Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[CH:4]=1.[Br:13]Br.O>ClCCl>[Br:13][C:4]1[C:5]([O:11][CH3:12])=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: BrBr
Reactant: COc1cc(OC)cc(OC)c1
Solvent: O
Solvent: ClCCl
Product: COc1cc(OC)c(Br)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
KM03 Dissolve 1,3,5-trimethoxybenzene (10.0 g, 59.46 mmol) in anhydrous dichloromethane (100 mL), cool the reaction mixture to −78° C., add dropwise bromine (3.0 mL, 59.44 mmol) stir the mixture for 1 h between −70° C. and −40° C. Warm up the solution to 0° C. and add water. Separate layers and extract the aqu. layer with EtAOc (3 times). Wash combined organic layer with water and brine and dry it with Na2SO4. Remove solvent and purify the crude product by recrystallization from hot EtOAc and cyclohexane to obtain 2-Bromo-1,3,5-trimethoxy-benzene (48) as a white solid (8.84 g, 60%). 1H NMR (400 MHz, CDCl3): 3.80 (s, 3 H); 3.86 (s, 6 H); 6.15 (s, 2 H).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[C:6](=[O:19])[N:7]=[C:8](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:9][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:13]1(/[CH:12]=[CH:11]/[C:8]2[N:9]=[CH:10][C:5]3[CH2:4][CH2:3][CH2:2][O:19][C:6]=3[N:7]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=c1nc(/C=C/c2ccccc2)[nH]cc1CCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C(=C/c1ncc2c(n1)OCCC2)\c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 85 %

Procedure:
To 5-(3-hydroxypropyl)-2-[(E)-2-phenylethenyl]-4(1H)-pyrimidinone (1.0 g; 4.0 mmol) in THF (20 ml) was added triphenyl phosphine (1.6 g; 6.0 mmol) and diethyl azodicarboxylate (1.0 g; 6.0 mmol). The reaction was allowed to stir at room temperature under nitrogen for 14 hours. The reaction was partitioned between water (20 ml) and EtOAc (100 ml), and the aqueous phase was further extracted with EtOAc (2×50 ml). The combined organic extracts were dried with Na2SO4, the solvents were removed and the crude residue was purified by column chromatography on silica gel using a 0-2.5% MeOH in DCM gradient to provide the desired compound (0.81 g; 84%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](O)=[O:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[NH2:27][CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C.O>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23]([NH:27][CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:24])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)O)cc2)cc1
Reactant: CC(C)(C)OC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)NCCC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)propanoic acid (30 mg, 0.089 mmol), tert-butyl 3-aminopropanoate hydrochloride (19.38 mg, 0.107 mmol), and TEA (0.037 mL, 0.267 mmol) in DMF (1 mL) was added HATU (40.6 mg, 0.107 mmol). The reaction was stirred at room temperature overnight. The mixture was added H2O (1 mL) and 1M HCl (1 mL) and purified by HPLC to give the title compound. LCMS m/z=465.5 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.27 (d, J=6.8 Hz, 0.4H), 1.44 (s, 9H), 1.46 (d, J=6.5 Hz, 2.6H), 1.69-1.82 (m, 1H), 2.02-2.12 (m, 2H), 2.23-2.32 (m, 1H), 2.35 (t, J=6.6 Hz, 2H), 2.46 (t, J=7.6 Hz, 2H), 2.93 (t, J=7.6 Hz, 2H), 3.05-3.22 (m, 4H), 3.31-3.38 (m, 2H), 3.38-3.49 (m, 1H), 3.52-3.63 (m, 1H), 3.72-3.82 (m, 1H), 6.50 (s, 1H), 7.32 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.2 Hz, 2H), 7.57 (d, J=8.2 Hz, 2H), 7.63 (d, J=8.2 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14].[CH2:22](C([Sn])=C(CCCC)CCCC)[CH2:23]CC>C(#N)C>[CH:22]([C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[CH2:23]
Reactant: COc1ccc(Br)c2ccn(S(=O)(=O)c3ccccc3)c12
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Solvent: CC#N
Product: C=Cc1ccc(OC)c2c1ccn2S(=O)(=O)c1ccccc1

Procedure:
4-Bromo-7-methoxy-1-(phenylsulfonyl)-1H-indole (200 mg, 0.55 mmol, Intermediate 43), tributylvinyltin (348 mg, 1.1 mmol) and bis(acetate)bis(triphenylphosphine)-palladium(II) (46 mg, 0.06 mmol) were mixed in dry acetonitrile (2 mL) and heated in microwave at 180 deg for 10 min. The reaction mixture was filtered through celite and concentrated. The crude product was purified by column chromatography on silica (CHCl3/hexane 7:3) to give 4-vinyl-7-methoxy-1-(phenylsulfonyl)-1H-indole, 0.19 g, which was used immediately in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:12][CH:13](O)[CH:14]=[CH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:12]([CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)[C:8]1=[O:11])[CH:13]=[CH:14][CH3:15]
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2ccc(Br)cc2C1=O
Yield: 78 %

Procedure:
A solution of 10.0 g of 6-bromo-1-indanone, 9.79 ml of 3-buten-2-ol and 100 mg of p-toluenesulfonic acid in 100 ml of 2,2-dimethoxypropane was boiled under reflux for 71 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 1:1). In addition to 3.07 g of educt, there were obtained 9.86 g (78%) of (RS)-2-(2-buten-1-yl)-6-bromo-1-indanone as a yellow oil.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]1([CH2:16][O:17][C:18]([NH:20][C:21]2([C:27]([NH:29][C@H:30]([CH2:34][OH:35])[CH:31]([CH3:33])[CH3:32])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CS(C)=O.C(Cl)Cl>[C:10]1([CH2:16][O:17][C:18]([NH:20][C:21]2([C:27]([NH:29][C@H:30]([CH:34]=[O:35])[CH:31]([CH3:33])[CH3:32])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)[C@@H](CO)NC(=O)C1(NC(=O)OCc2ccccc2)CCCCC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@@H](C=O)NC(=O)C1(NC(=O)OCc2ccccc2)CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.9 %

Procedure:
Under an argon gas atmosphere, 1.22 g (9.44 mmol) of N,N-diisopropylethylamine was added dropwise to a solution of 1.50 g (9.44 mmol) of sulfur trioxide-pyridine complex in 10 ml of anhydrous dimethyl sulfoxide and 5 ml of anhydrous methylene chloride under ice-cooling, and the mixture was stirred for 15 minutes. Further, under ice-cooling, a solution of 570 mg (1.57 mmol) of N-[[1-[[(phenylmethoxy)carbonyl]amino]cyclohexyl]carbonyl]-L-valinol in 3 ml of anhydrous dimethyl sulfoxide was added to the reaction solution, and the mixture was stirred at the same temperature for 2 hours. The reaction solution was poured to ice-water and extracted with ethyl acetate twice. After the organic layer was washed with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogencarbonate solution and then saturated brine and dried with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. 20 ml of diisopropyl ether was added to the residue, and the mixture was stirred at room temperature for 18 hours. The obtained crystal was collected by filtration to obtain 435 mg (77%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[C:10]1[O:11][C:12]2[C:17]([C:18](=[O:20])[CH:19]=1)=[C:16]([O:21]C)[CH:15]=[C:14]([O:23]C)[C:13]=2[C@@H:25]1[CH2:29][CH2:28][N:27]([CH3:30])[C@H:26]1[CH2:31][OH:32].Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:10]1[O:11][C:12]2[C:17]([C:18](=[O:20])[CH:19]=1)=[C:16]([OH:21])[CH:15]=[C:14]([OH:23])[C:13]=2[C@@H:25]1[CH2:29][CH2:28][N:27]([CH3:30])[C@H:26]1[CH2:31][OH:32]
Reactant: COc1ccc(Cl)c(-c2cc(=O)c3c(OC)cc(OC)c([C@@H]4CCN(C)[C@H]4CO)c3o2)c1
Agent: Cl
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4cc(O)ccc4Cl)oc23)[C@@H]1CO

Procedure:
Compound of example 70 (0.75 g, 1.63 mmol) was demethylated using pyridine hydrochloride (8.0 g, 69.0 mmol) as described in example 17 to obtain the title compounds.
Reaction SMILES: [CH2:1]([NH:7][C:8](=[O:33])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:34][CH2:35][C@H:36]([OH:51])[CH2:37][O:38][C:39]1[CH:48]=[CH:47][C:46]([OH:49])=[C:45]2[C:40]=1[CH2:41][CH2:42][C:43](=[O:50])[NH:44]2>>[CH2:1]([NH:7][C:8]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:27][CH2:28][CH:29]([NH:34][CH2:35][C@H:36]([OH:51])[CH2:37][O:38][C:39]4[CH:48]=[CH:47][C:46]([OH:49])=[C:45]5[C:40]=4[CH2:41][CH2:42][C:43](=[O:50])[NH:44]5)[CH2:30][CH2:31]3)=[CH:22][CH:21]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1)=[O:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: NC[C@H](O)COc1ccc(O)c2c1CCC(=O)N2
Product: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)COc4ccc(O)c5c4CCC(=O)N5)CC3)cc2)cc1

Procedure:
The title compound was prepared from 4-(3-hexyl-ureido)-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzensulfonamide (which was obtained in Example 225) and 5-(3-amino-(2S)-2-hydroxy-propoxy)-8-hydroxy-3,4-dihydro-1H-quinolin-2-one (which was obtained in Example 12) according to the procedure of Example 278 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.86 (t, J=5.1 Hz, 3 H), 1.20–1.35 (m, 8 H), 1.35–1.50 (m, 2 H), 1.75–1.90 (m, 2 H), 2.39 (t, J=5.1 Hz, 2 H), 2.50–2.75 (m, 5 H), 2.82 (t, J=5.1 Hz, 2 H), 3.05 (q, J=5.1 Hz, 2 H), 3.40–3.55 (m, 2 H), 3.75–3.85 (m, 3 H), 4.90 (brs, 1 H), 6.30 (t, J=5.1 Hz, 1 H), 6.44 (d, J=6.6 Hz, 1 H), 6.59 (d, J=6.6 Hz, 1 H), 6.76 (d, J=6.9 Hz, 1 H), 6.85 (d, J=6.9 Hz, 1 H), 7.46 (d, J=6.9 Hz, 2 H), 7.50 (d, J=6.9 Hz, 2 H), 8.67 (s, 1 H), 8.84 (s, 1 H), 9.10 (brs, 1 H), 9.50 (brs, 1 H); MS (ES) m/z: 709.2 (MH+); HRMS Calcd. for C36H49N6O7S (MH+): 709.3383. Found: 709.3391.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([OH:25])=O.C(OC([NH:50][CH2:51][CH2:52][NH2:53])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([NH:50][CH2:51][CH2:52][NH2:53])=[O:25]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: NCCNC(=O)CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and N-tert.-butyloxycarbonyl-ethylenediamine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:13][C:11]=3[N:12]=2)[CH:7]=1.[CH:28]1[C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]2[C:37]([O:39][C:40](=O)[C:30]=2[CH:29]=1)=[O:38]>>[CH2:24]([NH:23][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[C:37](=[O:38])[C:31]3[C:30](=[CH:29][CH:28]=[C:33]([C:34]([OH:36])=[O:35])[CH:32]=3)[C:40]2=[O:39])=[CH:7][C:6]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][C:11]=2[N:12]=1)[CH2:25][CH2:26][CH3:27]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: CCCCNc1ccc(N)cc1-c1nc2cc(-c3ccccc3)ccc2o1
Product: CCCCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 1b), from 2-(5-amino-2-butylaminophenyl)-5-phenylbenzoxazole (409 mg, 1.14 mmol) and 1,2,4-benzenetricarboxylic anhydride (219 mg, 1.14 mmol) the title compound was obtained (390 mg, 64%). 1H NMR (DMSO) δ 8.71(t, 1H), 8.65(dd, 1H), 8.36(d, 1H), 8.29(m, 2H), 8.08(d, 1H), 8.00(d, 2H), 7.93(dd, 1H), 7.73(m, 3H) 7.62(t, 1H), 7.27(d, 1H), 3.60(m, 2H), 1.97(q, 2H), 1.74(m, 2H), 1.22(t, 3H) MS 532 m/z (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][N:4]=1)=[CH2:2].COC(=O)C1C=C(F)C(C(OC)=O)=CC=1N>>[CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][N:4]=1)[CH3:2]
Reactant: C=Cc1ccc(C#N)cn1
Agent: COC(=O)c1cc(F)c(C(=O)OC)cc1N
Product: CCc1ccc(C#N)cn1

Procedure:
Compound 384B was prepared from 384A by a route analogous to that described for the preparation of compound 174B. HPLC retention time=1.24 min. (Condition A), M+=133.
Reaction SMILES: [C:1]([N:6]([CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][CH2:8][CH2:9][CH2:10][C:11](O)=[O:12])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[NH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31].[OH-].[K+]>C(O)C>[C:1]([N:6]([CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:12])(=[O:5])/[CH:2]=[CH:3]/[CH3:4]
Reactant: C/C=C/C(=O)N(CCCCC(=O)O)C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CCN
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C/C=C/C(=O)N(CCCCC(=O)NCCC(=O)O)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-crotonoyl-5-benzhydrylaminovaleric acid and ethyl 3-aminopropionate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-(N-crotonoyl-5-benzhydrylaminopentanoyl)-3-aminopropionic acid.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[CH2:25]([O:27][CH2:28][C:29](Cl)=[O:30])[CH3:26].[Cl-].[Na+]>C1COCC1>[CH2:25]([O:27][CH2:28][C:29]([N:9]1[CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][O:11][C:10]1=[O:13])=[O:30])[CH3:26]
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CCOCC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOCC(=O)N1C(=O)OCC1Cc1ccccc1
Temperature: -78 °C
Reaction time: 24 h

Procedure:
36.7 g (207 mmol) of (S)-4-benzyloxazolidin-2-one in 800 ml of THF are introduced into a round-bottomed flask under a stream of nitrogen. The reaction medium is cooled to −78° C. and 83 ml (207 mmol) of 2.5M n-butyllithium hexane are added dropwise. 30 minutes later, 25.4 g (207 mmol) of ethoxyacetyl chloride obtained in Example 81(b) are added, at −78° C. The reaction medium is stirred for 24 hours and then poured into saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated. After purification by chromatography on a column of silica eluted with a heptane/ethyl acetate mixture (6/4), 30.6 g (56%) of the expected product are obtained in the form of an orange-colored oil.
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:10]=[C:9]([CH3:19])[C:5]=2[C:6]([OH:8])=O)[CH2:3][CH2:2]1.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C.[NH2:50][CH2:51][CH2:52][C@@H:53]([OH:58])[C:54]([CH3:57])([CH3:56])[CH3:55]>ClCCl.O>[CH:1]1([C:4]2[CH:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:10]=[C:9]([CH3:19])[C:5]=2[C:6]([NH:50][CH2:51][CH2:52][C@@H:53]([OH:58])[C:54]([CH3:57])([CH3:56])[CH3:55])=[O:8])[CH2:2][CH2:3]1
Reactant: CC(C)(C)[C@H](O)CCN
Reactant: Cc1cc(N2CCOCC2)cc(C2CC2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N2CCOCC2)cc(C2CC2)c1C(=O)NCC[C@@H](O)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 39 %

Procedure:
To a stirred solution of 2-cyclopropyl-6-methyl-4-morpholin-4-yl-benzoic acid (synthesized according to the methods described in sections a) to f)) (0.34 g, 1.3 mmol) in dichloromethane (10 ml) are added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.30 g, 1.56 mmol), hydroxybenzotriazole (0.21 g, 1.56 mmol) and diisopropylethylamine (0.65 ml, 3.9 mmol) at 0° C. and stirred for 15 min before the addition of (3R)-1-amino-4,4-dimethyl-pentan-3-ol (synthesized according to the methods described in sections g) to k)) (0.28 g, 1.69 mmol). The resulting mixture is stirred at room temperature for 16 h. Water (20 ml) is added to the mixture and extracted with dichloromethane (3×20 ml). The combined organic layers are washed with 10% sodium hydrogen carbonate solution (30 ml), brine (30 ml), dried over sodium sulfate and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, 55% ethyl acetate/dichloromethane) yielding 2-cyclopropyl-N-[(3R)-3-hydroxy-4,4-dimethyl-pentyl]-6-methyl-4-morpholin-4-yl-benzamide (example 28) (0.19 g, 0.51 mmol, 39%). [M+H]+ 375.3. [α]D25=+30.0° (c 1.0, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[C:16]([OH:17])=[C:15]([C:18]([OH:20])=[O:19])[C:14]3[C:9](=[C:10]4[CH2:24][CH2:23]C[CH2:21][C:11]4=[CH:12][CH:13]=3)[N:8]=2)=[CH:4][CH:3]=1.N1C2C(=CC=C3C=2CCC3)C(=O)C1=O.C(OCC(=O)CC1C=CC(Cl)=CC=1)(=O)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:16]([OH:17])=[C:15]([C:18]([OH:20])=[O:19])[C:14]3[C:9]([N:8]=2)=[C:10]2[CH2:24][CH2:23][CH2:21][C:11]2=[CH:12][CH:13]=3)=[CH:25][CH:26]=1
Reactant: O=C(O)c1c(O)c(Cc2ccc(Cl)cc2)nc2c3c(ccc12)CCCC3
Agent: CC(=O)OCC(=O)Cc1ccc(Cl)cc1
Agent: O=C1Nc2c(ccc3c2CCC3)C1=O
Product: O=C(O)c1c(O)c(Cc2ccc(Cl)cc2)nc2c3c(ccc12)CCC3
Yield: 14 %

Procedure:
This compound was synthesized by the procedure described above for Compound 1, reacting 1,6,7,8-tetrahydro-1-aza-as-indacene-2,3-dione 10 (0.36 g, 1.92 mmol) with 3-(4-chlorophenyl)-2-oxopropyl acetate 2 (0.54 g, 2.40 mmol). The crude acid was purified as described above for Compound 4 to give pure product Compound 5 as a bright yellow powder (94 mg, 14% yield): 1H NMR (400 MHz, DMSO-D6) δ 2.15 (quint., 2H) 3.05 (t, J=7.3 Hz, 2H) 3.28 (t, J=7.5 Hz, 2H) 4.32 (s, 2H) 7.33 (s, 4H) 7.49 (d, J=8.3 Hz, 1H) 8.36 (d, J=8.1 Hz, 1H); HRMS (ESI+) calcd for C20H17ClNO3 (MH+) 354.0892, found 354.0898.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>O1CCOCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[CH:6][CH:7]=1
Reactant: Brc1ccc(C2CCCN2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CCCC1c1ccc(Br)cc1
Reaction time: 8 h
Yield: 81.9 %

Procedure:
A solution of 2-(4-bromophenyl)pyrrolidine (2.26 g, 10 mmol) in dioxane (18 mL) and water (12 mL) was added potassium carbonate (5.52 g, 40 mol) and benzyl chloroformate (1.88 g, 11 mmol) at ambient temperature and stirred overnight. Then the mixture was partitioned between ethyl acetate and brine. The organic phase was concentrated in vacuo and the residue was purified by column chromatography (silica gel, EtOAc:hexane=1:10) to give the title compound (2.95 g, 82%) as a colorless oil. LC-MS (ESI) m/z: 360 (M+1)+.
Reaction SMILES: [CH2:1]([CH:9]1[C:17]2[C:13](=[N:14][C:15]3[C:16]=2[CH2:18][CH:19]=[CH:20][C:21]=3[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:12][CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>>[CH2:1]([CH:9]1[C:17]2[C:13](=[N:14][C:15]3[C:16]=2[CH:18]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:19]=[CH:20][C:21]=3[O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:12][CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCBr
Reactant: CCCCCCCCC1CCCC2=NC3=C(OCc4ccccc4)C=CCC3=C21
Product: CCCCCCCCC1C=CC(OCc2ccccc2)=C2N=C3CCCC(CCCCCCCC)C3=C21
Yield: 61.6 %

Procedure:
Using the procedure of Example 9, 2.9 g of 1,2,3,4-tetrahydro-1-octyl-6-phenylmethoxy-9H-dibenzo[b,d]pyrrole from Example 62 was alkylated with 1.68 g of 1-bromooctane to produce 2.3 g (61.7%) of rac-1,2,3,4-tetrahydro-1,9-dioctyl-6-phenylmethoxy-9H-dibenzo[b,d]pyrrole as a yellow oil after chromatographic purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH:5]([N:22]=[C:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][CH:8]=1)[CH3:2].[F:37][C:38]1[CH:43]=[CH:42][C:41](I)=[CH:40][CH:39]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC>[CH2:1]([O:3][C:4](=[O:36])[CH:5]([N:22]=[C:23]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:41]2[CH:42]=[CH:43][C:38]([F:37])=[CH:39][CH:40]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: Fc1ccc(I)cc1
Reactant: CCOC(=O)C(Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N=C(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Product: CCOC(=O)C(Cc1ccc(-c2ccc(F)cc2)cc1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
2-(Benzhydrylidene-amino)-3-(4′-fluoro-biphenyl-4-yl)-propionic acid ethyl ester is prepared according to the general procedure reported by Satoh et al. (Tetrahedron Letter Vol. 48, 7645 (1997)). A 50-mL flask is charged with the boronate intermediate of step 1 (600 mg, 1.01 mmol), 1-fluoro-4-iodo-benzene (247 mg, 1.11 mmol), PdCl2(dppf) (37 mg, 0.051 mmol), K3PO4 (860 mg, 4.04 mmol), and 10 mL of DME. The reaction mixture is heated at reflux for 12 hours then cooled to room temperature, and partitioned between EtOAc and water. The organic phase is separated and washed with brine, dried over MgSO4, filtered, and concentrated. The residue is purified by chromatography on silica gel (gradient elution with 5-10% EtOAc/hexane) to furnish the above imine as a light brown oil. 1H NMR (300 MHz, CDCl3) δ 7.50-7.70 (m, 4H), 7.25-7.40 (m, 8H), 7.05-7.20 (m, 4H), 6.55-6.70 (m, 2H), 4.15-4.30 (m, 3H), 3.15-3.35 (m, 2H), 1.15-1.25 (two t, 3H).