Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]([N:19]1[CH2:22][CH2:21][CH:20]1[C:23](=N)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)(O)[O-:32].[Na+]>CO>[CH:6]([N:19]1[CH2:22][CH2:21][CH:20]1[C:23](=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C([O-])O
Reactant: N=C(c1ccccc1)C1CCN1C(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: O=C(c1ccccc1)C1CCN1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Add 68 ml of 3.6 N aqueous sulfuric acid to a stirred solution of 40.0 g of 1-benzhydryl-2-benzimidoylazetidine in 800 ml. of methanol. Stir under a nitrogen atmosphere for 1.5 hours at room temperature. Slowly pour the mixture, with continuous stirring, into 234 ml. of 1.1 N aqueous sodium bicarbonate. Filter the resultant solid, and extract the filter cake with methylene chloride. Combine the methylene chloride extracts with the methanolic filtrate and remove all solvent in vacuo. Dissolve the residual solid in ether, wash with water, and dry over anhydrous sodium sulfate. Remove the drying agent, concentrate the solution in vacuo to a volume of 350 ml. and triturate the solid which precipitates. Filter to obtain the analytically pure product, m.p. 114°-115° C.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22](=[O:23])[C:21]([CH3:25])([CH3:24])[CH2:20][O:19]2)=[C:13]([Cl:26])[CH:12]=1.O>C(O)C>[Cl:26][C:13]1[CH2:12][C:11](=[N:10][CH2:1][C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[OH:4])[CH:16]=[CH:15][C:14]=1[CH2:17][N:18]1[C:22](=[O:23])[C:21]([CH3:25])([CH3:24])[CH2:20][O:19]1
Reactant: O=Cc1ccccc1O
Reactant: CC1(C)CON(Cc2ccc(N)cc2Cl)C1=O
Solvent: CCO
Solvent: O
Product: CC1(C)CON(CC2=C(Cl)CC(=NCc3ccccc3O)C=C2)C1=O

Procedure:
A warmed solution of 0.48 gram (0.004 mole) of salicylaldehyde in 35 mL of ethanol was stirred, and 1.0 gram (0.004 mole) of 2-[(4-amino-2-chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone was added in one portion. The reaction mixture was heated an additional 30 minutes and then 15 mL of water was added. The mixture was filtered, and the filtrate was cooled. The resultant oily suspension solidified when abraded. The solid was collected by filtration to yield, when dried, 0.87 gram of 2-[[2-chloro-4-[(2-hydroxyphenyl)methylimino]phenyl]-methyl]-4,4-dimethyl-3-isoxazolidinone; m.p. 105°-107° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[S:17][C:16]([S:18]([N:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)(=[O:20])=[O:19])=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[S:17][C:16]([S:18]([N:21]3[CH:25]=[CH:24][CH:23]=[CH:22]3)(=[O:19])=[O:20])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Product: COc1ccc(-c2ccc(S(=O)(=O)n3cccc3)s2)cc1

Procedure:
N-[5-(4-methoxyphenyl)thiophene-2-sulfonyl]pyrrole was prepared, in the same manner as described in Example 32C, from 4-methoxyphenyl-boronic acid and N-(5-bromothiophene-2-sulfonyl)pyrrole. Recrystallization using hexane/ethyl acetate gave a solid in quantitative yield.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:16][C:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH:21]([CH3:23])[CH3:22])[C:18]([OH:20])=[O:19].C(C(C1C=CC(Cl)=CC=1)C(OC(F)C1C=CC=C(OC2C=CC=CC=2)C=1)=O)(C)C>>[F:16][C:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH:21]([CH3:23])[CH3:22])[C:18]([O:20][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1)=[O:19]
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: CC(C)C(F)(C(=O)O)c1ccccc1
Agent: CC(C)C(C(=O)OC(F)c1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Product: CC(C)C(F)(C(=O)OCc1cccc(Oc2ccccc2)c1)c1ccccc1

Procedure:
This compound was prepared from 3-phenoxybenzyl bromide and α-fluoro-α-isopropylphenylacetic acid following the method used in Example 2 Method B for the preparation of α-fluoro-3-phenoxybenzyl α-isopropyl-4-chlorophenylacetate. The product, a colourless oil, was characterised by pmr spectroscopy. Chemical shift ppm (solvent CDCl3): 0.69(3H, d, J=6Hz, CH3); 1.05 (3H, d of d, J=6Hz and J=2Hz, CH3); 2.34(1H, m, CH(CH3)2); 3.27(1H, d, J=10Hz, CH); 7.17(1H, d of d, J=56Hz and J=2Hz, CHF) and c. 7.20(14H, m, aromatic protons).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:13])[C:9](=O)[CH2:10][OH:11])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N:20]#[C:21][NH2:22].[OH-].[Na+]>O1CCCC1.O>[NH2:22][C:21]1[O:11][CH:10]=[C:9]([CH:8]([C:6]2[CH:5]=[CH:4][C:3]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:2]([F:1])[CH:7]=2)[CH3:13])[N:20]=1
Reactant: N#CN
Reactant: CC(C(=O)CO)c1ccc(-c2ccccc2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1coc(N)n1
Reaction time: 8 h

Procedure:
To 3-(2-Fluoro-4-biphenylyl)-2-oxo-1-butanol (3.57 g, 13.8 mmol) in tetrahydrofuran (35 ml) was added cyanamide (3.65 g, 77.6 mmol) in water and 2N-sodium hydroxide to pH 10. After the addition, the mixture was stirred overnight, then cyanamide (3.65 g, 77.6 mmol) was added to the reaction mixture to pH 10, the mixture was stirred overnight. The reaction mixture was extracted with ether and the extracts were washed with water, dried over and evaporated under reduced pressure to a residue, which was chromatographed to afford 2-Amino-4-(1-(2-fluoro-4-biphenylyl)ethyl)oxazole as crystalline material (1.05 g, 27% yield): mp 150.5°-151.5° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:25][CH3:26])=[CH:20][C:21]([CH:23]=[O:24])=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:27][Mg]I>C1COCC1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:25][CH3:26])=[CH:20][C:21]([CH:23]([OH:24])[CH3:27])=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: C[Mg]I
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C=O)cc(OC)c21
Solvent: C1CCOC1
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C(C)O)cc(OC)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 114.7 %

Procedure:
A solution of 150 mg (0.426 mmol) 2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carbaldehyde in 2 ml THF is treated with excess methylmagnesiumiodide (prepared from 207 mg methyliodide and 35 mg magnesium in 5 ml diethyl ether). The resulting mixture is stirred at room temperature for 1 h. The reaction mixture is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo to afford 180 mg of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:3]=1[CH2:21][C:22]([O:24][CH3:25])=[O:23].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:36]1[CH2:40]OC[CH2:37]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:3]=1[CH:21]([CH2:37][CH2:36][CH3:40])[C:22]([O:24][CH3:25])=[O:23]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1cccnc1)CCCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1cccnc1)CCCC3
Yield: 184.9 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(pyridin-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.096 g; 0.27 mmol), LHMDS 1N in THF (0.3 mL; 0.3 mmol), 1-iodopropane (0.039 mL; 0.4 mmol) in DMF (1.1 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-30%) in heptane furnished 0.197 g (77%) of the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:20][C@@H:21]1[CH2:26][C@@H:25]2[CH2:27][C@@H:23]([C:24]2([CH3:29])[CH3:28])[C@H:22]1[CH3:30].[Cu](C#N)[C:32]#[N:33].O>CN1CCCC1=O>[C:32]([C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:20][C@@H:21]1[CH2:26][C@@H:25]2[CH2:27][C@@H:23]([C:24]2([CH3:29])[CH3:28])[C@H:22]1[CH3:30])#[N:33]
Reactant: N#C[Cu]C#N
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCc3ccncc3)c(=O)c1Br)C2(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCc3ccncc3)c(=O)c1C#N)C2(C)C
Temperature: 110 °C
Reaction time: 24 h
Yield: 4.9 %

Procedure:
2-[5-Bromo-6-oxo-4{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-(pyridin-4-ylmethyl)acetamide (100 mg, 0.21 mmol) in N-methylpyrrolidone (2.5 mL) was mixed with copper cyanide (100 mg, 1.05 mmol) at room temperature and stirred at 110° C. for 24 hours. After completion of the reaction, the reaction solution was mixed with water and extracted with ethyl acetate and chloroform. The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to give the desired product (4.3 mg, 5% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[O:26]=[C:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:32][CH2:33][C:34](O)=[O:35]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:34](=[O:35])[CH2:33][CH2:32][N:28]3[CH2:29][CH2:30][CH2:31][C:27]3=[O:26])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: O=C(O)CCN1CCCC1=O
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CNC[C@@H]1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)CCN2CCCC2=O)C[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound rac-{(3R,4S)-4-(3,4-dichloro-phenyl)-1-[3-(2-oxo-pyrrolidin-1-yl)-propionyl]-pyrrolidin-3-yl}-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 3-(2-oxo-pyrrolidin-1-yl)-propionic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as a colorless oil. MS m/e: 522.2 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([C:14]2[C:22]3[C:17](=[C:18]([CH2:23][S:24][CH3:25])[CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:11][C:12]#[N:13])=[C:4]([F:26])[CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:38])C=1>CO>[Cl:1][C:2]1[CH:3]=[C:4]([F:26])[C:5]([CH:9]([C:14]2[C:22]3[C:17](=[C:18]([CH2:23][S:24]([CH3:25])=[O:38])[CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:11][C:12]#[N:13])=[C:6]([F:8])[CH:7]=1
Reactant: CSCc1cccc2c(C(CCC#N)c3c(F)cc(Cl)cc3F)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: CS(=O)Cc1cccc2c(C(CCC#N)c3c(F)cc(Cl)cc3F)c[nH]c12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
231 mg (0.59 mmol) of the compound from Example 153 were introduced into 40 ml of dichloromethane at 0° C., 198 mg (0.81 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at 0° C. for 2 h. 2 ml of methanol were added, and the solution was concentrated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the solvents were removed in a rotary evaporator. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to result in 171 mg (71% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[N:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>CO>[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][N:16]=3)=[CH:29][CH:28]=2)[CH:8]=1
Reactant: O=Cc1ccc(-c2cnccn2)cc1
Reactant: COC(=O)CCc1cccc(CN)c1
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1cccc(CNCc2ccc(-c3cnccn3)cc2)c1

Procedure:
The title compound of Step A was prepared from 3-(3-aminomethyl-phenyl)-propionic acid methyl ester hydrochloride salt, of Preparation 44, and 4-pyrazin-2-yl-benzaldehyde, of Preparation 27, using the method described in Example 1, Step A except the imine was formed in MeOH at reflux over 2 h. 1H NMR (400 MHz, CDCl3) δ 9.02 (d, 1H), 8.61 (m, 1H), 8.48 (d, 1H), 7.98 (d, 2H), 7.49 (d, 2H), 7.25 (m, 1H), 7.19 (m, 2H), 7.09 (d,1H), 3.87 (s, 2H), 3.79 (s, 2H), 3.66 (s, 3H), 2.94 (t, 2H), 2.63 (t, 2H); MS 362 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:6][CH2:7][C:8]1[S:9][C:10]2[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:15]=2[N:16]=1.[Br:29][C:30]1[CH:40]=[CH:39][C:33]([O:34][CH2:35][C:36](O)=[O:37])=[CH:32][CH:31]=1>>[NH2:23][C:12]1[N:13]=[C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:36](=[O:37])[CH2:35][O:34][C:33]3[CH:39]=[CH:40][C:30]([Br:29])=[CH:31][CH:32]=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:26]([O:27][CH3:28])=[C:3]([O:2][CH3:1])[CH:4]=3)[S:9][C:10]=2[N:11]=1
Reactant: O=C(O)COc1ccc(Br)cc1
Reactant: COc1ccc(CCc2nc3c(N4CCNCC4)nc(N)nc3s2)cc1OC
Product: COc1ccc(CCc2nc3c(N4CCN(C(=O)COc5ccc(Br)cc5)CC4)nc(N)nc3s2)cc1OC
Yield: 74 %

Procedure:
This compound was prepared from 2-(3,4-dimethoxyphenethyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-bromophenoxyacetic acid in a yield of 74%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=2)[CH2:7]1)(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>O1CCOCC1>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=2)[CH2:7]1)(=[S:29])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N)c(F)c2)C(=O)O1
Solvent: C1COCCO1
Product: CC(=S)NC[C@H]1CN(c2ccc(N)c(F)c2)C(=O)O1
Yield: 98 %

Procedure:
A mixture of 5-(S)-acetamidomethyl-3-[4′-amino-3′-fluorophenyl]oxazoli-dine-2-one. (0.100 g, 0.374 mmol) and Lawesson's reagent (0.151 g, 0.374 mol) in dioxane (2 ml) was stirred at 65° C. for 2 h. The solution was concentrated under vacuum and the residue purified by PTLC (10% methanol/dichloromethane) to give a tan solid (0.104 g, 98%); mp 137-88° C.; MS: (M+H)+=284.
Reaction SMILES: [CH:1]([N:4]([CH:16]([CH3:18])[CH3:17])[C:5](=[O:15])[CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)O)([CH3:3])[CH3:2].[CH:19]1[C:24]([OH:25])=[CH:23][CH:22]=[C:21]([CH3:26])[CH:20]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[OH:25][C:24]1[CH:23]=[CH:22][C:21]([CH3:26])=[CH:20][C:19]=1[CH:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:6][C:5]([N:4]([CH:16]([CH3:18])[CH3:17])[CH:1]([CH3:2])[CH3:3])=[O:15]
Reactant: Cc1ccc(O)cc1
Reactant: CC(C)N(C(=O)CC(O)c1ccccc1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccc(O)c(C(CC(=O)N(C(C)C)C(C)C)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 34.5 %

Procedure:
A three-necked round-bottom flask equipped with condenser, mechanical stirrer, thermometer, is loaded with N,N-diisopropyl-3-phenyl-3-hydroxy-propionamide (1.0 g; 0.0041 mol), p-cresol (0.48 g; 0.0044 mol) and polyphosphoric acid (16.5 g). After five hours under stirring at room temperature the reaction is completed. The reaction mixture is poured in ice/water (10 g), alkalinized to pH 9-10 with NaOH 50% w/w and left under stirring for 30 minutes, then diluted with toluene (30 ml). The phases are separated and the aqueous phase is extracted with toluene (2×30 ml). The combined organic phases are dried over sodium sulfate and evaporated to dryness. The resulting oil is purified by flash chromatography (hexane/ethyl acetate 7:3). 0.48 g of product, as a pale yellow oil, are obtained.
Reaction SMILES: CO[C:3](=[O:26])[CH2:4][NH:5][C:6](=[O:25])[C@H:7]([CH3:24])[NH:8][C:9](=[O:23])[CH2:10][NH:11][C:12](=[O:22])[CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].O.[NH2:28][NH2:29]>CO>[C:18]([O:17][C:15]([NH:14][CH2:13][C:12]([NH:11][CH2:10][C:9]([NH:8][C@H:7]([C:6]([NH:5][CH2:4][C:3]([NH:28][NH2:29])=[O:26])=[O:25])[CH3:24])=[O:23])=[O:22])=[O:16])([CH3:19])([CH3:20])[CH3:21]
Reactant: COC(=O)CNC(=O)[C@H](C)NC(=O)CNC(=O)CNC(=O)OC(C)(C)C
Reactant: NN
Solvent: O
Solvent: CO
Product: C[C@H](NC(=O)CNC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)NN
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a cooled (ice bath), stirred solution of Boc-Gly-Gly-Ala-Gly-OMe (2.5 g, 6.7 mmoles, described in Example 4) in methanol (50 ml) is added hydrazine hydrate (2.5 ml). The solution is stirred at 0° C for 3 hr and at room temperature overnight. The precipitate is separated by filtration, washed with methanol and dried to yield the title compound; amino acid analysis: Gly 3, Ala 0.99.
Reaction SMILES: [CH3:1][Si:2]([CH3:20])([CH3:19])[CH2:3][CH2:4][O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14](O)[CH3:15])=[C:10]([Cl:17])[CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:40]=[N+:41]=[N-:42].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.ClCCl>[CH3:1][Si:2]([CH3:20])([CH3:19])[CH2:3][CH2:4][O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([N:40]=[N+:41]=[N-:42])[CH3:15])=[C:10]([Cl:17])[CH:9]=1
Reactant: [N-]=[N+]=N
Reactant: CC(O)c1ccc(NC(=O)OCC[Si](C)(C)C)cc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(N=[N+]=[N-])c1ccc(NC(=O)OCC[Si](C)(C)C)cc1Cl

Procedure:
To a solution of [3-chloro-4-(1-hydroxy-ethyl)-phenyl]-carbamic acid 2-trimethylsilanyl-ethyl ester (1.25 g) in tetrahydrofuran (20 mL) at 0° C. under an atmosphere of argon is added triphenyl-phosphine (2.6 g), hydrazoic acid (approximately 2.5 molar equivalents in dichloromethane, prepared by the method of Fieser and Fieser, Reagents for Organic Synthesis, Vol. 1, pg. 446; Wiley, N.Y.) and diethyl azodicarboxylate (1.72 g). After approximately 10 minutes the solvent is removed under reduced pressure and the residue is chromatographed over silica gel (5% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([N:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][CH2:31]2)=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:30]1([C:28]([C:24]2[N:25]=[CH:26][N:27]=[C:22]([N:17]3[CH2:18][CH2:19][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:15][CH2:16]3)[CH:23]=2)=[O:29])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31]1
Reactant: O=C(c1cc(Cl)ncn1)N1CCc2ccccc21
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5ccccc54)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
110 mg (0.4 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one were added to 100 mg (0.39 mmol) (6-chloropyrimidin-4-yl)-(2,3-dihydroindol-1-yl)-methanone and 100 μL (0.58 mmol) DIPEA in 10 mL DMF. The reaction mixture was stirred for 2 h at RT and then evaporated down i. vac. The residue was combined with 20 mL water and stirred for 30 min at RT. The precipitated product was suction filtered, stirred with methanol, suction filtered again and dried at 40° C. in the CAD.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[H-].[Na+].Cl[CH2:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16]>C1COCC1>[O:16]=[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:14][CH2:13][O:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: O=C(CCCl)c1ccccc1
Reactant: CC(C)(C)OC(=O)NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NOCCC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 69.7 %

Procedure:
To a cooled (0° C.) solution of tert-butyl hydroxycarbamate (1.90 g, 14.2 mmol) in THF (30 mL) was added NaH (0.285 g, 11.9 mmol). After stirring at 0° C. for 5 minutes and at room temperature for 10 minutes, the mixture was added to a solution of 3-chloro-1-phenylpropan-1-one (2.00 g, 11.9 mmol) in THF (10 mL). After stirring at room temperature for 30 minutes, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed (20% ethyl acetate in hexanes) to provide the product (2.20 g, 69%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.[NH2:29][CH:30]([CH2:33][OH:34])[CH2:31][OH:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[OH:32][CH2:31][CH:30]([NH:29][C:23](=[O:24])[C:22]1[CH:21]=[CH:20][C:19]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:10][C:9]([C:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[O:28])=[CH:27][CH:26]=1)[CH2:33][OH:34]
Reactant: NC(CO)CO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NC(CO)CO)cc1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with 2-aminopropane-1,3-diol using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as an off-white solid, MS (ESI+): m/z=449.2 [M+H]+.
Reaction SMILES: O[CH:2]([CH2:5][CH2:6][C:7]([F:23])([F:22])[CH:8]([N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])[CH:9]=[CH2:10])[CH:3]=[CH2:4].[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:24]1(=[O:34])[N:28]([CH:2]([CH2:5][CH2:6][C:7]([F:23])([F:22])[CH:8]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])[CH:9]=[CH2:10])[CH:3]=[CH2:4])[C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=CC(O)CCC(F)(F)C(C=C)N1C(=O)c2ccccc2C1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC(CCC(F)(F)C(C=C)N1C(=O)c2ccccc2C1=O)N1C(=O)c2ccccc2C1=O
Reaction time: 20 h

Procedure:
A mixture of 3-hydroxy-6,6-difluoro-7-phthalimido-1,8-nonadiene (148 mg, 0.46 mmoles), phthalimide (73.5 mg, 0.5 mmoles), triphenylphosphine (131.5 mg, 0.5 mmoles) and diethyl azodicarboxylate (73 l, 0.6 mmoles) in tetrahydrofuran (5 ml) is kept under nitrogen at 25° C. for 20 hours. After concentration under reduced pressure, the title compound is obtained after purification by chromatography on silica (dichloromethane, RF: 0.43): 95 mg (46%).