Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[C:5](=O)[NH:4][CH:3]=1.P(Br)(Br)([Br:22])=O.P(Br)(Br)(Br)=O.C(#N)C.C(=O)(O)[O-].[Na+]>C(#N)C.O.C1(C)C=CC=CC=1>[Br:22][C:5]1[C:6](=[O:18])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:2]([CH3:1])=[CH:3][N:4]=1
Reactant: O=P(Br)(Br)Br
Reactant: Cc1c[nH]c(=O)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC#N
Product: Cc1cnc(Br)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
6-Methyl-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyrazine-2,3-dione (289.34 g @ 100%, 1 eq) and toluene (3 L) were charged to a flask and the slurry heated to reflux. Azeotroped water (53 ml) was collected and the slurry cooled to 25° C. The toluene was then removed under reduced pressure at <50° C. to give an off-white powder. This material was then added to acetonitrile (2.95 L) and the reaction mixture heated to 64-67° C. In a separate 2 L 3 necked flask, phosphorus oxybromide (368.4 g, 1.2 eq) was dissolved in acetonitrile (1.475 L). The POBr3/acetonitrile solution was then added to the original flask over 45 minutes at 64-67° C. The reaction mixture was then held at 64-67° C. for 4.5 hours and was then cooled to 20-25° C. Saturated sodium bicarbonate in water (10.3 L) was added over 30 minutes to quench the reaction. The mixture was then stirred for 6 hours at 20-25° C. The solid was then filtered off and the filter-cake washed with water (2×0.55 L) to give the title compound as a water-wet solid (486.4 g, 74.3% @ 100%).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]1([N:17]2[CH2:22][CH2:21][CH:20]([NH:23][C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=3[OH:34])[CH2:19][CH2:18]2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[Cl:35][C:36](Cl)([O:38]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[ClH:35].[CH3:10][C:11]1([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[C:24]4[CH:29]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:27]=[CH:26][C:25]=4[O:34][C:36]3=[O:38])[CH2:19][CH2:18]2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: CC1(N2CCC(Nc3cc(C(F)(F)F)ccc3O)CC2)CCOCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(N2CCC(n3c(=O)oc4ccc(C(F)(F)F)cc43)CC2)CCOCC1
Product: Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
DIPEA (0.1 mL, 0.57 mmol) was added to a solution of 2-{[1-(4-methyltetrahydro-2H-pyran-4-yl)-4-piperidinyl]amino}-4-(trifluoromethyl)phenol (D14, 89 mg, 0.25 mmol) in DCM (5 mL) at rt under Ar. The reaction was cooled to 0° C. and the triphosgene (31 mg, 0.10 mmol) was added. The mixture was stirred for 3 h at 0° C. The reaction was quenched with sat. NaHCO3 (5 mL) and partitioned between DCM and H2O. The aqueous layer was extracted with DCM (2×) and the combined organics were dried (Na2SO4) and concentrated by rotary evaporation to give a pale yellow solid. The residue was purified via flash column chromatography (silica, DCM to 0.5% NH3/9.5% MeOH/90% DCM) to give the free base of the title compound as a colourless oil. HCl (0.5 mL, 0.5 mmol, 1 M in Et2O) was added to a solution of the free base in DCM (5 mL) and the reaction stirred for 30 min. The solvent was removed by rotary evaporation and the resulting solid triturated with Et2O to give 3-[1-(4-methyltetrahydro-2H-pyran-4-yl)-4-piperidinyl]-5-(trifluoromethyl)-1,3-benzoxazol-2(3H)-one hydrochloride (E3, 81 mg, 73%) as a white solid.
Reaction SMILES: [ClH:1].C([O:6][C:7](=[O:24])[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:18])[CH2:16][NH2:17])[C@@H:11]([CH:19]([CH3:22])[CH2:20][CH3:21])[C:10]1=[O:23])(C)(C)C.Cl.[NH:26]([C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)[C:27]([NH2:29])=[NH:28]>>[ClH:1].[NH:26]([C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:17][CH2:16][C:15]([N:12]2[CH2:13][CH2:14][N:9]([CH2:8][C:7]([OH:6])=[O:24])[C:10](=[O:23])[C@@H:11]2[CH:19]([CH3:22])[CH2:20][CH3:21])=[O:18])=[O:35])=[CH:32][CH:31]=1)[C:27]([NH2:29])=[NH:28]
Reactant: CCC(C)[C@H]1C(=O)N(CC(=O)OC(C)(C)C)CCN1C(=O)CN
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Agent: Cl
Product: CCC(C)[C@H]1C(=O)N(CC(=O)O)CCN1C(=O)CNC(=O)c1ccc(NC(=N)N)cc1

Procedure:
(S)-4-Glycyl-3-(1-methylpropyl)-2-oxopiperazine-1-acetic acid t-butyl ester hydrochloride obtained in Working Example 64 (364 mg) and 215 mg of 4-guanidino benzoic acid hydrochloride were subjected to substantially the same procedure as in Working Example 39 to afford 190 mg of the title compound as colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7](/[CH:9]=[CH:10]/[C:11]2[N:29]=[C:14]3[CH:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])[CH2:16][CH2:17][CH2:18][N:13]3[N:12]=2)[CH:6]=[CH:5][C:4]=1[N:30]1[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]1.[C:36]([O:44][C@@H:45]([C@H:49]([O:53][C:54](=[O:61])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:50]([OH:52])=[O:51])[C:46]([OH:48])=[O:47])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CC(O)C.C(#N)C>[C:54]([O:53][C@@H:49]([C@H:45]([O:44][C:36](=[O:43])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:46]([OH:48])=[O:47])[C:50]([OH:52])=[O:51])(=[O:61])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.[CH3:1][O:2][C:3]1[N:8]=[C:7](/[CH:9]=[CH:10]/[C:11]2[N:29]=[C:14]3[C@H:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])[CH2:16][CH2:17][CH2:18][N:13]3[N:12]=2)[CH:6]=[CH:5][C:4]=1[N:30]1[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]1
Reactant: COc1nc(/C=C/c2nc3n(n2)CCCC3c2ccccc2C(F)(F)F)ccc1-n1cnc(C)c1
Agent: O=C(O[C@H](C(=O)O)[C@H](OC(=O)c1ccccc1)C(=O)O)c1ccccc1
Solvent: CC#N
Solvent: CC(C)O
Product: COc1nc(/C=C/c2nc3n(n2)CCC[C@H]3c2ccccc2C(F)(F)F)ccc1-n1cnc(C)c1

Procedure:
2-{(E)-2-[6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-[2-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine (100 mg, 0.208 mmol) was dissolved in the mixture of 2-propanol (1.6 mL) and acetonitrile (2.0 mL) at 45° C., and the solution of (2S,3S)-2,3-bis(benzoyloxy)succinic acid (D-DBTA) (89.5 mg, 0.250 mmol) in acetonitrile (1.6 mL) was added. Traces of seed crystal of the title compound which was obtained by the method similar to this step was added to the solution at 33° C., and the mixture was stirred at room temperature for 18 hours. The solids were collected by filtration, washed with acectonitrile/2-propanol=2/1 (0.5 mL) and dried at 50° C. under the reduced pressure to obtain the title compound (62.3 mg, 35.7% yield, 90.7% de). The title compound (50.7 mg, 90.7% de) was suspended in acectonitrile/2-propanol=1/1 (0.5 mL), and the mixture was stirred at 80° C. for 25 minutes, and then stirred at room temperature for 15 hours. The solids were collected by filtration and dried at 50° C. under the reduced pressure to obtain the title compound (35.9 mg, 70.8% yield, 98.1% de)
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH:11]([CH2:15][C:16](=[O:34])[N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[NH:25][C:24]4=[O:33])[CH2:19][CH2:18]3)[C:12]([OH:14])=O)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:38][CH2:37]1>>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH:11]([CH2:15][C:16]([N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[NH:25][C:24]4=[O:33])[CH2:19][CH2:18]3)=[O:34])[C:12]([N:45]3[CH2:44][CH2:43][CH:42]([N:39]4[CH2:38][CH2:37][N:36]([CH3:35])[CH2:41][CH2:40]4)[CH2:47][CH2:46]3)=[O:14])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: O=C(O)C(CC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)Cc1ccc2c(c1)CCC2
Product: CN1CCN(C2CCN(C(=O)C(CC(=O)N3CCC(N4Cc5ccccc5NC4=O)CC3)Cc3ccc4c(c3)CCC4)CC2)CC1

Procedure:
Prepared analogously to Example 76e) from and 2-indan-5-ylmethyl-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid and 1-methyl-4-piperidin-4-yl-piperazine
Reaction SMILES: [OH-].[Na+].[C:3]([CH2:5][CH:6]=[CH:7][C:8]1[CH:25]=[CH:24][C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][CH2:21][C:22]#[N:23])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)#[N:4].[N:26]([O:28]C)=O.[N:30]([O-])=[O:31].[Na+]>CO>[C:22]([C:21](=[N:26][OH:28])[CH:20]=[CH:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][C:11]2[CH:24]=[CH:25][C:8]([CH:7]=[CH:6][C:5](=[N:30][OH:31])[C:3]#[N:4])=[CH:9][CH:10]=2)=[CH:18][CH:17]=1)#[N:23]
Reactant: N#CCC=Cc1ccc(Cc2ccc(C=CCC#N)cc2)cc1
Reactant: O=N[O-]
Reactant: CON=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#CC(C=Cc1ccc(Cc2ccc(C=CC(C#N)=NO)cc2)cc1)=NO
Reaction time: 48 h
Yield: 76 %

Procedure:
A solution of sodium hydroxide (0.8 g; 0.02 mol) in 30 ml of methanol is added to a suspension of 4-{4-[4-(3-cyano-propenyl)-benzyl]-phenyl}-but-3-enenitrile (3.0 g; 0.01 mol), prepared as described in example 6.2, in 20 ml of methanol. Methyl nitrite, generated from 2.07 g (0.03 mol) of sodium nitrite as described in example 2.2, is bubbled through the suspension at 2° C. for 25 min, and the mixture is then left at room temperature for 48 h. The solvent is then evaporated, the residue is dissolved in 200 ml of water, extracted with toluene (the extract is discarded), and acidified with conc. hydrochloric acid. The beige precipitate is taken up in ethyl acetate, washed neutral with water, dried (MgSO4) and concentrated by evaporation. 2.7 g (76%) of 4-{4-[4-(3-cyano-3-hydroxyimino-propenyl)-benzyl]-phenyl}-2-hydroxyimino-but-3-enenitrile are obtained as a light brown solid, melting point 142-145° C. (dec).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:20][C:19]=3[CH3:33])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[H][H]>[Pd].CO.CCOC(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])=[CH:20][C:19]=3[CH3:33])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: Cc1cc(C=CC(=O)OC(C)(C)C)ccc1-c1nsc(-c2ccc(OC(C)C)c(C#N)c2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(CCC(=O)OC(C)(C)C)ccc1-c1nsc(-c2ccc(OC(C)C)c(C#N)c2)n1

Procedure:
A mixture of 120 mg (0.26 mmol) of tert-butyl 3-(4-(5-(3-cyano-4-isopropyloxyphenyl)-1,2,4-thiadiazol-3-yl)-3-methylphenyl)-2-propenoate (from Step C) and 41 mg of palladium on activated carbon (10% w/w; 0.025 mmol) in 15 mL of methanol/EtOAc (1/1) was hydrogenated under atmospheric pressure of hydrogen for 2 h. The heterogeneous mixture was filtered through a disposable frit to remove palladium and the filtrate was concentrated. The crude product was found to be pure by ESI-MS and 1H NMR analyses and used in subsequent step without purification: 1H NMR (500 MHZ, CDCl3) δ 1.46 (s, 9H), 1.49 (d, J=6.5, 6H), 2.61 (t, J=7.5, 2H), 2.65 (s, 3H), 2.97 (t, J=7.5, 2H), 4.79 (sep, J=6.5, 1H), 7.11 (d, J=9.0, 1H), 7.18 (d, J=9.0, 1H), 7.23 (s, 1H), 7.69 (d, J=8.0, 1H), 8.18 (d, J=2.0, 1H), 8.24 (dd, J=8.0, 2.0, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22])[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][N:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22]
Reactant: Brc1ccccn1
Reactant: C#CCCn1ccc2ccccc2c1=O
Product: O=c1c2ccccc2ccn1CCC#Cc1ccccn1
Yield: 9.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (100 mg, 0.63 mmol) and 2-but-3-ynyl-2H-isoquinolin-1-one (120 mg, 0.63 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 17 mg (62 μmol, 10%) of 2-(4-(pyridin-2-yl)but-3-ynyl)isoquinolin-1(2H)-one as a white solid (M.P.=85-90° C.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH3:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>CN(C=O)C>[CH2:22]([O:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCBr
Reactant: COC(=O)c1ccc(O)cc1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCOc1ccc(C(=O)OC)c(C(=O)OC)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
Dimethyl 4-hydroxyphthalate (10.0 g, 47 mmol) was dissolved in DMF (100 ml), and potassium carbonate (30 g, 217 mmol) and n-amyl bromide (10 ml, 80 mmol) were added to this solution. The mixture was stirred at 90° C. for 2 hours, and the solid was removed by filtration through Celite. The filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/1) to give dimethyl 4-pentyloxyphthalate (12.7 g, 45.4 mmol, 97%) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1)#[N:2].C1C(C(OO)=O)=CC=CC=1.[Br:20]N1C(=O)CCC1=O>C1C=CC=CC=1>[Br:20][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=1
Reactant: Cc1ccc(C#N)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OO)c1ccccc1
Solvent: c1ccccc1
Product: N#Cc1ccc(CBr)nc1
Temperature: 75 °C
Reaction time: 48 h

Procedure:
0.3 g (2.5 mmol) of 5-cyano-2-methylpyridine was dissolved in 15 ml of benzene. 10 mg of perbenzoic acid and 0.49 g (2.8 mmol) of N-bromosuccinimide were added to the obtained solution, and they were stirred at 75° C. for 2 days. The solvent was evaporated and the crude product was purified by the silica gel column chromatography.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].[F:36][C:37]1[C:44]([O:45][Si:46]([CH:53]([CH3:55])[CH3:54])([CH:50]([CH3:52])[CH3:51])[CH:47]([CH3:49])[CH3:48])=[CH:43][C:42]([O:56][CH3:57])=[CH:41][C:38]=1[CH:39]=O.C[Si]([C:62]#[N:63])(C)C>C1COCC1>[C:62]([CH:39]([NH:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1)[C:38]1[CH:41]=[C:42]([O:56][CH3:57])[CH:43]=[C:44]([O:45][Si:46]([CH:47]([CH3:48])[CH3:49])([CH:53]([CH3:54])[CH3:55])[CH:50]([CH3:51])[CH3:52])[C:37]=1[F:36])#[N:63]
Reactant: C[Si](C)(C)C#N
Reactant: COc1cc(C=O)c(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c1
Reactant: N#Cc1ccc(N)cc1F
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Product: COc1cc(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c(C(C#N)Nc2ccc(C#N)c(F)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Fluoro-4-aminobenzonitrile [CAS No. 53312-80-4] (1.02 g), MS3A (7 g), and Yb(OTf)3 (465 mg) were added to 30 ml of a THF solution containing 2.45 g of 2-fluoro-5-methoxy-3-triisopropylsilanyloxybenzaldehyde (Example (3b)) under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours, and then 1.1 ml of trimethylsilyl cyanide was added thereto. The mixture was stirred at room temperature for 3 days. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give 4-{[cyano-(2-fluoro-5-methoxy-3-triisopropylsilanyloxyphenyl)methyl]amino}-2-fluorobenzonitrile (2.05 g) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:22]=1[CH2:23]Cl>CN(C=O)C.C(OCC)(=O)C>[CH3:20][C:21]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:22]=1[CH2:23][O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(CCl)c(C)c1
Reactant: CCOC(=O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cccc(OCc2ccc(C)cc2C)c1
Reaction time: 16 h

Procedure:
To a stirred solution of Ethyl 2-(3-hydroxyphenyl)acetate (3 g, 16.6 mmol) in DMF (20 ml) was added potassium carbonate (2.99 g, 21.6 mmol) at room temperature followed by drop wise addition of 2,4-Dimethylbenzyl chloride (3.11 g, 18.3 mmol). The reaction mixture was stirred for 16 hours and taken in ethyl acetate, washed with water (2×), brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hex:ethyl acetate 4:1) to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:35][C:36]4[N:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=4)[CH:31]=3)[O:26]2)=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC>ClCCl.O>[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:35][C:36]4[N:41]=[CH:40][C:39]([NH:42][C:13](=[O:15])[C:12]5[CH:11]=[CH:10][C:9]([CH2:8][N:5]6[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]6)=[CH:17][CH:16]=5)=[CH:38][CH:37]=4)[CH:31]=3)[O:26]2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccc(F)cc2)O3)nc1
Reactant: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CN1CCN(Cc2ccc(C(=O)Nc3ccc(Oc4ccc5c(c4)CCC(c4ccc(F)cc4)O5)nc3)cc2)CC1
Reaction time: 3 h

Procedure:
4-(4-Methylpiperazin-1-ylmethyl)benzoic acid (ca 0.19 g), 6-[2-(4-fluoro-phenyl)-chroman-6-yloxy]pyridin-3-ylamine (0.18 g) and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (0.12 g) were added into dichloromethane (12 ml). The mixture was stirred at room temperature and after 4 hours more 4-(4-methylpiperazin-1-ylmethyl)-benzoic acid (ca 0.11 g) and 1-(3-dimethyl-amino-propyl)-3-ethylcarbodiimide hydrochloride (0.0.46 g) were added. Stirring was continued for additional 3 hours. Water and dichloromethane were added and organic and water phases were separated. Water phase was extracted with dichloromethane. The product was purified by column chromatography using dichloromethane-methanol (9:1) as an eluent to give N-{6-[2-(4-fluorophenyl)chroman-6-yloxy]-pyridin-3-yl}-4-(4-methylpiperazin-1-ylmethyl)benzamide. 1H NMR (300 MHz, d6-DMSO) δ: 1.90-2.08 (m, 1H), 2.11-2.21 (m, 1H), 2.18 (s, 3H), 2.38 (bs, 8H), 2.68-2.79 (m, 1H), 2.91-3.05 (m, 1H), 3.54 (s, 2H), 5.13 (dd, 1H, J 2.0, 10.1 Hz), 6.86 (d, 2H, J 1.2 Hz), 6.90 (s, 1H), 6.98 (d, 1H, J 8.8 Hz), 7.19-7.27 (m, 2H), 7.43-7.54 (m, 4H), 7.92 (d, 2H, J 8.2 Hz), 8.18 (dd, 1H, J 2.7, 8.9 Hz), 8.48 (d, 1H, J 2.7 Hz), 10.31 (s, 1H).
Reaction SMILES: CC1(C)O[C@H](CN2C=CC(N[C:14](=[O:35])[C@@H:15]([N:20]3[CH2:24][C:23]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28](Br)[C:27]=4[F:33])=[CH:22][C:21]3=[O:34])[CH2:16][CH:17]([CH3:19])[CH3:18])=N2)CO1.C([Sn](CC[CH2:50][CH3:51])(CCCC)C=C)CCC.[C:52](OCC)(=[O:54])[CH3:53]>CN(C)C=O.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>[CH2:52]([O:54][C:14](=[O:35])[C@@H:15]([N:20]1[CH2:24][C:23]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH:50]=[CH2:51])[C:27]=2[F:33])=[CH:22][C:21]1=[O:34])[CH2:16][CH:17]([CH3:18])[CH3:19])[CH3:53]
Reactant: CCOC(C)=O
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2cccc(Br)c2F)=CC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)OCC)C2)c1F
Temperature: 80 °C
Reaction time: 14 h
Yield: 73 %

Procedure:
To a mixture of (S)-2-[4-(3-bromo-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid ethyl ester (prepared as in Example 128, 0.624 g, 1.51 mmol), tetrakis(triphenylphosphine)palladium(0) (0.200 g, 0.17 mmol) in N,N-dimethylformamide (7 mL) was added tributyl(vinyl)tin (0.652 g, 2.05 mmol) and the resulting mixture stirred at 80° C. for 14 h. The mixture was taken up in ethyl acetate and dilute hydrochloric acid and separated. The organic phase was washed with, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over sodium sulfate. The mixture was filtered, evaporated and the residue purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 50 g, 10% to 50% ethyl acetate/hexanes) which afforded (S)-2-[4-(2-fluoro-3-vinyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid ethyl ester (0.400 g, 73%) as a clear oil.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][C:15]2[N:11]([C:12]([C:23](=[O:35])[C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[C:26]([O:33][CH3:34])[CH:25]=3)=[C:13]([CH3:22])[C:14]=2[C:18]([O:20][CH3:21])=[O:19])[CH:10]=1)C1C=CC=CC=1.[H][H]>CN(C)C=O.O1CCCC1.[Pd]>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]([C:12]2[N:11]3[C:15]([CH:16]=[CH:17][C:9]([OH:8])=[CH:10]3)=[C:14]([C:18]([O:20][CH3:21])=[O:19])[C:13]=2[CH3:22])=[O:35])=[CH:25][C:26]=1[O:33][CH3:34]
Reactant: [H][H]
Reactant: COC(=O)c1c(C)c(C(=O)c2ccc([N+](=O)[O-])c(OC)c2)n2cc(OCc3ccccc3)ccc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)c(C(=O)c2ccc(N)c(OC)c2)n2cc(O)ccc12

Procedure:
100 mg of Pd/C (10%) are added to 1.0 g (2.17 mmol) of methyl [6-(benzyloxy)-3-(3-methoxy-4-nitrobenzoyl)-2-methylindolizin-1-yl]carboxylate in suspension in 30 mL of dimethylformamide and 30 mL of tetrahydrofuran. The reaction mixture is stirred at 10 bar of hydrogen for 48 hours.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH:23]=O)[CH:9]=1.[Cl-:25].C[NH3+].[C:28]([BH3-])#[N:29].[Na+]>>[ClH:25].[CH3:28][NH:29][CH2:23][C:10]1[CH:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[N:12]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)(=[O:14])=[O:15])[CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)cc2-c2ccccc2C)cc1
Reactant: [Cl-]
Reactant: [BH3-]C#N
Agent: C[NH3+]
Agent: [Na+]
Product: CNCc1cc(-c2ccccc2C)n(S(=O)(=O)c2ccc(C)cc2)c1
Product: Cl
Yield: 69.8 %

Procedure:
Using 5-(2-methylphenyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrole-3-carbaldehyde (0.46 g), methylammonium chloride (1.11 g) and sodium cyanoborohydride (0.26 g), a procedure as in Example 4 was performed to give the title compound as colorless crystals (yield 0.37 g, 80%).
Reaction SMILES: C(N(C(C)C)[CH:4]([CH3:6])[CH3:5])C.[CH2:10](Br)[CH2:11][CH3:12].[NH2:14][CH2:15][C:16]1[O:20][C:19]([C:21]2[N:22]=[CH:23][N:24]3[C:30]4[CH:31]=[CH:32][S:33][C:29]=4[C:28](=[O:34])[N:27]4[CH2:35][CH2:36][CH2:37][C@H:26]4[C:25]=23)=[N:18][N:17]=1>CN(C)C=O>[CH2:10]([N:14]([CH2:15][C:16]1[O:20][C:19]([C:21]2[N:22]=[CH:23][N:24]3[C:30]4[CH:31]=[CH:32][S:33][C:29]=4[C:28](=[O:34])[N:27]4[CH2:35][CH2:36][CH2:37][C@H:26]4[C:25]=23)=[N:18][N:17]=1)[CH2:5][CH2:4][CH3:6])[CH2:11][CH3:12]
Reactant: CCCBr
Reactant: NCc1nnc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2sccc2-3)o1
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1nnc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2sccc2-3)o1
Reaction time: 12 h
Yield: 37.7 %

Procedure:
1.5 ml (8.6 mmol) of N-ethyldiisopropylamine and 0.4 ml (4.4 mmol) of propyl bromide were added to a solution of 0.300 g (0.87 mmol) (S)-1-(5-aminomethyl-1,3,4-oxadiazol-2-yl)-10,11,12,12a-tetrahydro-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-8-one in 20 ml of dimethylformamide, whereupon the mixture was stirred at 70° for 12 hours. The dimethylformamide was evaporated and the residue was partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase was washed twice with methylene chloride and the organic phases were dried with sodium sulfate, filtered and evaporated. Chromatography (silica gel, ethyl acetate/methanol 20:1) yielded 0.140 g (38%) of (S)-1-(5-dipropylaminomethyl-1,3,4-oxadiazol-2-yl)-10,11,12,12a-tetrahydro-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-8-one as a colourless foam, Rf=0.28 (silica gel, ethyl acetate/methanol 20:1).