Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22](OCC)=[O:23])[C:4]1=[O:27])[CH3:2].[NH2:28][CH2:29][CH:30]([OH:32])[CH3:31]>>[CH2:1]([N:3]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22]([NH:28][CH2:29][CH:30]([OH:32])[CH3:31])=[O:23])[C:4]1=[O:27])[CH3:2]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC)c1=O
Reactant: CC(O)CN
Product: CCn1c(=O)c(C(=O)NCC(C)O)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 38 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-ethyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (30 mg, 0.081 mmol) and 1-amino-2-propanol (0.05 mL) was prepared 1-ethyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxypropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (12 mg, 38% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.49 (s, 1 H), 8.56 (s, 1 H), 7.37 (s, 1 H), 7.18 (m, 2 H), 7.05-7.07 (m, 2 H), 4.23-4.06 (m, 5 H), 3.62 (m, 1 H), 3.38 (m, 1 H), 1.29-1.22 (m, 6 H); HRMS m/z calcd for C21H23FN3O4: 400.1667. Found: 400.1673.
Reaction SMILES: [CH3:1][Si:2]([O:9][CH3:10])([O:7][CH3:8])[CH2:3][CH2:4][CH2:5][OH:6].[OH-].[K+].[CH:13]#[CH:14]>CS(C)=O>[CH:13]([O:6][CH2:5][CH2:4][CH2:3][Si:2]([CH3:1])([O:9][CH3:10])[O:7][CH3:8])=[CH2:14]
Reactant: CO[Si](C)(CCCO)OC
Reactant: C#C
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: C=COCCC[Si](C)(OC)OC
Yield: 95 %

Procedure:
In a similar manner to Example 1, 30 g (0.17 mol) of 3-(methyldimethoxysilyl)propanol, 3 g of KOH and 120 g of DMSO were reacted at 60° C. with acetylene. 3-(Methyldimethoxysilyl)propyl vinyl ether was obtained in 95% yield.
Reaction SMILES: [CH:1]1([P:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li:23]CCCC>CCOCC.CCCCCC>[C:11]1([P:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:1]2([Li:23])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C1=CC(P(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: [Li]C1(P(c2ccccc2)c2ccccc2)C=Cc2ccccc21
Reaction time: 8 h
Yield: 87.3 %

Procedure:
(1H-Inden-1-yl)diphenylphosphine (5.00 g, 16.65 mmol) was dissolved in a mixture of 60 mL of ether and 60 mL of hexane. n-BuLi (7.35 mL, 18.31 mmol) was added to the mixture within 10 minutes. After stirring overnight no precipitate appeared. Solvent was removed under reduced pressure leaving a waxy yellow residue. This residue was triturated with 120 mL of hexane for 15 minutes The hexane solution was decanted and the residue was dried under reduced pressure to give 4.45 g of off-white solid. Yield 87 percent.
Reaction SMILES: [CH:1]1([CH2:6][O:7][C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[C:11]([C:17]([OH:19])=O)[NH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.Cl.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]2)[CH2:26][CH2:25]1>>[OH:38][CH:35]1[CH2:34][CH2:33][N:32]([CH2:31][CH2:30][N:27]2[CH2:26][CH2:25][CH:24]([NH:23][C:17]([C:11]3[NH:12][C:13]4[C:9]([CH:10]=3)=[C:8]([O:7][CH2:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:16]=[CH:15][CH:14]=4)=[O:19])[CH2:29][CH2:28]2)[CH2:37][CH2:36]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Reactant: O=C(O)c1cc2c(OCC3CCCC3)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCC(O)CC2)CC1)c1cc2c(OCC3CCCC3)cccc2[nH]1

Procedure:
This compound is synthesized analogously to Example 1 from 4-Cyclopentylmethoxy-1H-indole-2-carboxylic acid 86 (preparation see below) and amine 21.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])[C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][N:3]=1.[S:24]([NH2:34])(=[O:33])([C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)=[O:25].CO>C(O)CCC>[S:24]([C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:2]2[N:7]=[C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])[C:9]3[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=3[F:16])[CH:5]=[CH:4][N:3]=2)=[CH:28][CH:27]=1)(=[O:25])(=[O:33])[NH2:34]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1ccc(F)c(N(CCCC(F)(F)F)c2ccnc(Cl)n2)c1
Solvent: CO
Solvent: CCCCO
Product: Cc1ccc(F)c(N(CCCC(F)(F)F)c2ccnc(Nc3ccc(S(N)(=O)=O)cc3)n2)c1
Temperature: 95 °C
Yield: 54.6 %

Procedure:
2-Chloro-4-(N-4,4,4,-trifluorobutyl-2-fluoro-5-methylanilino)pyrimidine (215 mg, 0.62 mmol) was dissolved in n-butanol (2 ml) and sulphanilamide (85 mg, 0.50 mmol) was added. The resulting suspension was treated with methanol until all the solid dissolved. The reaction mixture was heated at 95° C. for 12 hours and allowed to cool to ambient temperature. The solid that had precipitated was collected by filtration, washed with a small volume of methanol and dried in vacuo to yield a white solid (132 mg). NMR (400 MHz@373K): 1.85 (m, 2H), 2.31 (m, 2H), 2.35 (s, 3H), 3.97 (t, 2H), 6.04 (d, 1H), 7.29 (m, 3H) 8.02 (d, 1H), 10.00 (br s, 1H); MS (M+H)+: 484.4.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10](=[O:38])[CH2:11][C@H:12]([OH:37])[CH2:13][C:14](=[O:36])/[CH:15]=[CH:16]/[C:17]2[N:18]([CH:33]([CH3:35])[CH3:34])[C:19]3[C:24]([C:25]=2[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([C@@H](NC(=O)C[C@H](O)C[C@H](O)/C=C/C2C(C3CC3)=NC3C(C=2C2C=CC(F)=CC=2)=CC=CC=3)C)C=CC=CC=1>>[C:1]1([C@@H:7]([NH:9][C:10](=[O:38])[CH2:11][C@H:12]([OH:37])[CH2:13][C@H:14]([OH:36])/[CH:15]=[CH:16]/[C:17]2[N:18]([CH:33]([CH3:35])[CH3:34])[C:19]3[C:24]([C:25]=2[C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)n1c(/C=C/C(=O)C[C@@H](O)CC(=O)N[C@@H](C)c2ccccc2)c(-c2ccc(F)cc2)c2ccccc21
Agent: C[C@H](NC(=O)C[C@H](O)C[C@H](O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1)c1ccccc1
Product: CC(C)n1c(/C=C/[C@@H](O)C[C@@H](O)CC(=O)N[C@@H](C)c2ccccc2)c(-c2ccc(F)cc2)c2ccccc21

Procedure:
can be prepared from (E)-(R)-7-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-3-hydroxy-5-oxo-hept-6-enoic acid ((S)-1-phenyl-ethyl)-amide according to the procedures described above for the preparation of (E)-(3R,5S)-7-[2-Cyclopropyl-4-(4-fluoro-phenyl)quinolin-3-yl]-3,5-dihydroxy-hept-6-enoic acid ((S)-1-phenyl-ethyl)-amide. Chromatography on silicagel with ethyl acetate/hexanes (9:1) as eluent affords (E)-(3R,5S)-7-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-3,5-dihydroxy-hept-6-enoic acid ((S)-1-phenyl-ethyl)-amide as a light yellow foam. Rf=0.175 (TLC on silicagel, ethyl acetate/hexanes 9:1 as eluent). [α]D20 =−16.7° (CH3OH, c=1). MS (ES+, m/z): 537 ([M+Na]+, 100%); IR(KBr): 3310 (broad), 3049, 2974, 2934, 2875, 1644, 1604, 1545, 1501, 1457, 1420, 1371, 1346, 1219, 1155, 1104, 1065, 1045, 1018, 970, 944, 837, 814, 742, 718, 700, 565.
Reaction SMILES: BrBr.[OH-].[Na+].[Br:5][C:6]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:7]=1[C:8](C1C=CC=CC=1)=[O:9].S([O-])([O-])=[O:23].[Na+].[Na+].Br[O-].[Na+].Cl>>[Br:5][C:6]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:7]=1[C:8]([OH:9])=[O:23]
Reactant: O=S([O-])[O-]
Reactant: COc1ccc(C(=O)c2ccccc2)c(Br)c1
Agent: BrBr
Agent: Cl
Agent: [Na+]
Product: COc1ccc(C(=O)O)c(Br)c1
Reaction time: 0.17 h
Yield: 95 %

Procedure:
In an ice bath, bromine (2.8 mL, 35.1 mmol) is slowly added dropwise into an aqueous NaOH (4.5 g, 111.4 mmol) solution (10 mL) and stirred for 10 mins. Then 2-bromo-4-methoxy benzophenone (2.1 g, 9.2 mmol) is added dropwise into the reaction, and stirred for 15 hrs at the temperature. After completion of the reaction, aqueous sodium sulfite is added to eliminate the unreacted sodium hypobromite. The resultant mixture is extracted with ethyl acetate to isolate neutral compound. The aqueous phase is then acidified with 6N HCl in an ice bath to give large quantities of white solid. The resultant is filtered under vacuum to give white solid (IV) (2.0 g, 95%).
Reaction SMILES: Cl.[C:2](=[NH:10])([O:7][CH2:8][CH3:9])[C:3]([CH3:6])([CH3:5])[CH3:4].N1C(C)=CC(C)=CC=1C.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)Cl>[CH2:24]([O:23][C:21]([N:10]=[C:2]([O:7][CH2:8][CH3:9])[C:3]([CH3:6])([CH3:5])[CH3:4])=[O:22])[CH3:25]
Reactant: CCOC(=N)C(C)(C)C
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)N=C(OCC)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.4 %

Procedure:
Ethyl pivalimidate hydrochloride (Example B3) (0.75 g, 4.5 mmol) was suspended in hexanes (11.3 mL) and DCM (11.3 mL) and cooled to 0° C. 2,4,6-Collidine (2.1 mL, 15.9 mmol) and ethyl chloroformate (0.98 g, 9.1 mmol) were sequentially added and the reaction mixture was allowed to warm to RT and stirred for 12 h. The solvent was removed in vacuo and the residue was slurried with EtOAc (50 mL). The solids were removed by filtration through a pad of diatomaceous earth. The filter cake was washed with EtOAc (3×10 mL) and the combined filtrates were concentrated in vacuo to afford ethyl N-ethoxycarbonylpivalimidate (0.81 g, 89%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 4.05 (q, J=7.1 Hz, 2H), 3.95 (q, J=7.0 Hz, 2H), 1.18 (t, J=7.1 Hz, 3H), 1.18 (t, 7.1 Hz, 3H), 1.15 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=2[CH2:24][N:25]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:26][CH3:27])[CH:7]=1)[CH3:2].CN(C)N.C>CCO>[CH2:1]([O:3][C:4](=[O:38])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:24][N:25]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:26][CH3:27])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CN(CC)C(=O)OCc2ccccc2)c1
Agent: C
Agent: CN(C)N
Solvent: CCO
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN(CC)C(=O)OCc2ccccc2)c1
Temperature: 65 °C

Procedure:
(3-{2-[(Benzyloxycarbonyl-ethyl-amino)-methyl]-4-nitro-phenoxy}-4-methoxy-phenyl)-acetic acid ethyl ester (0.1 g, 0.19 mmol), 1,1-dimethylhydrazine (0.1 g, 1.3 mmol), ferric chloride (0.01 g), and DARCO (0.05 g) were combined in EtOH (5 mL), and the reaction was stirred at 65° C. until complete. The mixture was worked up to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])=[CH:9][CH:8]=[C:7]2[O:17]C.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]([N:14]([CH3:15])[CH3:16])=[O:13])=[CH:9][CH:8]=[C:7]2[OH:17]
Reactant: COc1ccc(C(=O)N(C)C)c2c(Cl)cccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(O)c2cccc(Cl)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
8-chloro-4-methoxy-N,N-dimethyl-1-naphthamide (step-5 intermediate) (0.5 g, 1.90 mmol) in DCM (15 mL) was cooled to −78° C. Then, BBr3 (0.72 mL, 7.58 mmol) in DCM (7.5 mL) was added dropwise to the mixture at −78° C. The reaction mixture was warmed to RT and stirred for 2 h, and quenched with brine solution. The aqueous layer was extracted with DCM, and the combined organic layer was washed with, water, brine, dried over Na2SO4 and filtered. The solvent was evaporated to provide the desired phenol as pale brown solid (445 mg, 94%) that was used in next step without any further purification.
Reaction SMILES: [O:1]=[O+][O-].[F:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C:12]1([S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH:35]=C)=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:17][CH2:16][CH:15]([NH:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])[CH2:14][CH2:13]1.CSC>ClCCl.CO>[F:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C:12]1([S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH:35]=[O:1])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:17][CH2:16][CH:15]([NH:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])[CH2:14][CH2:13]1
Reactant: C=Cc1ccc(S(=O)(=O)C2(c3cc(F)ccc3F)CCC(NS(=O)(=O)C(F)(F)F)CC2)cc1
Reactant: O=[O+][O-]
Solvent: CO
Solvent: CSC
Solvent: ClCCl
Product: O=Cc1ccc(S(=O)(=O)C2(c3cc(F)ccc3F)CCC(NS(=O)(=O)C(F)(F)F)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ozone was bubbled through a solution of the product of Example 79 (2.5 g, 4.9 mmol) in dichloromethane/methanol (125 ml/25 ml) at −78° C. until a blue colour was observed. Oxygen was bubbled through the mixture for 10 minutes until the blue colour disappeared. The mixture was quenched with dimethyl sulfide (2.16 ml, 29.5 mmol), allowed to warm to room temperature and stirred for 16 hours. The mixture was concentrated in vacuo to give an oil (2.80 g), which was chromatographed on silica, eluting with 20% ethyl acetate/isohexane to give the aldehyde (2.18 g, 87%). 1H NMR (CDCl3, 360 MHz): 1.59-1.70 (2H, m), 2.04-2.09 (2H, m), 2.48 (2H, t, J=12.3), 2.61-2.68 (2H, m), 3.82 (1H, m), 5.75 (1H, d, J=7.7), 6.77-6.86 (1H, m), 7.07-7.11 (2H, m), 7.57 (2H, d, J=8.1), 7.90 (2H, d, J=8.3), 10.10 (1H, s)
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1.[F:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:21]=1[CH:22]=[O:23]>C1COCC1>[F:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:21]=1[CH:22]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1)[OH:23]
Reactant: COc1ccc(C=O)c(F)c1
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccc3cc(OC)ccc3c2)c(F)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 1953 %

Procedure:
n-Butyllithium (2.5 M, 16.9 mL) was added dropwise into a cold (−78° C.) solution of 2-bromo-6-methoxynaphthalene (10.0 g, 42.2 mmol), and THF (200 mL). The reaction mixture was stirred at −78° C. for 2 h, and then 2-fluoro-4-methoxybenzaldehyde (6.5 g, 42 2 mmol) in THF (10 mL) was added. The mixture was allowed to warm up to 0° C. stirred for 10 min, and then quenched with aqueous ammonium cholride. The mixture was poured into water, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/EtOAc 3/1) gave a brown solid (12.2 g, 93% yield, m.p. 68-69° C.); MS m/e 312 (M+).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[OH:28][C@@H:29]([CH2:35][CH3:36])[CH2:30][C:31](OC)=[O:32]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][C@@H:29]([OH:28])[CH2:35][CH3:36])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: CC[C@H](O)CC(=O)OC
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CC[C@H](O)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (66 mg, 77%), MS (ISP) m/z=431.4 [(M+H)+], mp 158° C., was prepared in accordance with the general method of example 2 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (88 mg, 0.2 mmol) and (S)-methyl 3-hydroxy-pentanoate.
Reaction SMILES: [C:1]([N:6]1[CH2:10][CH2:9][O:8][C:7]1=[O:11])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CS(O)(=O)=O>C(OCC)(=O)C>[C:13]1([NH:12][CH:3]([CH3:4])[CH2:2][C:1]([N:6]2[CH2:10][CH2:9][O:8][C:7]2=[O:11])=[O:5])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: C/C=C/C(=O)N1CCOC1=O
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Product: CC(CC(=O)N1CCOC1=O)Nc1ccccc1
Temperature: 0 °C
Yield: 14.9 %

Procedure:
To a solution of 3-crotonoyl-1,3-oxazolidin-2-one (155 mg, 1.0 mmol) in ethyl acetate (3 ml) in a stream of nitrogen was added Pd((R)-binap)(H2O)2(OTf)2 (26.6 mg, 0.025 mmol), and the resulting mixture was cooled to 0° C. Aniline (0.11 ml, 1.2 mmol) was added to the mixture, and to the solution was added slowly methanesulfonic acid (0.078 ml, 1.2 mmol). Then, the cooling ice-bath was removed and the reaction mixture was reacted at room temperature for 18 hours with stirring. After completion of the reaction, the solvent was evaporated off, and the crude product obtained was purified by a silica gel column chromatography (hexane:ethyl acetate=1:1) to give the objective compound 3-(3-phenylaminobutyryl)-oxazolidin-2-one (37 mg, 15% yield). Enantiomeric excess ratio of this product was determined by a liquid chromatography using a column for separation of optical isomers (column: AD-H) to be 82% e.e.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:5](OCC)=[O:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:10]=[CH:11][C:12]=1[CH3:13]
Reactant: CCOC(=O)c1ccc(C)c(Br)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(CO)cc1Br
Temperature: 0 °C
Yield: 90 %

Procedure:
Ethyl 3-bromo-4-methylbenzoate was reduced follows: 2 equivalents lithium aluminium hydride (LAH) in THF was cooled to 0° C. Ethyl 3-bromo-4-methylbenzoate in anhydrous THF (10 mL) was added slowly to the cooled solution of LAH over 10 minutes, while stirring. The mixture was stirred at room temperature for 1 hour. The reaction was cooled to 0° C. and poured into ether (100 mL). The mixture was acidified by adding 1N HCl (aqueous) dropwise over 10 minutes. Separate fractions and wash aqueous phase with ether (50 mL). The fractions were combined and dried over magnesium sulfate. Solvent removal left a clear oil. The yield was 90%. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 7.5 (s, 1H) 7.2 (d, 1H) 7.1 (d, 1H), 4.6 (s, 2H) 2.3 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[N:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].B1([C:39]2[CH:44]=[CH:43][CH:42]=[N:41][CH:40]=2)OCCCO1>O1CCOCC1.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>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:39]4[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=4)[CH:12]=3)=[CH:9][N:10]=[C:4]2[N:3]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: Cc1ccn2c(-c3cccc(OS(=O)(=O)C(F)(F)F)c3)cnc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccn2c(-c3cccc(-c4cccnc4)c3)cnc2n1
Temperature: 80 °C

Procedure:
To a degassed solution of trifluoromethanesulfonic acid 3-(7-methyl-imidazo[1,2-a]pyrimidin-3-yl)phenyl ester (0.1 g, 0.28 mmol) in 1,4-dioxane (3 ml) was added potassium phosphate (0.119 g, 0.56 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (0.092 g, 0.56 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.016 g, 13.8 mmol) and the mixture heated at 80° C. for 22 h. After cooling to ambient temperature the solvent was evaporated in vacuo. The residue was stirred with 10% methanol in dichloromethane and the solid material filtered off. The filtrate was applied to two preparative TLC plates (silica gel) and eluted with 6% methanol in dichloromethane. The appropriate band was collected and processed to give an oil which crystallised from diethyl ether as a white solid (26 mg): δH (400 MHz, CDCl3) 2.67 (3H, s), 6.80 (1H, d, J 7), 7.42 (1H, td, J 8 and 1), 7.57 (1H, m), 7.65 (2H, m), 7.71 (1H, s), 7.86 (1H, s), 7.92 (1H, m), 8.53 (1H, d, J 7), 7.65 (1H, m), 8.89 (1H, s); m/z (ES+) 287 (M++H).
Reaction SMILES: [C:1]([NH:4][C:5]1([CH2:10][C:11]([OH:13])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].N[C@@H:15](C1C=CC=CC=1)[CH2:16]C(O)=O.CC#N.O.CC#N>O>[C:1]([NH:4][C@@H:5]([C:9]1[CH:8]=[CH:7][CH:6]=[CH:16][CH:15]=1)[CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)NC1(CC(=O)O)CCCC1
Reactant: N[C@H](CC(=O)O)c1ccccc1
Solvent: O
Solvent: CC#N
Product: CC(=O)N[C@H](CC(=O)O)c1ccccc1

Procedure:
The title compound is prepared analogously as described for (1-acetylamino-cyclopentyl)-acetic acid from (R)-3-amino-3-phenylpropionic acid. MS (LC-MS): [M+H]+=208.2. tR (HPLC, Waters Symmetry C18 column, 10-95% CH3CN/H2O/3.5 min, 95% CH3CN/H2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 1.16 min.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:43])[CH2:5][C@H:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][C@H:16]3[C:24]4[C:19](=[C:20]([CH2:29][N:30]5[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]5)[C:21]([C:25]([F:28])([F:27])[F:26])=[CH:22][CH:23]=4)[CH2:18][CH2:17]3)=[CH:14][C:9]=2[O:8][CH2:7]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.ClCCl>[CH3:2][O:3][C:4](=[O:43])[CH2:5][C@H:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][C@H:16]3[C:24]4[C:19](=[C:20]([CH2:29][N:30]5[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]5)[C:21]([C:25]([F:26])([F:27])[F:28])=[CH:22][CH:23]=4)[CH2:18][CH2:17]3)=[CH:14][C:9]=2[O:8][CH2:7]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCNCC3)ccc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
4 M HCl in 1,4-dioxane (5 mL) is added to a solution of {(S)-6-[(R)-4-(4-tert-butoxycarbonyl-piperazin-1-ylmethyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (0.42 g) in dichloromethane (5 mL) at room temperature. The solution is stirred at room temperature for 2.5 h. The solution is basified with aqueous K2CO3 solution and extracted with dichloromethane. The combined extract is dried (Na2SO4) and concentrated to give the crude title compound that is used without further purification in subsequent transformations. LC (method 4): tR=0.98 min; Mass spectrum (ESI+): m/z=491 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12].FC1C=CC([B:23]([OH:25])[OH:24])=C(O[C@H](CC=C)C)C=1>>[F:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([B:23]([OH:25])[OH:24])=[C:3]([O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])[CH:4]=1
Reactant: C=CC[C@H](C)Oc1cc(F)c(F)cc1Br
Reactant: C=CC[C@H](C)Oc1cc(F)ccc1B(O)O
Product: C=CC[C@H](C)Oc1cc(F)c(F)cc1B(O)O
Yield: 100 %

Procedure:
Prepared from (S)-1-bromo-4,5-difluoro-2-(pent-4-en-2-yloxy)benzene in 100% yield following the same procedure as (S)-(4-fluoro-2-(pent-4-en-2-yloxy)phenyl)boronic acid. NMR is complex and suggests an oligomeric mixture. The material, however, was used as is and was fully compentent for undergoing a Suzuki coupling.