Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl-].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][Zn+])=[CH:17][CH:16]=1.O>O1CCCC1.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>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([CH2:19][C:18]2[CH:21]=[CH:22][C:15]([F:14])=[CH:16][CH:17]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: Fc1ccc(C[Zn+])cc1
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(Cl)cnc1Cc1ccc(F)cc1
Temperature: 60 °C
Yield: 88 %

Procedure:
To a stirred solution of methyl 2,5-dichloronicotinate (Journal of Chemical and Engineering Data 1981, 26, 332, 350 mg, 1.70 mmol) and tetrakis(triphenylphosphine)palladium(0) (196 mg, 0.17 mmol) in tetrahydrofuran (6 mL) was added a 0.5 M solution of 4-fluorobenzylzinc chloride in tetrahydrofuran (4.08 mL, 2.04 mmol) at 0° C. under nitrogen. The resulting mixture was heated at 60° C. for 16 h. The mixture was poured into water (50 mL) and the aqueous mixture was extracted with ethyl acetate (100 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (6/1) to afford 416 mg (88%) of the title compounds as colorless oil: 1H-NMR (CDCl3) δ 8.64 (1H, d, J=2.6 Hz), 8.17 (1H, d, J=2.6 Hz), 7.24–7.20 (2H, m), 6.96–6.90 (2H, m), 4.50 (2H, s), 3.89 (3H, s).
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH2:4]([C:6]1[O:10][C:9]([CH2:11][CH2:12][NH:13][C:14]([NH:16][C:17]2[S:18][C:19]([C:23]3[CH:28]=[C:27]([CH3:29])[N:26]=[C:25](S(C)=O)[N:24]=3)=[C:20]([CH3:22])[N:21]=2)=[O:15])=[N:8][CH:7]=1)[CH3:5]>CO>[CH2:4]([C:6]1[O:10][C:9]([CH2:11][CH2:12][NH:13][C:14]([NH:16][C:17]2[S:18][C:19]([C:23]3[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]([O:2][CH3:1])[N:24]=3)=[C:20]([CH3:22])[N:21]=2)=[O:15])=[N:8][CH:7]=1)[CH3:5]
Reactant: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3cc(C)nc(S(C)=O)n3)s2)o1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3cc(C)nc(OC)n3)s2)o1
Reaction time: 18 h

Procedure:
Sodium methoxide (2M in MeOH, 0.115 ml, 0.23 mmol) is added to a stirred solution of 1-[2-(5-ethyl-oxazol-2-yl)-ethyl]-3-[5-(2-methanesulfinyl-6-methyl-pyrimidin-4-yl)-4-methyl-thiazol-2-yl]-urea (Example 40) (0.050 g, 0.115 mmol) in methanol (3 ml) at room temperature. After 18 hours, the solvent is removed and the residue is dissolved in DCM and washed with water. The product is extracted into 1M HCl and the aqueous extract is washed with DCM. The aqueous phase is then basified with aq. NaOH and the product is extracted into DCM. After drying MgSO4) the solvent is removed to give the titled compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CS[C:17](SC)=[CH:18][N+:19]([O-:21])=[O:20].C(N(CC)CC)C>C(#N)C>[C:11]([O:10][C:8]([NH:7][CH2:6][CH2:5][N:4]1[CH2:3][CH2:2][NH:1][C:17]1=[CH:18][N+:19]([O-:21])=[O:20])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CC(C)(C)OC(=O)NCCNCCN
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCN1CCNC1=C[N+](=O)[O-]
Yield: 64.6 %

Procedure:
A stirred mixture of 2.03 gram (0.010 mole) of N-{2-[(2-aminoethyl)amino]ethyl}(tert-butoxy)carboxamide (commercially available), 1.18 gram (0.010 mole) of 1,1-di(methylthio)-2-nitroethene and 2 mL (excess) of triethylamine in 40 mL of acetonitrile was warmed to reflux where it was maintained for four hours. After this time the reaction mixture was concentrated under reduced pressure to a solid residue. The residue was washed with diethyl ether and dried, yielding 1.76 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.N1CCNCC1.[CH:15](=[O:24])/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C1(C)C=CC=CC=1>[CH3:8][C:3]1[CH:2]=[CH:1][C:6]2[O:7][CH:15]([OH:24])[CH2:16][CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:5]=2[CH:4]=1
Reactant: Cc1ccc(O)cc1
Reactant: O=C/C=C/c1ccccc1
Agent: C1CNCCN1
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)C(c1ccccc1)CC(O)O2
Temperature: 80 °C

Procedure:
p-Cresol (150 g, 1.387 mol) was stirred with piperazine (72 g, 0.832 mol, 0.6 eq) in toluene (1.5 L, 10 ml/g) and then heated at reflux under Dean & Stark conditions for at least 30 minutes to remove water giving a clear pale yellow solution. Trans-Cinnamaldehyde (262 ml, 275 g, 2.081 mol, 1.5 eq) was then added over 2 hours whilst maintaining the reaction mixture at reflux under Dean & Stark conditions. Once the addition was complete, heating of the reaction mixture was continued at reflux under Dean & Stark conditions for a further 4 hours. The black solution was allowed to cool to 80° C. and then slowly quenched over 45 minutes with a solution of 0.67M HCl(aq) (750 ml, 0.601 mol, 1.3 eq). The two-phase solution was then stirred vigorously for at least 12 hours at a temperature of 75-80° C. The stirring was then stopped and the mixture allowed to cool to room temperature and the phases separated. The toluene solution was then washed with 1M HCl(aq) (750 ml, 5 ml/g), then water (3×750 ml, 5 ml/g). The 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-ol was not isolated but instead the toluene solution was used directly in the reductive amination step (Example 2).
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1.[Br:65][C:66]1[CH:71]=[CH:70][C:69]([F:72])=[C:68](C(C)=C)[CH:67]=1.CCO[C:79]([CH3:81])=[O:80]>C(O)(C)(C)C.O>[Br:65][C:66]1[CH:67]=[CH:68][C:69]([F:72])=[C:70]([C@@:79]([OH:80])([CH3:81])[CH2:1][OH:4])[CH:71]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(C)=O
Reactant: C=C(C)c1cc(Br)ccc1F
Agent: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: C[C@@](O)(CO)c1cc(Br)ccc1F
Temperature: 0 °C
Reaction time: 14 h

Procedure:
To a suspension of K3Fe(CN)6 (186 g, 561 mmol), K2CO3 (78 g, 561 mmol), (DHQ)2-PHAL (1.311 g, 1.674 mmol) and K2OsO2(OH)4 (0.378 g, 1 mmol) in t-BuOH—H2O 1:1 (1600 ml) was added 4-bromo-1-fluoro-2-isopropenyl-benzene (36 g, 167 mmol) at 0° C. and the reaction mixture was stirred for 14 h at 0° C. After careful addition of Na2S2O5 (100 g) at 0-5° C. the reaction mixture was stirred for 1 h before extraction with EtOAc. Combined extracts were washed with 5% NaS3O3 solution and brine, dried over MgSO4, filtered and concentrated to give the title compound as a white solid: TLC (hexane-EtOAc 1:1): Rf=0.46; HPLC RtH5=0.767 min; ESIMS: 266, 268 [(M+NH4)+]; 1H NMR (360 MHz, CDCl3): δ 7.71 (dd, 1H), 7.27 (m, 1H), 6.83 (dd, 1H), 3.85 (d, 1H), 3.62 (d, 1H), 2.94 (s, 3H), 2.01 (s, 1H), 1.43 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14](O)[CH3:15].C1(C)C=CC=CC=1.S(=O)(=O)(O)O>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:14][CH3:15])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CCO
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Yield: 91.9 %

Procedure:
4-Fluoro-3-nitrobenzoic acid (5.3 g, 0.029 mol), ethanol (15 mL, 0.26 mol), toluene (40 mL, 0.4 mol) and sulfuric acid (1.75 mL, 0.0328 mol) were added to a 100 mL round-bottomed flask fitted with a Dean Stark trap and reflux condenser. The reaction mixture was heated with stirring under nitrogen to reflux and maintained at reflux for 5 hours. The reaction mixture was concentrated to about half volume diluted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, water and dried over sodium sulfate. Concentration yielded a straw colored oil (5.68 g, 93%), which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=O)C(F)(F)F)[CH2:16][CH2:15]2)[CH:10]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[CH2:9]1)=[O:7].CI>C(Cl)(Cl)Cl>[F:40][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)[CH:10]([C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)[CH2:9]2)=[O:7])[CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=1
Reactant: Cc1ccc(C2CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCC2N2CCN(C(=O)C(F)(F)F)CC2)cc1
Solvent: ClC(Cl)Cl
Solvent: CI
Product: Cc1ccc(C2CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCC2N2CCN(C)CC2)cc1

Procedure:
The title compound, MS: m/e=514.4 (M+H+), [α]58920=−25.92, [α]54620=−32.60, [α]43620=−71.06, [α]36520=−152.15 (c=0.1196, chloroform), was prepared in accordance with the general method of example 102 from (−)-(1-{4-[1-(3,5-bis-trifluoromethyl-benzoyl)-3-p-tolyl-piperidin-4-yl]-piperazin-1-yl}-2,2,2-trifluoro-ethanone and methyl iodide.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22]CC4C=CC=CC=4)=[C:16]([Br:30])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]1[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=21.Cl>C(O)(=O)C.O>[NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([OH:22])=[C:16]([Br:30])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]1[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=21
Reactant: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2ccccc32)cc(Br)c1OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2ccccc32)cc(Br)c1O
Temperature: 25 °C

Procedure:
2-Amino-4-(4-benzyloxy-3-bromo-5-methoxy-phenyl)-4H-benzo[h]chromene-3-carbonitrile (2) (2 g, 3.89 mmol) was taken in 20 ml acetic acid and charged with 10M hydrochloric acid (10 ml) under vigorous stirring at room temperature, and stirred further at room temperature until the reaction was complete. The reaction mixture was then diluted with 50 ml water, stirred for 3 h at room temperature, thus formed solids were separated by filtration, washed with water and then dried under high vacuum (1.61 g, 3.8 mmol, 97.8%).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([C:10](C)([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]1[N:26](O)[CH:27]=[CH:28][C:5]=21.[OH:30][CH2:31]N1C2C(=C(O)C=CC=2)C=C1.BrC1C(OC)=C(OC)C=C(C=1)C=O.C(#N)CC#N.N1CCCCC1>>[NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]1[N:26]([CH2:31][OH:30])[CH:27]=[CH:28][C:5]=21
Reactant: OCn1ccc2c(O)cccc21
Reactant: COc1cc(C2(C)C(C#N)=C(N)Oc3c2ccc2c3ccn2O)cc(Br)c1OC
Agent: COc1cc(C=O)cc(Br)c1OC
Solvent: C1CCNCC1
Solvent: N#CCC#N
Product: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2c3ccn2CO)cc(Br)c1OC

Procedure:
2-Amino-4-(3-bromo-4,5-dimethoxyphenyl)-3-cyano-7-hydroxy-methyl-4H-pyrrolo[2,3-h]chromene: The title compound was prepared from 1-hydroxymethyl-4-hydroxy-indole (550 mg, 3.37 mmol), 5-bromoveratraldehyde (826 mg, 3.37 mmol), malononitrile (222 mg, 3.37 mmol) and piperidine (0.17 mL, 1.7 mmol), similar to Example 16, to yield 1.15 g (75%) of a white solid. 1H NMR (CDCl3): 7.22-7.18 (m, 2H), 6.90 (d, J=1.8 Hz, 1H), 6.81 (d, J=8.4 Hz, 1H), 6.75 (d, J=1.8 Hz, 1H), 6.64 (d, J=3.3 Hz, 1H), 5.61 (s, 21), 4.77 (s, 1M, 4.70 (brs, 2H), 3.83 (s, 31), 3.82 (s, 3H), 2.47 (brs, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]#N)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[F:13].[OH-:14].[Na+].Cl.C([OH:19])C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:19])=[O:14])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[F:13]
Reactant: [OH-]
Reactant: CCO
Reactant: N#CC1(c2ccc(Br)c(F)c2)CC1
Agent: Cl
Agent: [Na+]
Product: O=C(O)C1(c2ccc(Br)c(F)c2)CC1
Temperature: 100 °C

Procedure:
To a room temperature solution of 1-(4-bromo-3-fluorophenyl)cyclopropanecarbonitrile from Step 4 (4.3 g) in ethyl alcohol (40 mL) was added a solution of 20 mL of sodium hydroxide (25% NaOH in water W/W). The mixture was heated at 100° C. overnight. It was cooled to room temperature and poured into ice and hydrogen chloride (1 N), and extracted with dichloromethane (2×100 mL). The combined extracts were washed with brine, dried with magnesium sulfate and the solvent removed in vacuo. The residue was purified by swish using methyl t-butyl ether and hexanes to yield the title compound.
Reaction SMILES: C(OO)(=[O:3])C.[Cl:6][C:7]1[C:8]([O:22][CH:23]2[CH2:26][CH2:25][CH2:24]2)=[N:9][CH:10]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH:12]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C.O>[Cl:6][C:7]1[CH:12]=[C:11]([OH:3])[CH:10]=[N:9][C:8]=1[O:22][CH:23]1[CH2:26][CH2:25][CH2:24]1
Reactant: CC(=O)OO
Reactant: CC1(C)OB(c2cnc(OC3CCC3)c(Cl)c2)OC1(C)C
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Oc1cnc(OC2CCC2)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
Acetic acid solution of peracetic acid (35%, 4.2 mL, 21.3 mmol) was added to a solution of 3-chloro-2-cyclobutoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Preparation 20, 4.4 g, 14.2 mmol) in glacial acetic acid (26 mL) and water (13 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour. Aqueous solution of sodium thiosulfate (0.5 M, 80 mL) was added and the mixture was stirred for 30 minutes at room temperature. The aqueous layer was extracted with EtOAc (3×40 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with 10% EtOAc in heptane to afford the title compound as a clear oil (2.05 g, 72%):
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([OH:10])[CH3:9].[BH4-].[Na+].Cl.C[C:15](=[O:17])C>O>[O:10]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH2:7][CH2:9][C@@H:8]1[CH2:15][OH:17]
Reactant: Cc1ccccc1
Reactant: CCO
Reactant: CC(C)=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: OC[C@H]1CCc2ccccc2O1
Temperature: 50 °C

Procedure:
A mixture of toluene (1000 ml) and ethanol (absolute. 520 ml) was stirred. Sodium borohydride (2.13 mol) was added at room temperature, under an inert atmosphere. The mixture was heated to 50° C. Intermediate (2) (2.14 mol) was added dropwise at 50° C. in a 90-minutes period (exothermic temperature rise of 15° C., cooling required). The reaction mixture was stirred for 90 minutes at 50° C. Water (1500 ml) was added while stirring. Then, 2-propanone (100 ml) was added dropwise under slight cooling. The mixture was decomposed with HCl (180 ml). The organic layer was separated, dried, filtered and the solvent evaporated, yielding 295 g of (−)-(R)-3,4-dihydro-2H-1-benzopyran-2-methanol (interm. 3).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH:56]1[CH2:61][CH2:60][CH:59]([O:62][CH2:63][C:64]([N:66]2[CH2:70][CH2:69][CH2:68][CH2:67]2)=[O:65])[CH2:58][CH2:57]1>CC(N(C)C)=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:56]1[CH2:61][CH2:60][CH:59]([O:62][CH2:63][C:64](=[O:65])[N:66]2[CH2:67][CH2:68][CH2:69][CH2:70]2)[CH2:58][CH2:57]1)=[O:5]
Reactant: O=C(COC1CCNCC1)N1CCCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1)N1CCCC1
Reaction time: 2 h

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.20 g, 0.67 mmol) and HBTU (0.381 g, 1.01 mmol) were added to DMA (4 mL), to this was added N-ethyl-N-isopropylpropan-2-amine (0.179 mL, 1.01 mmol) and then 2-(piperidin-4-yloxy)-1-(pyrrolidin-1-yl)ethanone (106) (0.142 g, 0.67 mmol). The reaction was stirred for 2 hours before being evaporated to dryness and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH+) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to the desired compound as a white solid (0.168 g, 50.9%); 1H NMR (400.132 MHz, CDCl3) δ 1.90-1.56 (m, 6H), 2.01-1.93 (m, 2H), 3.16-3.07 (m, 1H), 3.57-3.42 (m, 6H), 3.72 (septet, J=3.6 Hz, 1H), 4.06-4.00 (m, 1H), 4.12 (q, J=11.9 Hz, 2H), 4.26 (s, 2H), 7.02 (t, J=8.8 Hz, 1H), 7.32-7.25 (m, 2H), 7.79-7.70 (m, 3H), 8.47-8.44 (m, 1H), 10.01-9.97 (m, 1H); m/z (LC-MS, ESI+), RT=1.66 (M+H 493).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.[CH2:22]([C@@H:29]1[CH2:33][O:32][C:31](=[O:34])[N:30]1[C:35](=[O:45])[C@H:36]([CH2:40][S:41](Cl)(=[O:43])=[O:42])[CH:37]([CH3:39])[CH3:38])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl>[CH2:22]([C@@H:29]1[CH2:33][O:32][C:31](=[O:34])[N:30]1[C:35](=[O:45])[C@H:36]([CH2:40][S:41]([N:19]1[CH2:20][CH2:21][N:16]([C:13]2[N:14]=[CH:15][C:10]([C:7]3[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=3)=[CH:11][N:12]=2)[CH2:17][CH2:18]1)(=[O:43])=[O:42])[CH:37]([CH3:39])[CH3:38])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Fc1ccc(-c2cnc(N3CCNCC3)nc2)cc1
Reactant: CC(C)[C@@H](CS(=O)(=O)Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.3 %

Procedure:
5-(4-Fluorophenyl)-2-piperazin-1-ylpyrimidine dihydrochloride (0.57 g) was added to a solution of 4-(R)-benzyl-3-(2-(R)-chlorosulfonylmethyl-3-methylbutyryl)-oxazolidin-2-one (0.77 g) in dichloromethane (20 ml) followed by triethylamine (0.84 ml), and the mixture stirred at room temperature for 18 h. The solvent was evaporated under reduced pressure, and the residue dissolved in ethyl acetate (40 ml) and washed with 10% citric acid (2×20 ml), water (20 ml), saturated sodium bicarbonate solution (20 ml), water (20 ml), saturated brine (20 ml), dried (Na2SO4) and evaporated. The resultant residue was then purified by silica gel column chromatography with 3.5% diethyl ether/dichloromethane as eluent to provide the title compound as a white solid (0.70 g, 69%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C([O-])([O-])=O.[K+].[K+].Cl>O.CC#N>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)[CH3:23]
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CCOC(=O)CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CCCOc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 80 °C
Yield: 79.8 %

Procedure:
A mixture of 4-(4-bromophenyl)phenol (3.74 g, 15.0 mmol), MeCN (20 ml), ethyl 4-bromobutyrate (4.42 g, 22.7 mmol), and K2CO3 (3.12 g, 22.6 mmol) was stirred at 80° C. After 16 h water (100 ml) and 1N HCl (40 ml) were added, and the product was extracted (3×AcOEt), the combined extracts were washed with brine (2×), dried (MgSO4), and concentrated. The residue was recrystallized from EtOH (40 ml) to yield 4.35 g (80%) of 4-(4′-bromobiphenyl-4-yloxy)butyric acid ethyl ester as colorless plates.
Reaction SMILES: [OH-].[Na+].O.CC[O:6][C:7]([C@@H:9]([NH:18][C@H:19]([C:21]([N:23]1[C@H:31]([C:32]([OH:34])=[O:33])[CH2:30][C@@H:29]2[C@@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28]2)=[O:22])[CH3:20])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8].[ClH:35]>[OH-].[Na+].C(O)C>[CH3:20][C@H:19]([NH:18][C@H:9]([C:7]([OH:8])=[O:6])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:21]([N:23]1[C@H:31]([C:32]([OH:34])=[O:33])[CH2:30][C@@H:29]2[C@@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28]2)=[O:22].[Cl-:35]
Reactant: Cl
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1[C@H](C(=O)O)C[C@H]2CCCC[C@@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@H](N[C@@H](CCc1ccccc1)C(=O)O)C(=O)N1[C@H](C(=O)O)C[C@H]2CCCC[C@@H]21
Product: [Cl-]
Reaction time: 14 h

Procedure:
A solution of NaOH (1.84 g, 43.48 mmol; assay=94.52%), water (45 ml), ethanol (45 ml, technical grade, contains ˜5% 2-propanol) and Trandolapril (9.0 g, 20.78 mmol; assay=99.4%) was stirred at an internal temperature ranging from about 20° C. to about 25° C. for 14 hours. After an in process control showed an almost complete saponification (by HPLC), the reaction mixture was concentrated in vacuo to an amount of 64.64 g One half of the concentrated reaction mixture was used and the pH was adjusted to 3.8 by an addition of 2N aqueous hydrochloric acid (21.61 mmol) and a few drops of 2N aqueous NaOH solution. Initially during acidification, a sticky flocculent precipitation at a pH of 6 was observed, and upon further acidification a suspension containing a fine white solid was formed. The suspension was stirred at a temperature ranging from about 20° C. to about 25° C. for 16 hours and filtered off. The wet product was washed with water (30 ml) and acetone (30 ml) and dried in vacuo (1-5 mbar), 24 hours at 40° C. and 24 hours at room temperature) to give crystalline Trandolaprilat Form C (yield: 3.18 g, 7.45 mmol, 71.7% (extrapolated); assay (0.1N HClO4)=94.35%; HPLC purity=100%; water content: 5.67%, chloride content=0.16%).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([CH:7]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[CH:8]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH2:9][C:10]([OH:12])=[O:11])#[N:6].[C:27]1(=O)[CH2:32][CH2:31][CH2:30][C:29](=[O:33])[CH2:28]1.C(N(CC)CC)C>ClCCl>[C:5]([CH:7]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[CH:8]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH2:9][C:10]([O:12][C:27]1[CH2:32][CH2:31][CH2:30][C:29](=[O:33])[CH:28]=1)=[O:11])#[N:6]
Reactant: N#CC(c1cccc(F)c1)C(CC(=O)O)c1ccc(F)cc1
Reactant: O=C1CCCC(=O)C1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CC(c1cccc(F)c1)C(CC(=O)OC1=CC(=O)CCC1)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
1.79 g (15 mmol) of thionyl chloride were added to 0.452 g (1.5 mmol) of 4-cyano-3-(4-fluorophenyl)-4-(3-fluorophenyl)butanoic acid, and the mixture was stirred at 80° C. for 1.5 h. Excess thionyl chloride was removed under reduced pressure. The reaction mixture concentrated in this manner (which contains acid chloride) was dissolved in 3 ml of dichloromethane and, at 0° C., added dropwise (about 30 min) to a mixture of 0.252 g (2.25 mmol) of 1,3-cyclohexanedione and 0.304 g (3 mmol) of triethylamine in dichloromethane (10 ml). After 3 h of stirring at 25° C., the solvent was removed under reduced pressure, the residue was taken up in ethyl acetate and the mixture was washed twice with in each case 25 ml of water. The combined organic phases were dried over sodium sulphate and the solvent was removed under reduced pressure.