Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:28]([OH:30])=[O:29])[CH2:20][NH:21]C(OCC=C)=O)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1([SiH3])C=CC=CC=1>ClCCl.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>[NH2:21][CH2:20][C@@H:19]([C:28]([OH:30])=[O:29])[NH:18][C:16]([O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:17]
Reactant: C=CCOC(=O)NC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Solvent: ClCCl
Product: NC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reaction time: 0.58 h

Procedure:
A mixture of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-3-[(2-propenyloxy)carbonyl]amino-L-alanine resin (Example 64; 2 g), tetrakis(triphenylphosphine)palladium(0) (509 mg, 0.45 mmol), and phenylsilane (21.9 mmol) in dichloromethane (20 mL) was shaken for 35 min. The resin was washed with dichloromethane and methanol, then vortexed with dimethylformamide/water (1:1) at room temperature for 10 min, and washed again with dichloromethane and methanol to give 3-amino-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-alanine on Wang resin.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH:3]1[O:7][N:6]=[C:5]([CH2:8]O)[CH2:4]1.O1CCN(S(F)(F)[F:19])CC1.C([O-])(O)=O.[Na+]>ClCCl>[F:19][CH2:8][C:5]1[CH2:4][CH:3]([C:2]([F:11])([F:10])[F:1])[O:7][N:6]=1
Reactant: OCC1=NOC(C(F)(F)F)C1
Reactant: FS(F)(F)N1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FCC1=NOC(C(F)(F)F)C1
Reaction time: 0.5 h
Yield: 35.9 %

Procedure:
To a solution of crude (5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)methanol (7.0 g, 41.4 mmol) in dichloromethane (140 ml) was added at −78° C. morpholinosulfur trifluoride (7.98 g, 45.5 mmol) and stirring was continued at −78° C. for 15 min, at 0° C. for 1 h and at 22° C. for 30 min. The solution was treated with cold aqueous NaHCO3, the organic layer was dried, evaporated (70 mbar/40° C.) and the residue was distilled from bulb to bulb at 100° C./0.8 mbar to give 3-(fluoromethyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (2.54 g) as a pale yellow liquid. MS: m/z=171 [M]+.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13](Cl)(=[O:23])[C:14]1[CH:22]=[CH:21][CH:20]=[C:16]([C:17](Cl)=[O:18])[CH:15]=1>>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:13](=[O:23])[C:14]2[CH:22]=[CH:21][CH:20]=[C:16]([C:17]([O:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=3)=[O:18])[CH:15]=2)=[CH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Product: CCOC(=O)c1ccc(OC(=O)c2cccc(C(=O)Oc3ccc(C(=O)OCC)cc3)c2)cc1

Procedure:
A similar procedure to Example 5 is carried out by using ethyl p-hydroxybenzoate and isophthalic dichloride. The reaction product is recrystallized from chloroform-ethyl acetate (1:1) to yield di(p-ethoxycarbonylphenyl)isophthalate, m.p. 123°-125° C., as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2Cl.[CH3:16][NH:17][CH2:18][CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[CH3:20]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:17]([CH2:18][CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[CH3:20])[CH3:16]
Reactant: CNCC(C)c1ccccn1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Product: COc1cc2ncnc(N(C)CC(C)c3ccccn3)c2cc1OC

Procedure:
Reaction of 6,7-dimethoxy-4-chloroquinazoline with 2-(1-[N-methylamino]prop-2-yl)pyridine, according to the procedure of Example I, afforded the title compound, isolated as its dihydrochloride trihydrate, m.p. 235°C.
Reaction SMILES: [CH:1]([CH:4]([C:9](=O)[CH3:10])[CH2:5][CH2:6][C:7]#[N:8])([CH3:3])[CH3:2].[NH3:12]>[O-2].[O-2].[Ti+4].[H][H]>[CH:1]([CH:4]([CH:9]([NH2:12])[CH3:10])[CH2:5][CH2:6][CH2:7][NH2:8])([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(=O)C(CCC#N)C(C)C
Reactant: [H][H]
Agent: [Ti+4]
Agent: [O-2]
Product: CC(C)C(CCCN)C(C)N
Yield: 90 %

Procedure:
10 g of 4-isopropyl-5-oxohexanenitrile (purity 95.7%) and 115 g of liquid ammonia were pumped hourly from bottom to top at 250 bar and 80° C. through a tubular reactor (diameter 16 mm, fill level 50 cm, oil-heated twin jacket) arranged before the hydrogenation reactor and filled with 63.5 g (100 ml) of titanium dioxide (anatase) in the form of 1.5 mm pellets. 100 l (s.t.p.)/h of hydrogen were subsequently passed in, and the product discharged from the upstream imination reactor was passed through the hydrogenation reactor from bottom to top at 250 bar and 110° C. The mixture was decompressed at atmospheric pressure, the ammonia was removed by distillation, and the discharge from 72 hours was separated by fractional distillation on a 30 cm packed column (3-mm glass rings). 640 g of 4-isopropyl-1,5-hexanediamine were obtained as a colorless liquid (b.p. 80° C./1 mbar), corresponding to a yield of 90 %.
Reaction SMILES: [F:1][C:2]1([CH2:6][NH:7][C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:5][O:4][CH2:3]1.[H-].[Na+].[CH:32]1([CH2:35]Br)[CH2:34][CH2:33]1>CN(C)C=O>[F:1][C:2]1([CH2:6][NH:7][C:8]([C:10]2[N:11]([CH2:35][CH:32]3[CH2:34][CH2:33]3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:3][O:4][CH2:5]1
Reactant: BrCC1CC1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)NCC4(F)COC4)cc3c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)NCC2(F)COC2)n3CC2CC2)CC1
Yield: 40 %

Procedure:
The title compound was synthesized in analogy to example 51, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid (3-fluoro-oxetan-3-ylmethyl)-amide, sodium hydride and cyclopropylmethyl bromide in N,N-dimethylformamide, to give the desired product as a colorless foam (40%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([C@@H:9]([OH:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[C:14]([O:18][C:19]([N:21]1[CH2:24][CH:23]([O:25][C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=2O)[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:14]([O:18][C:19]([N:21]1[CH2:24][CH:23]([O:25][C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=2[O:11][C@@H:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=2)[CH3:10])[CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: C[C@H](O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2O)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](Oc1ccc(Cl)cc1OC1CN(C(=O)OC(C)(C)C)C1)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 48 h
Yield: 90.5 %

Procedure:
To (S)-1-(3-trifluoromethyl-phenyl)-ethanol (2.30 g, 12.1 mmol), 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (3.80 g, 12.7 mmol) and PPh3 (3.80 g, 14.5 mmol) in THF (60 mL) at 0° C. was added DEAD (2.3 g, 2.1 mL, 13 mmol) in THF (10 mL) dropwise over 30 min. After 48 h, the reaction was concentrated and 15% EtOAc in hexanes was added. The flask was cooled to 0° C. and filtered. The filtrate was concentrated and this procedure repeated 2 more times. The resulting oil was then purified using silica gel chromatography (10-40% EtOAc in hexanes) to give 5.17 g (91%) of the title compound as a clear oil. 1H NMR (CDCl3): 7.66 (s, 1H), 7.56-7.53 (m, 2H), 7.46 (t, J=7.7 Hz, 1H), 6.79 (dd, J=8.6, 2.4 Hz, 1H), 6.71 (d, J=8.6 Hz, 1H), 6.52 (d, J=2.4 Hz, 1H), 5.29 (q, J=6.5 Hz, 1H), 4.88-4.82 (m, 1H), 4.33-4.29 (m, 2H), 4.08-4.01 (m, 2H), 1.67 (d, J=6.5 Hz, 3H), 1.46 (s, 9H).
Reaction SMILES: CN[C@H](C(O)=O)CC(C)C.N[C@H](C(O)=O)C.C([S:25][CH2:26][CH2:27][C:28]([N:30]([CH3:39])[C@H:31]([C:36]([OH:38])=[O:37])[CH2:32][CH:33]([CH3:35])[CH3:34])=[O:29])(=O)C1C=CC=CC=1.N[C@H](C(O)=O)CC(C)C>>[SH:25][CH2:26][CH2:27][C:28]([N:30]([CH3:39])[C@H:31]([C:36]([OH:38])=[O:37])[CH2:32][CH:33]([CH3:35])[CH3:34])=[O:29]
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C(=O)CCSC(=O)c1ccccc1
Agent: CC(C)C[C@H](N)C(=O)O
Agent: CN[C@@H](CC(C)C)C(=O)O
Agent: C[C@H](N)C(=O)O
Product: CC(C)C[C@@H](C(=O)O)N(C)C(=O)CCS

Procedure:
By substituting N-methyl-L-leucine for the L-alanine in the procedure of Example 1, and then treating the product by the procedure of Example 2, N-(3-benzoylthiopropanoyl)-N-methyl-L-leucine, and N-(3-mercaptopropanoyl)-N-methyl)-L-leucine are obtained.
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([N:14](CC)CC)[CH3:13].ClC(Cl)(O[C:23](=[O:29])[O:24][C:25](Cl)(Cl)Cl)Cl.[CH3:31][OH:32]>C(Cl)Cl>[CH3:31][O:32][CH2:13][C@H:12]1[CH2:25][O:24][C:23](=[O:29])[NH:14]1
Reactant: CO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN(CC)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: COC[C@H]1COC(=O)N1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38 %

Procedure:
TsOH (800 mg, 4.21 mmol) was added to a yellow solution of product from step 5.3 (1.013 g, 4.13 mmol) in MeOH (10 ml). The mixture was stirred at RT for 90 min. Then TsOH (140 mg, 0.74 mmol) was added and it was stirred for 70 min at RT. Then solvent was removed and the residue was dissolved in DCM (6 mL) with Triethylamine (1.44 ml, 10.32 mmol). A solution of triphosgene (0.613 g, 2.07 mmol) in DCM (4 mL) was slowly added to the mixture. The reaction mixture was stirred at RT for 2 h 30. The reaction was quenched with a few drops of water. It was then acidified to pH=4 with buffer was added and then the layers were separated. The aqueous one was extracted once more with some DCM. Organic layers were combined, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography (DCM/MeOH: 100%→90% DCM) to give the title compound (231 mg, 38%). ESI-MS: 132.1 [M+H]+ (LC-MS 1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH:10]([OH:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH:10]([O:21][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: OC1CN(Cc2ccccc2)CCC1c1cccc(F)c1
Product: Fc1cccc(C2CCN(Cc3ccccc3)CC2OCc2ccc3ccccc3c2)c1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating (3RS,4RS)-1-benzyl-4-(3-fluorophenyl)-piperidin-3-ol with 2-bromomethyinaphthalene there was obtained (3RS,4RS)-1-benzyl-4-(3-fluorophenyl)-3-(naphthalen-2-ylmethoxy)-piperidine as a colourless oil; MS: 426 (M+H)+. By cleavage of the benzyl protecting group with 2,2,2-trichloroethyl chloroformate in an analogous manner to that described in Example 12 (c) there was obtained 2,2,2-trichloroethyl (3RS,4RS)-4-(3-fluorophenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a yellow oil; MS: 510 (M+H)+.
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Na+:6].[Na+].[CH3:8][CH2:9][CH2:10][CH2:11][CH:12]([CH2:15][CH2:16][CH:17](O)[CH2:18][CH2:19][CH:20](CC)[CH2:21][CH3:22])CC>>[CH2:22]([O:2][S:1]([O-:5])(=[O:4])=[O:3])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8].[Na+:6]
Reactant: O=S(=O)([O-])[O-]
Reactant: CCCCC(CC)CCC(O)CCC(CC)CC
Agent: [Na+]
Product: CCCCCCCCCCCCCOS(=O)(=O)[O-]

Procedure:
sodium sulfate of 3,9-diethyltridecanol-6
Reaction SMILES: [N:1]1[C:9]2[CH2:8][C@H:7]([CH2:10][OH:11])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl.O>[N:1]1[C:9]2[CH2:8][CH:7]([CH2:10][O:11][S:20]([CH3:19])(=[O:22])=[O:21])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@@H]1Cc2cccnc2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCC1Cc2cccnc2C1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 102.7 %

Procedure:
To a solution of 895 mg (6 mmol) of (+)-(6R)-(6,7-dihydro-5H-[1]pyrindin-6-yl)-methanol in 50 ml of anhydrous dichloromethane was added, at −15° C., 0.918 ml (6.6 mmol) of triethylamine and 0.465 ml (6 mmol) of methanesulfonyl chloride. The resulting mixture was stirred at 0° C. for 45 min. The mixture was then diluted with water and dichloromethane and extracted with dichloromethane. Organic layer was dried and evaporated to give 1.4 g (100%) of methanesulfonic acid 6,7-dihydro-5H-[1]pyrindin-6-ylmethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C:19](=[O:21])[CH3:20])=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: NCCCc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCCCc1ccc(F)cc1
Reaction time: 0.33 h
Yield: 86.3 %

Procedure:
1-(para-fluorophenyl)-3-aminopropane (1.00 g, 6.53 mmol, 1 eq.) and triethylamine (0.91 mL, 6.53 mmol, 1 eq.) were dissoved in THF (10 mL) at 25° C. under N2. Then a THF solution (5 mL) of acetyl chloride (0.46 mL, 6.53 mmol, 1 eq.) was added dropwise via an addition funnel over 10 minutes. Worked up after 20 minutes by filtering off the solids then stripping the filtrate to obtain an amber oil. The oil was purified over silica gel in 1:1 Hexanes/EtOAc to 100% EtOAc to 4:1 EtOAc/MeOH. Obtained 1.10 g of an amber oil as product. MS (ESI) detects (M+H)+=196.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH:12]2[CH2:16][N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[C:14](=[O:28])[N:13]2[CH3:29])=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl.O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH:12]2[CH2:16][N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[C:14](=[O:28])[N:13]2[CH3:29])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CN1C(=O)N(Cc2ccc(C(F)(F)F)cc2)CC1CCCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
A solution of 4-[3-(4-methoxy-phenyl)-propyl]-3-methyl-1-(4-trifluoromethyl-benzyl)-imidazolidin-2-one (3.51 g, 8.63 mmol) in dry CH2Cl2 (60 mL), cooled to −78° C. and then treated dropwise with BBr3 (6.49 g, 25.9 mmol). The reaction was warmed 0° C. and stirred for 2 h under N2. The reaction mixture was diluted with water and extracted with CH2Cl2. The organic layer was dried (MgSO4), and the solvent removed in vacuo to give crude product that was purified by flash chromatography using 2:1 hexanes:acetone to afford 3.01 g (89%) 4-[3-(4-hydroxy-phenyl)-propyl]-3-methyl-1-(4-trifluoromethyl-benzyl)-imidazolidin-2-one. 1H NMR. MS (ES30) Calc'd for C21H24N2O2F3 (M+1) 393. Found m/z 393 (100%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][C:16]([CH3:24])([CH3:23])[C:15]=3[CH:14]=[C:13]([CH:25]=[O:26])[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:27]([Mg]Br)#[CH:28]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:20]3[C:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][C:16]([CH3:24])([CH3:23])[C:15]=3[CH:14]=[C:13]([CH:25]([OH:26])[C:27]#[CH:28])[CH:12]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C#C[Mg]Br
Reactant: CC(C)(C)c1ccc(-c2cc(C=O)cc3c2C(C)(C)CCC3(C)C)cc1
Product: C#CC(O)c1cc(-c2ccc(C(C)(C)C)cc2)c2c(c1)C(C)(C)CCC2(C)C
Yield: 80 %

Procedure:
In a manner similar to that of Example 1f, by reacting 350 mg (1 mmol) of 4-(4-tert-butylphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenecarbaldehyde with 2.6 mL (1.3 mmol) of 0.5 N ethynylmagnesium bromide solution. White crystals are obtained (m=300 mg; yield=80%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.C(N(CC)CC)C.[CH3:17][NH:18][C@@H:19]([CH3:22])[CH2:20][OH:21]>C(#N)C.CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([N:18]([CH3:17])[C@@H:19]([CH3:22])[CH2:20][OH:21])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: CN[C@@H](C)CO
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC#N
Product: C[C@@H](CO)N(C)c1cc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2,4,6-trichloropyrimidine (5.42 mL, 47.1 mmol) and triethylamine (19.7 mL, 141 mmol) in acetonitrile (40 mL) was slowly added (S)-2-(methylamino)propan-1-ol (6.30 g, 70.7 mmol) in N,N-dimethylformamide (DMF) (3.00 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h, filtered, dried over anhydrous Na2SO4, concentrated. Purification via flash chromatography column (petroleum ether/ethyl acetate=10/1) afforded the title product.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]2[S:7][CH:8]=[C:9]([CH3:10])[C:5]=2[CH:4]=1.C([Li])CCC.[C:18](=[O:20])=[O:19]>CCOCC>[OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]2[S:7][C:8]([C:18]([OH:20])=[O:19])=[C:9]([CH3:10])[C:5]=2[CH:4]=1
Reactant: O=C=O
Reactant: Cc1csc2ccc(CO)cc12
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1c(C(=O)O)sc2ccc(CO)cc12
Reaction time: 2 h

Procedure:
A solution of 5-hydroxymethyl-3-methylbenzo[b]thiophene (8.50 g.) in dry ether (120 ml.) was added dropwise to a stirred solution of n-butyl lithium (72 ml. of 1.6M solution in hexane) in dry ether (120 ml.) at 0° under an atmosphere of dry nitrogen. The resulting mixture was stirred at 0° for 2 hours and then poured onto a mixture of crushed solid carbon dioxide and ether. When all the carbon dioxide had evaporated the mixture was shaken with water. The aqueous layer was separated and acidified with concentrated hydrochloric acid. The solid was filtered off, washed well with water and crystallized from ethanol to give 5-hydroxymethyl-3-methylbenzo[b]thiophene-2-carboxylic acid (4.80 g.), m.p. 260°-262°.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:28][N:14]4[C:15](=[O:27])[CH2:16][CH2:17][N:18](C(OC(C)(C)C)=O)[CH2:19][C@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C([Cl:32])(=O)C>CO>[ClH:32].[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:28][N:14]4[C:15](=[O:27])[CH2:16][CH2:17][NH:18][CH2:19][C@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N2C[C@H](Oc3cnc(C4CC4)cn3)C[C@@H]2C1
Solvent: CO
Product: Cl
Product: O=C1CCNC[C@H]2C[C@@H](Oc3cnc(C4CC4)cn3)CN12
Temperature: 60 °C

Procedure:
tert-Butyl (8R,9aR)-8-[(5-cyclopropylpyrazin-2-yl)oxy]-5-oxohexahydro-1H-pyrrolo[1,2-a][1,4]diazepine-2(3H)-carboxylate (50 mg, 0.103 mmol, Part A) was dissolved in methanol (1.0 mL) in a 20-mL scintillation vial. In a separate 4-mL vial, acetyl chloride (0.090 ml, 1.29 mmol) was added to methanol (0.5 mL) at 0° C., and the resulting acidic solution was added to the reaction vial. The vial was capped, and the reaction mixture was heated to 60° C. for 0.5 hour. The reaction mixture was then cooled to room temperature and concentrated to provide (8R,9aR)-8-[(5-cyclopropylpyrazin-2-yl)oxy]octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one hydrochloride that was used in the next step without additional purification.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[NH:36][NH2:37])[CH:29]=[CH:28][N:27]=1>>[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[N:36]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:18][CH:19]=4)[N:8]=3)=[CH:4][CH:3]=[N:37]2)[CH:29]=[CH:28][N:27]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Reactant: NNc1cccc2ccncc12
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1cccc2ccncc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and isoquinolin-8-yl-hydrazine according to the method described for example 91. MS: M=450.1 (M+H)+
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=2[O:2]1.[Mg].I[CH2:14][CH3:15].[Cl-].[NH4+]>C(OCC)C.O>[CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH2:14][CH3:15])=[CH:4][C:3]=2[O:2]1
Reactant: CCI
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: CCC(O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3,4-methylenedioxybenzaldehyde (4.5 g, 30 mmol) of formula 2 prepared in dry diethyl ether is slowly added to an ethereal solution of Grignard reagent prepared from magnesium metal (0.84 g, 35 mmol) and iodoethane (3.0 ml, 40 mmol) and the contents stirred for 1 hour at room temperature. After the completion of the reaction, the mixture is processed by adding saturated aqueous solution of ammonium chloride (10 ml) followed by dilution with water (100 ml), separating the organic layer and extracting the aqueous layer with solvent ether (2×100 ml). The combined organic layer washed with water (2×20 ml) dried over anhydrous sodium sulfate and concentrated in vacuo to yield 1-(3,4-methylenedioxyphenyl) propan-1-ol, a semisolid of formula 3 (5.3 g, 97.5%).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C@H:6]([C:10]([NH:12][CH:13]([CH:21]([OH:44])[CH:22]([OH:43])[CH:23]([NH:31][C:32](=[O:42])[C@H:33]([CH:39]([CH3:41])[CH3:40])[NH:34][C:35](=[O:38])[CH2:36]Br)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].[SH:45][C:46]1[NH:47][CH:48]=[CH:49][N:50]=1>>[NH:47]1[CH:48]=[CH:49][N:50]=[C:46]1[S:45][CH2:2][C:3]([NH:5][C@H:6]([C:10]([NH:12][CH:13]([CH:21]([OH:44])[CH:22]([OH:43])[CH:23]([NH:31][C:32](=[O:42])[C@H:33]([CH:39]([CH3:41])[CH3:40])[NH:34][C:35]([CH2:36][S:45][C:46]1[NH:47][CH:48]=[CH:49][N:50]=1)=[O:38])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4]
Reactant: Sc1ncc[nH]1
Reactant: CC(C)[C@H](NC(=O)CBr)C(=O)NC(Cc1ccccc1)C(O)C(O)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)CBr)C(C)C
Product: CC(C)[C@H](NC(=O)CSc1ncc[nH]1)C(=O)NC(Cc1ccccc1)C(O)C(O)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)CSc1ncc[nH]1)C(C)C
Yield: 47.5 %

Procedure:
The resultant compound of Example 251 (150 mg, 0.2 mmol) was reacted with 2-mercaptoimidazole (40.6 mg) by the procedure described in Example 252 and similarly purified to afford the title compound (74 mg, 47%). 1H NMR (DMSO-d6, 300 MHz) δ0.63 (m, 12H), 1.84 (m, 2H), 2.25-2.80 (m, 4H), 3.05-3.82 (m, 12H), 4.44 (m, 2H), 7.14 (m, 14H), 7.48 (bd, 2H), 8.07 (bd, 2H). MS (FAB) m/e 779 (M+H)+.