-hydroxyphenylamino)benzoic acid with methanol and hydrochloric acid; or by esterification of 4-chloro-2-(4-methoxyphenylamino)benzoic acid with dimethyl sulfate, followed by de-etherification of the resulting methyl 4-chloro-2-(4-methoxyphenylamino)benzoate with boron tribromide.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][CH:8]=[CH:9][CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:4][N:3]=1.[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26]O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26][O:1][C:2]1[C:6]([CH2:7][CH:8]=[CH:9][CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:4][N:3]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: CC=CCc1c(O)noc1-c1ccccc1
Product: CC=CCc1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccccc1
Yield: 81.6 %

Procedure:
3-Hydroxy-4-(2-butenyl)-5-phenylisoxazole (215 mg) and 2-(N-tert-butoxycarbonylamino)ethanol (193 mg) were subjected to reaction and post-treatment in a similar manner to that described in Example 1(a) to obtain the title compound (292 mg, 82%) as colorless crystals.
Reaction SMILES: CC1(C)C[C@@H]1C(O)=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:17]([NH3+:19])[CH3:18])[CH:14]=[CH:15][CH:16]=1.Cl.[OH-].[Na+]>CCCCCC>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C@H:17]([NH2:19])[CH3:18])[CH:14]=[CH:15][CH:16]=1
Reactant: COc1cccc(C(C)[NH3+])c1
Agent: CC1(C)C[C@@H]1C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: CCCCCC
Product: COc1cccc([C@@H](C)N)c1
Yield: 100 %

Procedure:
The aqueous phases from Example 2 (87.4 g) and Example 3 (854.4 g), after decomposition of the 1-(3-methoxyphenyl)ethylammonium salts with hydrochloric acid and extraction with hexane, were combined and mixed with 94 g of 25 percent sodium hydroxide solution. The pure amine was extracted three times with 100 ml each of dichloromethane. After distilling off the solvent and vacuum distillation of the residue, 62.1 g of (R)-(+)-1-(3-methoxyphenyl)-ethylamine [content (GC) : 100%, [α]D20 : 22.0° (c=10, methanol)] was obtained as a colorless liquid.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.C[Si](C=[N+]=[N-])(C)C.[NH2:20][C:21]1[C:26]([CH:27]=O)=[CH:25][CH:24]=[C:23]([CH3:29])[N:22]=1.C(O)(=O)C>O.O1CCCC1>[C:27]([C:26]1[C:21]([NH2:20])=[N:22][C:23]([CH3:29])=[CH:24][CH:25]=1)#[CH:1]
Reactant: CC(C)NC(C)C
Reactant: Cc1ccc(C=O)c(N)n1
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(C)nc1N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.3 %

Procedure:
To a tetrahydrofuran (5 mL) solution of diisopropylamine (439 μL, 3.13 mmol) was added n-butyl lithium (1.81 mL, 1.6 M hexane solution, 2.89 mmol) under nitrogen atmosphere at −78° C., which was stirred for 15 minutes at 0° C. Then, trimethylsilyldiazomethane (1.81 mL, 2 M tetrahydrofuran solution, 3.62 mmol) was added to the reaction mixture at −78° C., which was stirred for 30 minutes at −78° C. To the reaction mixture was added a tetrahydrofuran (2 mL) solution of 2-amino-6-methyl-pyridine-3carbaldehyde (328 mg, 2.41 mmol) described in Manufacturing Example 170-1-4 at −78° C., which was stirred for 25 minutes while the temperature was slowly raised to −30° C. Acetic acid (414 mL, 7.23 mmol) was added to the reaction mixture at −78° C., and the temperature was slowly raised, after which water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (243 mg, 76%).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[C:28]([C:33](O)=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=1>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[C:28]([C:33]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Reactant: O=C(O)c1ccccc1-c1ccccc1F
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1ccccc1-c1ccccc1F

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 2′-Fluoro-biphenyl-2-carboxylic acid. LC-MS (basic): tR=1.33 min; [M+H]+=475.1.
Reaction SMILES: C([N:8]([CH:21]([CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[C:22]([O-])=[O:23])[CH2:9]/[C:10](/[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=1)=[N:11]\O)C1C=CC=CC=1>C(O)C.[Pd]>[F:20][C:15]1[CH:14]=[C:13]([CH:10]2[NH:11][C:22](=[O:23])[CH:21]([CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[NH:8][CH2:9]2)[CH:18]=[C:17]([F:19])[CH:16]=1
Reactant: O=C([O-])C(C1CCOCC1)N(C/C(=N\O)c1cc(F)cc(F)c1)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C1NC(c2cc(F)cc(F)c2)CNC1C1CCOCC1

Procedure:
4.2 g (9.4 mmol) ethyl (rac)-E/Z-{benzyl-[2-(3,5-difluoro-phenyl)-2-hydroxyimino-ethyl]-amino}-(tetrahydro-pyran-4-yl)-acetate in 100 ml of ethanol were hydrogenated under a hydrogen atmosphere together with 0.80 g of 10% palladium charcoal for 20 h at 50° C. More catalyst was added and the mixture was hydrogenated at 70° C. The catalyst was removed by suction filtering and the solvent was evaporated down. The residue was dissolved in ethanol, combined with 2 g sodium hydrogen carbonate and refluxed overnight. After cooling the insoluble constituents of the reaction mixture were suction filtered. The filtrate was evaporated down. The residue was purified by flash chromatography. The fractions were evaporated down and the residue was triturated with diisopropylether. The precipitate was suction filtered and dried.
Reaction SMILES: [C:1]([C:5]1[C:6]2[C:16](=[O:17])[CH2:15][CH2:14][C:7]=2[NH:8][C:9]=1[C:10]([O:12]C)=[O:11])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>>[C:1]([C:5]1[C:6]2[C:16](=[O:17])[CH2:15][CH2:14][C:7]=2[NH:8][C:9]=1[C:10]([OH:12])=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1[nH]c2c(c1C(C)(C)C)C(=O)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1c(C(=O)O)[nH]c2c1C(=O)CC2
Yield: 37.4 %

Procedure:
The title compound was synthesized from methyl 3-tert-butyl-4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (33 mg, 0.14 mmol) and lithium hydroxide monohydrate (30 mg, 0.71 mmol) according to General Procedure 7. Purification by reverse phase semi-preparative HPLC provided a pure fraction (11.6 mg, 37%) of 3-tert-butyl-4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylic acid (3). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.46 (s, 9H), 2.82-2.90 (m, 4H); LCMS-MS (ESI+) 221.7 (M−H); HPLC (UV=95.8%).
Reaction SMILES: C([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH2:30][CH2:29][CH:28]([O:31][CH3:32])[CH2:27][CH:26]=2)=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1>CO>[OH:15][C:14]1[C:9](=[O:8])[NH:10][N:11]=[C:12]([CH2:23][CH2:24][CH:25]2[CH2:30][CH2:29][CH:28]([O:31][CH3:32])[CH2:27][CH2:26]2)[CH:13]=1
Reactant: COC1CC=C(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)CC1
Solvent: CO
Product: COC1CCC(CCc2cc(O)c(=O)[nH]n2)CC1
Yield: 26 %

Procedure:
Prepared as described for 4-hydroxy-6-(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(4-methoxycyclohex-1-en-1-yl)ethynyl]pyridazine (Intermediate 20) except that the reaction was carried out in methanol. The resulting crude product was purified by preparative HPLC under acidic conditions to afford 4-hydroxy-6-[2-(4-methoxycyclohexyl)ethyl]pyridazin-3(2H)-one (mixture of isomers) as a white solid (26% yield).
Reaction SMILES: [C:1](#[N:3])[CH3:2].[Li]CCCC.[C:9]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20]CC)=O)[CH2:14][CH2:13]1)(=[O:11])[CH3:10]>C1COCC1>[C:9]([N:12]1[CH2:13][CH2:14][CH:15]([C:18](=[O:20])[CH2:2][C:1]#[N:3])[CH2:16][CH2:17]1)(=[O:11])[CH3:10]
Reactant: CC#N
Reactant: CCOC(=O)C1CCN(C(C)=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)N1CCC(C(=O)CC#N)CC1
Yield: 76.9 %

Procedure:
To a solution of ethyl isonipecotate (8.0 g) in THF (100 mL) was added triethylamine (5.7 g), dimethylaminopyridine (0.6 g) and acetyl chloride (4.4 g) at 0° C. and the mixture was stirred for an hour. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to give ethyl 1-acetylpiperidine-4-carboxylate (10 g) as a colorless oil. To a solution of acetonitrile (2.5 g) in THF (300 mL) was added n-BuLi (57 mmol) at −78° C. Further, ethyl 1-acetylpiperidine-4-carboxylate (10 g) was added and the mixture was stirred for an hour. After acidification with hydrochloric acid, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give 1-(1-acetylpiperidin-4-yl)-2-cyanoethan-1-one (7.5 g) as a colorless oil. A solution of 2,1,3-benzoxadiazole-4-aldehyde (0.3 g), 3-aminopyrazole (0.17 g) and 1-(1-acetylpiperidin-4-yl)-2-cyanoethan-1-one (0.4 g) in acetonitrile (10 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (0.49 g) as yellow crystals.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:66])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:24]([O:60][CH3:61])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:58][CH3:59])[C@@H:34]([CH3:57])[C:35]([NH:37][C@@H:38]([CH2:47][C:48]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[NH:50][CH:49]=1)[C:39]([N:41]1[CH2:46][CH2:45][CH2:44][CH2:43][O:42]1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])(O)=[O:2].[O:67]=[C:68]1[CH:72]=[CH:71][C:70](=[O:73])[N:69]1[CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][C:79]([NH:81][NH2:82])=[O:80]>>[O:73]=[C:70]1[CH:71]=[CH:72][C:68](=[O:67])[N:69]1[CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][C:79]([NH:81][NH:82][C:1](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:66])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:24]([O:60][CH3:61])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:58][CH3:59])[C@@H:34]([CH3:57])[C:35]([NH:37][C@@H:38]([CH2:47][C:48]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[NH:50][CH:49]=1)[C:39]([N:41]1[CH2:46][CH2:45][CH2:44][CH2:43][O:42]1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:10])[CH3:11])=[O:80]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C

Procedure:
This compound was prepared in analogy to the synthesis described in Intermediate 157 from 10 mg (11 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-3-(1H-indol-3-yl)-1-(1,2-oxazinan-2-yl)-1-oxopropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide and commercially available 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10](=[O:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:31][C:32]#[N:33]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:31][C:32]#[N:33])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10](=[O:19])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCBr
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CC#N)CCN(Cc2ccccc2)CC1=O
Temperature: 0 °C

Procedure:
Into a 250-mL 3-necked round-bottom flask was placed a solution of ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (10 g, 38.27 mmol, 1.00 equiv) in tetrahydrofuran (80 mL). This was followed by the addition of a solution of KHMDS in tetrahydrofuran (42 mL, 1M) dropwise with stirring at 0° C., and 30 min later, 2-bromoacetonitrile (6.89 g, 57.44 mmol, 1.50 equiv) was added dropwise with stirring at 0° C. The resulting solution was stirred for 4 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether to give the title compound.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[C:9]([O:16][CH2:17][CH3:18])[CH:8]=1)C.O[Li].O>CCO.O.CO>[CH2:17]([O:16][C:9]1[CH:8]=[C:7]([CH2:6][CH2:5][C:4]([OH:19])=[O:3])[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH3:15])[CH3:18]
Reactant: CCOC(=O)CCc1ccc(OCC)c(OCC)c1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: CCO
Product: CCOc1ccc(CCC(=O)O)cc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
To a solution of 0.94 g of 3-(3,4-diethoxy-phenyl)-propionic acid ethyl ester in 6 mL EtOH were added 0.59 g of LiOH.H2O dissolved in 3 mL H2O and 5 mL MeOH. The mixture was stirred at rt for 30 min. The reaction mixture was then concentrated in vacuo and the residue was partitioned between water and Et2O. The aq. layer was separated and acidified with 1N HCl. The resulting white solid was filtrated and dried to yield 0.67 g of 3-(3,4-diethoxy-phenyl)-propionic acid as white solid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:21]=[CH:20][C:11]([CH:12]=[C:13]2[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:10][CH:9]=1.[OH:22][C@@H:23]([CH2:36][NH2:37])[CH2:24][O:25][C:26]1[C:34]2[NH:33][C:32](=[O:35])[NH:31][C:30]=2[CH:29]=[CH:28][CH:27]=1>>[OH:22][C@H:23]([CH2:24][O:25][C:26]1[C:34]2[NH:33][C:32](=[O:35])[NH:31][C:30]=2[CH:29]=[CH:28][CH:27]=1)[CH2:36][NH:37][CH:6]1[CH2:5][CH2:4][N:3]([C:8]2[CH:21]=[CH:20][C:11]([CH:12]=[C:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:2][CH2:7]1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: O=C1NC(=O)C(=Cc2ccc(N3CCCCC3=O)cc2)S1
Product: O=C1NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)S1

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidine-1-yl)-benzylidene]-thiazolidine-2,4-dione (which was obtained in Example 36) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S. Pat. No. 5,786,356/1998) according to the procedure of Example 73 as a pale yellowish solid; mp >240° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.45-1.60 (m, 2H), 2.00-2.15 (m, 2H), 2.86 (brt, J=9.0 Hz, 2H), 2.90-3.60 (m, 3H), 3.91 (brd, J=9.4 Hz, 1H), 3.93-4.10 (m, 3H), 5.40 (brs, 1H), 6.59 (d, J=6.0 Hz, 1H), 6.63 (d, J=6.0 Hz, 1H), 6.86 (t, J=6.0 Hz, 1H), 7.02 (d, J=6.6 Hz, 2H), 7.36 (s, 1H), 7.40 (d, J=6.6 Hz, 2H), 11.60 (s, 1H), 11.70 (brs, 1H); MS (ES) m/z: 509.9 (MH+); HRMS Calcd. for C25H28N5O5S(MH+): 510.1811. Found: 510.1861.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:25](/[CH:26]=[CH:27]/[C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=4)=[N:24][N:23]([CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][O:36]4)[C:18]=3[N:19]=[C:20](Cl)[CH:21]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:41][C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:25](/[CH:26]=[CH:27]/[C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=4)=[N:24][N:23]([CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][O:36]4)[C:18]=3[N:19]=[C:20]([C:45]3[CH:46]=[CH:47][C:42]([OH:41])=[CH:43][CH:44]=3)[CH:21]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: OB(O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Cl)nc3c2c(/C=C/c2ccc(Cl)cc2)nn3C2CCCCO2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(-c3ccc(O)cc3)nc3c2c(/C=C/c2ccc(Cl)cc2)nn3C2CCCCO2)CC1
Yield: 80 %

Procedure:
To a solution of 4-[6-chloro-3-[(E)-2-(4-chloro-phenyl)-vinyl]-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (1.5 g, 2.56 mmol) in dioxane (38 ml) were added 4-hydroxyphenylboronic acid (0.39 g, 2.81 mmol) and an aqueous solution of cesium carbonate (0.3M, 4.6 mmol). The resulting solution was degassed using argon, tetrakis(triphenylphosphine)palladium (0.14 g, 0.13 mmol) was then added and the reaction mixture was refluxed for 3 hours. Solvents were removed under vacuum. The resulting crude mixture was submitted to a silica gel column chromatography using a gradient of ethyl acetate (0-45%) in cyclohexane to give the title compound (1.32 g, 80%) as a white solid.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=1.[C:21]1([C:27]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)Cl)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O.C(Cl)Cl>[C:21]1([C:27]([NH:8][C:9]2[S:10][CH:11]=[C:12]([C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.25 h

Procedure:
27 g of triethylamine are added to a solution of 90 g of ethyl 2-aminothiazol-4-ylglyoxylate in 225 ml of dimethylformamide and 375 ml of CH2Cl2 at -15° and 75 g of triphenylchloromethane are then added at -30°. After 15 minutes at -30°, the mixture is stirred for 3 hours without a cooling bath and 500 ml of CH2Cl2 are added to the resulting reaction mixture, the mixture is washed with 300 ml of 1N HCl and then twice with 200 ml of water, the organic phase is dried over Na2SO4 and the solvent is evaporated off.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][CH:9]=2)=[CH:5][CH:4]=1.[CH3:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([CH3:29])[CH:28]=1)[C:23](Cl)=[O:24]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:23](=[O:24])[C:22]2[CH:26]=[C:27]([CH3:29])[CH:28]=[C:20]([CH3:19])[CH:21]=2)=[CH:17][CH:18]=1
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: COc1ccc(Cc2coc3ccccc23)cc1
Solvent: ClCCl
Product: COc1ccc(Cc2c(C(=O)c3cc(C)cc(C)c3)oc3ccccc23)cc1

Procedure:
Acylation of 3-p-methoxybenzylbenzofuran with 3,5-dimethylbenzoyl chloride and stannic chloride in methylene chloride according to the procedure described in Example 1 gives 3-p-methoxybenzyl-2-(3',5'-dimethylbenzoyl)benzofuran.