Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1.[CH2:15]([N:22]1[CH2:26][CH2:25][C@@H:24]([NH2:27])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN(CC)CC>CN(C=O)C>[CH2:15]([N:22]1[CH2:26][CH2:25][C@@H:24]([NH:27][C:2]2[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=2)[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)/C=C/c1cnc(Cl)cn1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(Cc3ccccc3)C2)cn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 46.3 %

Procedure:
To a solution of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (1.50 g) in DMF (21 mL) was added (3R)-1-benzyl-3-pyrrolidinamine (2.24 g) and Et3N (3.44 mL). After stirring for 3 hours at 100° C., the reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(5-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate (1.15 g)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:30][CH3:31])[C:9]3[C:14]([O:15][CH2:16][C@H:17]4[O:22][CH2:21][CH2:20][NH:19][CH2:18]4)=[CH:13][N:12]=[C:11]([C:23]#[C:24][C:25]([CH3:28])([OH:27])[CH3:26])[C:10]=3[N:29]=2)=[N:4][O:5][N:6]=1.C=O.[C:34](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:30][CH3:31])[C:9]3[C:14]([O:15][CH2:16][C@H:17]4[O:22][CH2:21][CH2:20][N:19]([CH3:34])[CH2:18]4)=[CH:13][N:12]=[C:11]([C:23]#[C:24][C:25]([CH3:26])([OH:27])[CH3:28])[C:10]=3[N:29]=2)=[N:4][O:5][N:6]=1
Reactant: CC(=O)O
Reactant: CCn1c(-c2nonc2N)nc2c(C#CC(C)(C)O)ncc(OC[C@@H]3CNCCO3)c21
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CCn1c(-c2nonc2N)nc2c(C#CC(C)(C)O)ncc(OC[C@@H]3CN(C)CCO3)c21
Reaction time: 0.08 h
Yield: 75.5 %

Procedure:
To 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(2S)-2-morpholinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (0.13 g, 0.30 mmol) suspended in methanol (2 mL) was added formaldehyde (37% in water, 0.045 mL, 0.6 mmol). After 5 min, acetic acid (0.051 mL, 0.9 mmol) was added following by sodium triacetoxyborohydride (0.16 g, 0.75 mmol). After 1 h. the solvent was removed in vacuo and the residue suspended in 1N NaOH and extracted with ethyl acetate/tetrahydrofuran. The combined organic extracts were washed with brine and dried sodium sulfate. The filtrate was concentrated in vacuo to afford the desired compound as a solid (0.10 g, 77%) MS (ES+) m/z 442 [M+H]+.
Reaction SMILES: C([C:9]1[C:10]([NH:14][C:15](=[O:34])[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:18]([CH2:26][O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[C:17]=2[Cl:33])=[N:11][O:12][N:13]=1)(=O)C1C=CC=CC=1.ClC1C(COCC(F)(F)F)=C(S(C)(=O)=O)C=CC=1[C:38](O)=[O:39].NC1C(C(C2C=CC=CC=2)=O)=NON=1.C(N(CC)CC)C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>ClCCl.CN(C1C=CN=CC=1)C>[Cl:33][C:17]1[C:18]([CH2:26][O:27][CH2:28][C:29]([F:31])([F:30])[F:32])=[C:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:20]=[CH:21][C:16]=1[C:15]([NH:14][C:10]1[C:9]([O:39][CH3:38])=[N:13][O:12][N:11]=1)=[O:34]
Reactant: CS(=O)(=O)c1ccc(C(=O)Nc2nonc2C(=O)c2ccccc2)c(Cl)c1COCC(F)(F)F
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1COCC(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Agent: Nc1nonc1C(=O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1nonc1NC(=O)c1ccc(S(C)(=O)=O)c(COCC(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 30 h

Procedure:
Synthesis of N-(4-benzoyl-1,2,5-oxadiazol-3-yl)-2-chloro-4-(methylsulfonyl)-3-[(2,2,2-trifluoroethoxy)methyl]benzamide (example No. 11-5 in the tables) 204 mg (0.59 mmol) of 2-chloro-4-(methylsulfonyl)-3-[(2,2,2-trifluoroethoxy)methyl]-benzoic acid and 111 mg (0.59 mmol) of (4-amino-1,2,5-oxadiazol-3-yl)(phenyl)-methanone are dissolved in 10 ml of dichloromethane at RT and treated with 59 mg (0.599 mmol) of triethylamine, 14 mg (0.19 mmol) of DMAP and 561 mg (0.882 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in THF). The reaction mixture is stirred for 30 h at RT and subsequently washed twice with in each case 5 ml of water. The organic phase is dried over Na2SO4 and evaporated. The residue is purified by column chromatography (silica gel, heptane/ethyl acetate). Yield 50 mg (15%).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:6]=1.O.[NH4+].[OH-].[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([NH:1][C:2]1[O:3][C:4]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:6]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(-c2ccc(F)cc2)c(-c2ccncc2)o1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1nc(-c2ccc(F)cc2)c(-c2ccncc2)o1
Temperature: 25 °C

Procedure:
A mixture of 2-amino-4-(4-fluorophenyl)-5-(4-pyridyl)oxazole (0.090 g, 0.353 mmol) in acetic anhydride (4 mL) was stirred at room temperature. After 72 h the mixture was poured into H2O and neutralized with conc. NH4OH. The resulting precipitate was filtered and washed with H2O. Purification by column chromatography (0-5% MeOH/CHCl3), followed by recrystallization from MeOH afforded the title compound as a white solid (30.0 mg):ESMS (m/z): 298.0 (M++H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][CH2:8][CH3:9])[CH2:2]1.CS[C:12](=[N:17][CH3:18])[NH:13][N+:14]([O-:16])=[O:15]>CN(C1C=CN=CC=1)C.C(O)C>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][N:7]([CH2:8][CH3:9])[C:12]([NH:17][CH3:18])=[N:13][N+:14]([O-:16])=[O:15])[CH2:2]1
Reactant: CN=C(N[N+](=O)[O-])SC
Reactant: CCNCC1CCOC1
Agent: CN(C)c1ccncc1
Solvent: CCO
Product: CCN(CC1CCOC1)C(=N[N+](=O)[O-])NC
Yield: 23.8 %

Procedure:
A mixture comprising 5.5 g of N-{(tetrahydro-3-furanyl)methyl}-N-ethylamine, 3.0 g of S-methyl-N-nitro-N'-methyisothiourea, 30 ml of ethanol and 0.5 g of DMAP was refluxed for 4 hours. Then, the reaction fluid was concentrated under a reduced pressure to obtain an oily matter, which was purified by column chromatography. 1.1 g of 1-{(tetrahydro-3-furanyl)methyl}-1-ethyl-2-nitro-3-methylguanidine were obtained.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7](N2CCN(C(OC(C)(C)C)=O)CC2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:23]([O:27][C:28]([N:30]1[CH2:35][C@H:34]([CH3:36])[NH:33][CH2:32][C@H:31]1[CH3:37])=[O:29])([CH3:26])([CH3:25])[CH3:24].BrC1C=CC([N+]([O-])=O)=NC=1>>[CH3:37][C@@H:31]1[CH2:32][N:33]([C:7]2[CH:8]=[N:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C@@H:34]([CH3:36])[CH2:35][N:30]1[C:28]([O:27][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Reactant: C[C@@H]1CN[C@@H](C)CN1C(=O)OC(C)(C)C
Agent: O=[N+]([O-])c1ccc(Br)cn1
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])nc2)[C@@H](C)CN1C(=O)OC(C)(C)C
Yield: 75 %

Procedure:
Following the procedures as described for compound 101g, (2R,5S)-tert-butyl-2,5-dimethylpiperazine-1-carboxylate (1.5 g, 6.0 mmol), and 5-bromo-2-nitropyridine (1212 mg, 6.0 mmol) were reacted to give 122a as a yellow solid (1500 mg, 75%). LCMS: [M+H]+ 337
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:3].Cl[C:22]1[N:27]=[N:26][C:25]([C:28]([NH2:30])=[O:29])=[CH:24][CH:23]=1.C([O-])(O)=O.[Na+].O>CN1CCCC1=O.C(OCC)(=O)C>[CH2:14]([O:13][C:7]1[CH:8]=[CH:9][C:10]([Br:12])=[CH:11][C:6]=1[CH2:5][N:4]([C:22]1[N:27]=[N:26][C:25]([C:28]([NH2:30])=[O:29])=[CH:24][CH:23]=1)[CH2:2][CH3:3])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCNCc1cc(Br)ccc1OCc1ccccc1
Reactant: NC(=O)c1ccc(Cl)nn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(N)=O)nn1
Temperature: 115 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
A mixture of N-ethyl-N-(2-benzyloxy-5-bromobenzyl)amine hydrochloride salt (87 g), 6-chloropyridazine-3-carboxamide (35 g) and NaHCO3 (41 g) in 1-methyl-2-pyrrolidinone was heated at 115° C. for 24 hours, cooled to 20° C. and added to water (1100 ml) with vigorous stirring, maintaining the temperature below 30° C. with external cooling. Ethyl acetate (725 ml) was added and the mixture stirred at 20° C. for 2 hours. The precipitate was filtered, dried, washed with 40-60 petroleum ether and dried under vacuum at 65° C. to give 6-[N-(2-benzyloxy-5-bromobenzyl)-N-ethylamino]pyridazine-3-carboxamide (83 g, 84.7% yield), mpt. 171°-172° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3([N:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:5]([CH3:36])[O:4][N:3]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[C:5]([CH3:36])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(c1ccccc1)(N1CCN(C(=O)OC(C)(C)C)CC1)C(=O)N2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cc1noc(C)c1-c1ccc2c(c1)C(c1ccccc1)(N1CCNCC1)C(=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
To a solution of tert-butyl 4-(5-(3,5-dimethylisoxazol-4-yl)-2-oxo-3-phenylindolin-3-yl)piperazine-1-carboxylate (0.9 g, 1.8 mmol) in CH2Cl2 (5 mL) was added TFA (5 mL) at 0° C., after adding up, the reaction was stirred at room temperature for 2.0 h. The solvent was evaporated in vacuo to give crude product. It was dissolved in water (20 mL), and was neutralized with NaHCO3 to PH=7˜8, and then the mixture was extracted with EtOAc (2×30 mL), combined organic phase, dried with Na2SO4, filtrated, concentrated to give crude product, and the mixture was purified by chromatography (eluent. CH2Cl2/MeOH/NH3H2O=20/1/0.05) to give product (500 mg, 71.6%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δH 10.75 (s, 1H), 7.49 (d, J=8.0 Hz, 2H), 7.23-7.36 (m, 5H), 6.97 (d, J=8.0 Hz, 1H), 2.65-2.66 (m, 4H), 2.31-2.47 (m, 7H), 2.19 (s, 3H). MS (ESI) m/e [M+1]+ 389.
Reaction SMILES: CC1C=[C:12]2[O:14]C=1C[C@H](C(C)=C)CCC1C(=O)O[C@@H]([C@H]2C(C)=C)C=1.[C:24]([O:28][C:29](=[O:43])[N:30]([CH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([CH:39]=[C:40](Br)Br)[CH2:35][CH2:34]1)[CH3:31])([CH3:27])([CH3:26])[CH3:25].[Li]CCCC.C=O>C1COCC1>[C:24]([O:28][C:29](=[O:43])[N:30]([CH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([C:39]#[C:40][CH2:12][OH:14])[CH2:35][CH2:34]1)[CH3:31])([CH3:27])([CH3:26])[CH3:25]
Reactant: CN(C[C@H]1CC[C@H](C=C(Br)Br)CC1)C(=O)OC(C)(C)C
Reactant: C=C(C)[C@@H]1CCC2=C[C@@H](OC2=O)[C@@H](C(=C)C)c2cc(C)c(o2)C1
Agent: C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C[C@H]1CC[C@H](C#CCO)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
The following reaction was performed in analogy to the reaction described in: Marshall, James A.; Bartley, Gary S.; Wallace, Eli M. Total Synthesis of the Pseudopterane (−)-Kallolide B, the Enantiomer of Natural (+)-Kallolide B. J. Org. Chem. (1996), 61(17), 5729–5735 and Baker, Raymond; Boyes, Alastair L.; Swain, Christopher J. Synthesis of talaromycins A, B, C, and E. J. Chem. Soc., Perkin Trans. 1 (1990), (5), 1415–21.). A solution of 32.9 g (80 mmol) of trans-[4-(2,2-Dibromo-vinyl)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester in 640 ml THF was treated at −78° C. with 105 ml (168 mmol) of BuLi (ca 1.6 M in hexane). After 2 h at this temperature 24 g (800 mmol) of paraformaldehyde were added. The reaction mixture was warmed up to RT for 3 h and after 0.5 h at this temperature extracted with water/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried over Na2SO4 and evaporated. Purification by flash-chromatography on silica gel (hexane/EtOAc 9:1 to 2:1) yielded 12.1 g (54%) of trans-[4-(3-Hydroxy-prop-1-ynyl)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester, MS: 282 (MH+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CCO.[Pd]>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][N:20]([CH:17]1[CH2:18][CH2:19][N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:15][CH2:16]1)[C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH3:33]
Reactant: [H][H]
Reactant: CCOC(=O)CN(C(=O)OC(C)(C)C)C1CCN(C2CCN(Cc3ccccc3)CC2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CN(C(=O)OC(C)(C)C)C1CCN(C2CCNCC2)CC1
Reaction time: 5 h

Procedure:
A suspension of 1.30 g (2.83 mmol) ethyl [(1′-benzyl-[1,4′]bipiperidinyl-4-yl)-tert-butoxycarbonyl-amino]-acetate and 0.16 g 10% Pd/C in 25 mL EtOH was hydrogenated for 5 h at 50° C. and 50 psi hydrogen pressure. The catalyst was removed by suction filtering and the filtrate was evaporated to dryness. The product was obtained as a colourless oil, which was reacted further without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14]([C:16]2[C:17]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:24][C:18]=3[S:19][C:20]=2N(C)C)=[O:15])[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[N:36]1([CH2:41][CH2:42][O:43][C:44]2[CH:49]=[CH:48][C:47](Br)=[CH:46][C:45]=2[O:51][CH3:52])[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:14]([C:16]2[C:17]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:24][C:18]=3[S:19][C:20]=2[C:47]2[CH:48]=[CH:49][C:44]([O:43][CH2:42][CH2:41][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[C:45]([O:51][CH3:52])[CH:46]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: COc1cc(Br)ccc1OCCN1CCCC1
Reactant: Cc1cc(C(=O)c2c(N(C)C)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Product: COc1cc(-c2sc3cc(OCc4ccccc4)ccc3c2C(=O)c2ccc(CN3CCCC3)c(C)c2)ccc1OCCN1CCCC1
Yield: 30 %

Procedure:
The title compound was prepared from 6-benzyloxy-2-(dimethylamino)benzo[b]thiophen-3-yl 3-methyl-4-[(1-pyrrolidinyl)methyl]phenyl ketone (Example 124, Part C) and 4-bromo-2-methoxyphenyl 2-(1-pyrrolidinyl)ethyl ether (Part A) in 30% yield after PrepLC (SiO2; gradient of 80:15:5 to 70:25:5 hexanes-THF-TEA) by essentially following the procedure detailed in Example 123, Part A.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6]=[C:7]2[S:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[CH3:16][C:17]1([CH2:23]OS(C(F)(F)F)(=O)=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[OH:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6]=[C:7]2[S:11][C:10](=[O:12])[N:9]([CH2:16][C:17]3([CH3:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:8]2=[O:13])=[CH:4][CH:3]=1
Reactant: CC1(COS(=O)(=O)C(F)(F)F)CCCCC1
Reactant: O=C1NC(=O)C(=Cc2ccc(O)cc2)S1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(CN2C(=O)SC(=Cc3ccc(O)cc3)C2=O)CCCCC1
Yield: 42 %

Procedure:
A solution of compound vii (0.5 mmol), compound iii (0.6 mmol) and K2CO3 (0.65 mmol) were stirred in DMF (3 mL) at 80° C. for 4 hr, poured into water, extracted with ethyl acetate (3×10 mL), dried and concentrated. The residue was purified by chromatography, affording compound 9 in 42% yield. 1H NMR (300 MHz, CDCl3) δ 0.94 (s, 3H), 1.14-1.86 (m, 10H), 3.63 (s, 2H), 5.69 (s, 1H), 6.94 (d, J=8.40 Hz, 2H), 7.43 (d, J=8.40 Hz, 2H), 7.83 (s, 1H); HRMS exact mass of (M+Na)+, 354.1140 amu; observed mass of (M+Na)+, 354.1141 amu.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=S)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[F:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([NH:26][NH2:27])=O)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]2[NH:18][C:16]([NH:15][C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:27][N:26]=2)=[CH:22][CH:21]=1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: NNC(=O)c1ccc(F)cc1
Product: COc1cc(Nc2nnc(-c3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 71c) starting with [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (250 mg, 0.95 mmol) and 4-fluoro-benzohydrazide (162 mg, 0.95 mmol). Obtained as a brownish solid (41 mg, 12%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:15][CH2:16][CH2:17][CH2:18]Br.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][CH2:17][CH2:16][Br:15])=[CH:4][CH:3]=1
Reactant: BrCCCBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: BrCCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
To a suspension of 4-bromophenol (2.00 g, 11.56 mmol) and potassium carbonate (4.79 g, 34.68 mmol) in DMF (12 mL) was added 1,3-dibromopropane (7.00 g, 37.3 mmol). The mixture was stirred at room temperature overnight. Water was added, and the mixture was extracted with ethyl acetate (4×30 mL). The combined organic layers were washed with brine (3×20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (0-5% ethyl acetate/petroleum ether to afford the title compound (2.35 g, 69%) as a colorless oil. 1H NMR (400 MHz, CDCl3) ppm 7.39 (d, 2H), 6.80 (d, 2H), 4.16-4.01 (m, 2H), 3.55-3.53 (m, 2H), 2.41-2.26 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:16])[CH:14]=[CH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([NH2:28])[C:18]1[CH:27]=[CH:26][C:23]([O:24][CH3:25])=[C:20]([O:21][CH3:22])[CH:19]=1>C(#N)C>[C:1]([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:16])[CH2:14][CH2:15][N:28]([CH2:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[O:16])[CH2:17][C:18]1[CH:27]=[CH:26][C:23]([O:24][CH3:25])=[C:20]([O:21][CH3:22])[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Reactant: COc1ccc(CN)cc1OC
Solvent: CC#N
Product: COc1ccc(CN(CCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)CCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)cc1OC
Yield: 10.9 %

Procedure:
A solution of 1.0 g (4.44 mmol) (R)-1-acryloyl-pyrrolidine-2-carboxylic acid tert-butyl ester and 0.33 ml (2.22 mmol) veratrylamine in 25 ml acetonitrile was stirred for 16 h at 80° C. Concentration in vacuo and flash chromatography (gradient: 0-10% MeOH in EtOAc) afforded 150 mg (10%) of the title compound as a light brown oil.
Reaction SMILES: C([O:8][C@@H:9]([CH3:49])[C@H:10]([O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C@@H:11]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)[CH2:12][CH2:13][CH2:14][C@H:15]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:16]([O:18]CC1C=CC=CC=1)=[O:17])C1C=CC=CC=1>[Pd].CCOC(C)=O>[C:30]([O:29][C:27]([NH:26][C@@H:15]([CH2:14][CH2:13][CH2:12][C@H:11]([CH2:34][C:35]1[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=1)[C@@H:10]([O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C@@H:9]([OH:8])[CH3:49])[C:16]([OH:18])=[O:17])=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: Cc1ccc(C[C@@H](CCC[C@H](NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)[C@@H](Oc2ccccc2)[C@H](C)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(C[C@@H](CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)[C@@H](Oc2ccccc2)[C@H](C)O)cc1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
A 25 mL screw top vial was charged with (2S,6R,7R,8S)-benzyl 8-(benzyloxy)-2-((tert-butoxycarbonyl)amino)-6-(4-methylbenzyl)-7-phenoxynonanoate (741 mg, 1.11 mmol), EtOAc (10 mL), and 10% Pd/C (61 mg, 0.057 mmol). The vial was sealed with a septum-cap, and the reaction was briefly degassed under high vacuum, and then repressurized under about 1 atmosphere of H2 (balloon pressure). This process was repeated 2×, and the reaction was stirred at room temperature under balloon pressure of hydrogen. After stirring for 19 h, the solids were removed by filtration through a pad of Celite®, rinsing with excess EtOAc. The filtrate was concentrated and then dried under high vaccuum to afford the title compound as a white solid (516 mg, 91%): mp 48-51° C.; 1H NMR (400 MHz, CDCl3) δ 7.30-7.17 (m, 2H), 7.09 (s, 4H), 6.97-6.83 (m, 3H), 6.69-6.02 (m, 2H), 5.00 (d, J=8.3 Hz, 1H), 4.33-3.96 (m, 3H), 3.03 (dd, J=13.8, 5.3 Hz, 1H), 2.49 (dd, J=13.9, 8.9 Hz, 1H), 2.33 (s, 3H), 2.19-2.08 (m, 1H), 1.78-1.62 (m, 1H), 1.59-1.15 (m, 17H); 13C NMR (101 MHz, CDCl3) δ 176.73, 159.43, 155.73, 138.03, 135.33, 129.57, 129.10, 129.06, 120.88, 115.85, 82.16, 80.24, 68.15, 53.26, 41.47, 35.46, 32.45, 29.53, 28.35, 22.51, 21.05, 20.01; ESIMS: m/z 486 ([M+H]+).
Reaction SMILES: CCCCCC.C([Li])CCC.CO[B:14]([O:17]C)[O:15]C.Cl.CCCCCC.Br[C:27]1[C:32]2[O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:31]=2[CH:30]=[CH:29][CH:28]=1>O1CCCC1>[CH:30]1[C:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[O:33][C:32]=2[C:27]([B:14]([OH:15])[OH:17])=[CH:28][CH:29]=1
Reactant: COB(OC)OC
Reactant: Brc1cccc2c1oc1ccccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
In a 300 ml three-necked flask, 7.2 g of 4-bromodibenzofuran was dissolved in −78° C. anhydrous tetrahydrofuran (THF) under an argon atmosphere. Then, 20 ml of an n-butyl lithium-n-hexane solution (1.6 M, 1.1 eq) was added and stirred for 1 hour. 4.23 ml (1.3 eq) of trimethoxyborane (B(OMe)3) was added and stirred for 2 hours, and the temperature of the reaction system was increased to room temperature. 200 ml of 1 N hydrochloric acid was added into the reactant and stirred for 3 hours. An organic layer was separated, and solvents were distilled off. In the crude product thus obtained, hexane was added. Precipitated product was filtered to obtain 4.94 g of dibenzofuran-4-boronic acid as a white solid (yield 80%). The product was measured by FAB-MS, and dibenzofuran-4-boronic acid having a molecular weight of 212 was detected.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]([O:29][CH2:30][CH3:31])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:9][CH:8]=1)C.[OH-].[Li+]>O1CCCC1.O.O>[CH2:30]([O:29][CH:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:11][CH:12]=1)[C:4]([OH:32])=[O:3])[CH3:31]
Reactant: CCOC(=O)C(Cc1ccc(OCCCCc2ccccc2OS(C)(=O)=O)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(Cc1ccc(OCCCCc2ccccc2OS(C)(=O)=O)cc1)C(=O)O
Temperature: 25 °C
Yield: 79 %

Procedure:
2-Ethoxy-3-{4-(4-(2-methanesulfonyloxyphenyl)butoxy]phenyl}propanoic acid ethyl ester (2.7 g; 5.8 mmole) was dissolved in tetrahydrofuran: water (1:3, 100 ml). Lithium hydroxide (0.36 g; 8.7 mmole) dissolved in a small amount of water was added. The reaction mixture was stirred over night at room temperature and then evaporated. The residue was redissolved in ethyl acetate and hydrochloric acid (2M) and extracted. After separation the organic phase was extracted with sodium hydroxide (1M, 30 ml). The water phase was cooled, acidified with hydrochloric acid (conc) and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate and evaporation gave 2 g (79% yield) of 2-ethoxy-3-[4-(4-{2-methanesulfonyloxyphenyl}butoxy)phenyl]propanoic acid.