Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[CH3:12].[Br:13]N1C(=O)CCC1=O>ClC1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:13][CH2:12][C:3]1[CH:4]=[C:5]([F:11])[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Product: O=[N+]([O-])c1cc(F)c(CBr)cc1F
Temperature: 25 °C
Yield: 220.5 %

Procedure:
1,4-Difluoro-2-methyl-5-nitrobenzene (1 g) was dissolved in chlorobenzene (6 mL) and N-bromosuccinimide (1.54 g) added followed by benzoyl peroxide (0.2 g). The reaction mixture was stirred at reflux for 2.5 hours then additional benzoyl peroxide (0.2 g) and N-bromosuccinimide (1.54 g) were added. The reaction was refluxed for 2 hours then was cooled to room temperature, quenched with water and extracted with dichloromethane (3×). The combined organics were dried and concentrated under reduced pressure. The oil obtained was triturated with diethyl ether, filtered and the filtrate concentrated under reduced pressure to yield the title compound (3.21 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][C:3]=1[O:16][CH3:17].Cl[CH2:19][C:20]1[N:21]=[C:22]([C:25]2[S:26][C:27]([CH3:30])=[CH:28][CH:29]=2)[O:23][CH:24]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:19][C:20]3[N:21]=[C:22]([C:25]4[S:26][C:27]([CH3:30])=[CH:28][CH:29]=4)[O:23][CH:24]=3)=[C:3]([O:16][CH3:17])[CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Cc1ccc(-c2nc(CCl)co2)s1
Reactant: COc1cc(CCCn2ccnc2)ccc1O
Product: COc1cc(CCCn2ccnc2)ccc1OCc1coc(-c2ccc(C)s2)n1
Yield: 72 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxy-3-methoxyphenyl)propyl]imidazole was reacted with 4-chloromethyl-2-(5-methyl-2-thienyl)oxazole to obtain 4-[4-[3-(1-imidazolyl)propyl]-2-methoxyphenoxymethyl]-2-(5-methyl-2-thienyl)oxazole. The yield was 72%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 92-93° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([CH3:21])=[C:18]([C:22]([OH:24])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:38]1[CH2:42][CH2:41][N:40]=[C:39]1[C:43]1[CH:48]=[CH:47][C:46]([CH2:49][NH:50][CH3:51])=[CH:45][CH:44]=1.Cl.CCN(C(C)C)C(C)C>ClCCCl.CN(C=O)C>[NH:40]1[CH2:41][CH2:42][N:38]=[C:39]1[C:43]1[CH:44]=[CH:45][C:46]([CH2:49][N:50]([CH3:51])[C:22]([C:18]2[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]3[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH3:25])(=[O:12])=[O:11])[CH3:14])[O:20][C:19]=2[CH3:21])=[O:24])=[CH:47][CH:48]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)c(C)o2)c(C)c1
Reactant: CNCc1ccc(C2=NCCN2)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(C4=NCCN4)cc3)c(C)o2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-2-methylfuran-3-carboxylic acid (82 mg, 0.22 mmol) was dissolved in DCE (1 mL) and CDI (72 mg, 0.33 mmol) was added. The reaction was stirred at ambient temperature for 2 h and 0.5 mL of this solution was added to a flask containing 1-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylmethanamine.3 HCl (31 mg, 0.11 mmol) and DIPEA (0.076 mL, 0.44 mmol) in DMF (2 mL). The reaction was stirred at ambient temperature for 3 days, then heated in a microwave at 120° C., 250 psi, 200 W for 2×20 min. The reaction was concentrated and diluted with DCM, then washed with water and saturated brine, and dried over MgSO4. The filtrate was shaken with Ambersep and PL-MIA resins, then filtered. The solvent was removed in vacuo and a portion of the crude product purified using prep method C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Br:9][C:10]1C=[CH:14][C:13]([CH3:16])=[C:12](Cl)[CH:11]=1.Cl[CH2:19][Cl:20]>>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][Br:1])=[CH:14][C:19]=1[Cl:20]
Reactant: ClCCl
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Br)cc1Cl
Product: Clc1cc(CBr)ccc1Br
Temperature: 100 °C

Procedure:
A suspension of N-bromosuccinimide (16.4 g, 87.4 mmol), 4-bromo-chlorotoluene (18.2 g, 87.4 mmol) and α,α′-azoisobutyronitrile (0.67 g, 4 mmol) in 90 mL dichloromethane is heated in the microwave for 1 min at 100° C. and then cooled overnight at −20° C. The resulting white precipitate is filtered and the filtrate is evaporated down. The residue is stirred with 100 mL diethyl ether, filtered, evaporated down and filtered again.
Reaction SMILES: [CH2:1]([N:3]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[C:20]1[C:21]([O:32][CH3:33])=[N:22]C=C(C#C[Si](C)(C)C)[CH:25]=1)C(C1CC1)=O)[CH3:2].[O:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.B.[OH:40]O.[OH-].[Na+].[CH2:44]1[CH2:48][O:47][CH2:46][CH2:45]1>CO>[CH:37]1([C:38]([N:3]([CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=2[C:20]2[CH:25]=[C:44]([CH2:45][C:46]([OH:40])=[O:47])[CH:48]=[N:22][C:21]=2[O:32][CH3:33])[CH2:1][CH3:2])=[O:34])[CH2:35][CH2:36]1
Reactant: OO
Reactant: C1CCOC1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(C#C[Si](C)(C)C)cnc1OC)C(=O)C1CC1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)cnc1OC)C(=O)C1CC1
Reaction time: 2 h

Procedure:
To cyclopropanecarboxylic acid ethyl-[2-(2-methoxy-5-trimethylsilanylethynyl-pyridin-3-yl)-5-trifluoromethyl-benzyl]-amide (0.205 g, 0.42 mmol) in THF (2 mL) at 0° C. was added borane tetrahydrofuran complex (1M in THF; 0.48 mL, 0.48 mmol), and the reaction was stirred for 2 hours. Once no starting material was seen by analytical LCMS, MeOH (0.22 mL), hydrogen peroxide (0.04 mL, 0.43 mmol), and 3M aqueous sodium hydroxide (0.22 ml) was added, and the reaction was stirred for 1 hour. Additional hydrogen peroxide (0.1 mL) was added, and the reaction was stirred for another hour. The mixture was then acidified and extracted with EtOAc, and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by preparative HPLC to give Compound 10.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:25]3[CH2:28][CH2:27][CH2:26]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:11]=3)=[CH:4][CH:3]=1.Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([N+]([O-])=O)=C[CH:34]=1)=[O:31].N1C=CC=CC=1.C1([C@H](O)C)CC1>C(Cl)Cl.ClCCCl>[CH:38]1([C@H:33]([O:32][C:30](=[O:31])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:9]([CH:25]4[CH2:28][CH2:27][CH2:26]4)[C:10]4[C:15]([C:16]=3[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:11]=4)=[CH:6][CH:7]=2)[CH3:34])[CH2:37][CH2:36]1
Reactant: CS(=O)(=O)COc1ccc2c(C#N)c(-c3ccc(N)cc3)n(C3CCC3)c2c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: C[C@@H](O)C1CC1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H](OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCS(C)(=O)=O)cc3n2C2CCC2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
2-(4-Amino-phenyl)-1-cyclobutyl-6-methanesulfonylmethoxy-1H-indole-3-carbonitrile (100 mg, 0.25 mmol) was combined with p-nitrophenyl chloroformate (120 mg, 0.6 mmol), DCE (1 mL), and pyridine (60 μL, 0.75 mmol) and stirred at room temperature for 1 h. To this mixture was added (R)-1-Cyclopropylethanol (90 μL, 0.92 mmol) and then heated at 80° C. for 2 h. The reaction mixture was diluted with CH2Cl2 and washed with dilute aqueous NaOH solution. The organic layer was dried, concentrated and purified by silica gel chromatography (95:5 CH2Cl2/EtOAc) to provide (R)-[4-(3-cyano-1-cyclobutyl-6-methanesulfonylmethoxy-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (105 mg, 83%) as a white solid.
Reaction SMILES: N1(CCC[O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)CCCC1.Cl[CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30][CH2:29]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:34][CH:31]1[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][CH2:25][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:29][CH2:30]1
Reactant: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: OC1CCN(CCCCl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC1(c2ccc(OCCCN3CCC(O)CC3)cc2)CCOCC1
Yield: 60.9 %

Procedure:
4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile (533 mg, 2.62 mmol), 1-(3-chloro-propyl)-piperidin-4-ol (750 mg, 4.22 mmol), DMF (10 ml) and K2CO3 (1.44 g, 10.42 mmol) were reacted together according to general procedure E. Purification by chromatography on silica, eluant DCM:MeOH:NH3 (92:6:2) provided the title compound (550 mg, 61%) as an off white solid. 1H NMR (400 MHz, CDCl3), δ 7.38 (d, 2H), 6.93 (d, 2H), 4.13-4.04 (m, 2H), 4.02 (t, 2H), 3.89 (td, 2H), 3.70 (m, 1H), 2.87-2.71 (m, 2H), 2.50 (t, 2H), 2.23-1.84 (m, 10H), 1.68-1.49 (m, 3H).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:22])[CH2:15][CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH2:32]([O:39][CH2:40]Cl)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH:17]1([CH2:16][C@H:15]([CH2:40][O:39][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:14]([N:9]2[C@@H:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:12][O:11][C:10]2=[O:13])=[O:22])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=C(CCC1CCCC1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: ClCOCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H](COCc1ccccc1)CC1CCCC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 71.8 %

Procedure:
To a solution of (4S)-benzyl-3-(3-cyclopentylpropanoyl)oxazolidin-2-one (42.4 g, 141 mmol) in dichloromethane (500 mL) at 0° C. under nitrogen was added titanium (IV) chloride (1 M in DCM, 155 mL, 155 mmol) in a slow steady stream. After 5 min, diisopropylethylamine (27 mL, 155 mmol) was added dropwise. After stirring at 0° C. for 1 h, benzyloxymethylchloride (TCI-America) (39 mL, 280 mmol) was added in a slow steady stream to the resulting titanium enolate, and the mixture was maintained at 0° C. for 3.5 h. The reaction mixture was then quenched with water (400 mL). The aqueous layer was extracted with dichloromethane (150 mL×2). The organic extracts were washed with saturated NaHCO3, were dried (MgSO4) and were evaporated. The residue was washed with ether (2×), and then was triturated with hexanes/ether to provide 2 crops of (4S)-3-((2R)-3-cyclopentyl-2-{[(phenylmethyl)oxy]methyl}propanoyl)-4-(phenylmethyl)-1,3-oxazolidin-2-one as a pale yellow solid (42.7 g, 72%). LCMS: (M+H)+: 422.2.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:25]1[N:26]=[CH:27][S:28][CH:29]=1)\[C:5]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([O-:22])=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[CH2:13][S:14][C@H:9]12)=[O:6].[Na+].Br[CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:34](=[O:35])[O:33]1.Cl.C(OCC)(=O)C>CN(C)C=O>[CH3:1][O:2]/[N:3]=[C:4](/[C:25]1[N:26]=[CH:27][S:28][CH:29]=1)\[C:5]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([O:22][CH:32]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:34](=[O:35])[O:33]3)=[O:21])=[C:12]([CH2:15][O:16][C:17](=[O:19])[NH2:18])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(COC(N)=O)CS[C@H]12)c1cscn1
Reactant: O=C1OC(Br)c2ccccc21
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC3OC(=O)c4ccccc43)=C(COC(N)=O)CS[C@H]12)c1cscn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.4 %

Procedure:
Sodium 7-[(Z)-2-methoxyimino-2-(thiazol-4-yl)-acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylate (100 mg) was dissolved in dimethylformamide (1 ml). 3-Bromophthalide (69 mg) was added to the solution. After stirring for one hour at room temperature, the reaction mixture was added to a mixture of dil. HCl (10 ml) and ethyl acetate (20 ml). The resulting ethyl acetate layer was separated, washed successively with dil. HCl (10 ml) and saturated aqueous NaCl (10 ml×2), dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (2 ml) and the solution was added dropwise to a petroleum ether-diethyl ether mixture (100 ml) with stirring. Resulting crystals well filtered, and dried under reduced pressure to give the title compound (45 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:41][N:42]([CH3:57])[CH2:43][CH2:44][N:45]([CH3:56])[C:46]1[S:47][C:48]2[CH:54]=[C:53]([NH2:55])[CH:52]=[CH:51][C:49]=2[N:50]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[CH3:41][N:42]([CH3:57])[CH2:43][CH2:44][N:45]([CH3:56])[C:46]1[S:47][C:48]2[CH:54]=[C:53]([NH:55][C:12]([C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[CH:16][CH:15]=3)=[O:14])[CH:52]=[CH:51][C:49]=2[N:50]=1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)cc1
Reactant: CN(C)CCN(C)c1nc2ccc(N)cc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(-c4ccc(F)cc4)cc3)cc2s1
Yield: 59.6 %

Procedure:
Prepare according to Method A, using 4-(4-fluorophenyl)benzoic acid (572 mg, 2.65 mmol), HATU (1.06 g, 2.79 mmol), N2-(2-dimethylamino-ethyl)-N2-methyl-benzothiazole-2,6-diamine (500 mg, 2.00 mmol), DIEA (1.15 mL, 6.60 mmol), and a chromatography gradient of MeOH in CH2Cl2 (7-17%) to afford the title compound (535 mg, 60%). mass spectrum (m/e): 449.0 [M+H]. 1H NMR (400 MHz, DMSO-d6): δ 10.29 (s, 1H), 8.26 (d, 1H, J=2.2 Hz), 8.06 (d, 2H, J=8.4 Hz), 7.84-7.78 (m, 4H), 7.57 (dd, 1H, J=8.8, 2.2 Hz), 7.41 (d, 1H, J=8.8 Hz), 7.34 (t, 2H, J=8.8 Hz), 3.61 (t, 2H, J=6.8 Hz), 3.14 (s, 3H), 2.52 (m, 2H), 2.20 (s, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[CH2:5][N:4]1[C:11]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1N1N=CC=N1)=[O:12].CC1C=CC([C:35]2[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=2)=C(C=1)C(O)=O>>[NH2:1][CH2:2][CH:3]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[CH2:5][N:4]1[C:11]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[C:35]1[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=1)=[O:12]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CC3CCCC3C2CN)c1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)O)c1
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CC3CCCC3C2CN)c1

Procedure:
The title compound was prepared following the same general protocol as described for (1-(aminomethyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone in Example A68 using 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoic acid. MS (ESI) 339 (M+H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21]O)[CH2:16][CH2:15]1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].CN1CCOCC1.[CH3:30][O:31][C:32]([CH:34]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:33]>C(Cl)Cl.CS(C)=O>[C:7]([N:14]1[CH2:15][CH2:16][CH:17]([CH2:20]/[CH:21]=[CH:34]/[C:32]([O:31][CH3:30])=[O:33])[CH2:18][CH2:19]1)([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)/C=C/CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.05 h

Procedure:
A solution of oxalyl chloride (11.8 g) in methylene chloride (180 ml) is cooled to −78° C. and dimethyl sulfoxide (DMSO) (8.9 ml) is added dropwise. The solution is stirred at −78° C. for about 3 minutes and a solution of N-BOC-2-(piperidin-4-yl)ethanol (14.3 g) in methylene chloride (250 ml) is added over a period of about 10 minutes. The solution is stirred for about 1 hour and N-methyl morpholine (21.6 g) is added over a period of about 15 minutes. The solution is allowed to warm to room temperature and, after about 30 minutes, methyl (triphenylphosphoranylidene) acetate (68.6 g) is added. The solution is stirred at room temperature for about 18 hours, evaporated in vacuo and the residue taken up in ethyl acetate. The ethyl acetate solution is washed with water, 5% HCl, 5% sodium hypochlorite solution, water, brine, dried over sodium sulfate, filtered and evaporated in vacuo to give methyl 4-(N-BOC-piperidin-4-yl)trans-crotonate.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH2:8]([Li])[CH2:9][CH2:10]C.CO[C:15](=[O:22])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[CH3:21]>C1COCC1>[CH:1]1([NH:4][C:5]([CH3:7])=[CH:6][C:15]([CH:16]2[N:17]([CH3:21])[CH2:18][CH2:19][CH2:20]2)=[O:22])[CH2:3][CH2:10][CH2:9][CH2:8][CH2:2]1
Reactant: CC(C)NC(C)C
Reactant: COC(=O)[C@@H]1CCCN1C
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=CC(=O)C1CCCN1C)NC1CCCCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 99.8 %

Procedure:
Diisopropylamine (2.12 g, 21 mmol) and THF (35 mL) were added to a three-necked flask, which was flushed with N2. The solution was stirred with ice cooling, and n-butyllithium (1.6M in hexane, 12.5 mL, 20 mmol) was added dropwise over 20 min. To the resulting solution was added N-(1-methylethylidine)cyclohexanamine (prepared via the procedure of J. Org. Chem., 19:1054, 1954), over a 15 min period while maintaining the temperature at 0±2° C., and the resulting solution was stirred at 0° C. for 20 min. To this solution was added 1.43 g (10.0 mmol) of N-methyl proline methyl ester over a 1 hr period, with stirring and cooling to maintain a temperature of 0±2° C. The reaction was quenched by rapid addition of saturated aqueous ammonium chloride solution (10 mL). The layers were separated, and the aqueous layer was extracted one with 10 mL of ethyl acetate. The organic layers were combined and dried over Na2SO4. The solution was decanted from the solids and concentrated on a rotary evaporator to provide the product as a viscous oil (2.50 g). 1H NMR (CDCl3) δ: 11.18 (br, 1H), 5.20 (s, 1H),3.40 (m, 1H), 2.62 (m, 1H), 2.33 (s, 3H), 2.21 (m, 1H), 1.97 (s, 3H), 1.9-1.5 (m, 8H), 1.5-1.0 (m, 6H). 13C NMR (CDCl3) δ: 197.48 (s), 163.21 (s), 91.07 (d), 74.43 (d), 56.93 (t), 51.50 (d), 41.34 (q), 36.33 (t), 33.61 (t), 33.58 (t), 30.91 (t), 25.22 (t), 24.26 (t), 23.07 (t), 18.71 (q).
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9](N)[CH:10]=[CH:11][C:12]=3[OH:17])[C:7](=[O:19])[C:6]=2[C:5]([OH:20])=[CH:4][CH:3]=1.S([O-])(O)=[O:22].[Na+].Cl.[OH-:27].[Na+]>>[CH2:4]1[C:5](=[O:20])[C:6]2[C:15](=[C:14]([OH:16])[C:13]3[C:8]([C:7]=2[OH:19])=[C:9]([OH:22])[CH:10]=[CH:11][C:12]=3[OH:17])[C:2](=[O:27])[CH2:3]1
Reactant: [OH-]
Reactant: O=S([O-])O
Reactant: Nc1ccc(O)c2c1C(=O)c1c(O)ccc(N)c1C2=O
Agent: Cl
Agent: [Na+]
Product: O=C1CCC(=O)c2c1c(O)c1c(O)ccc(O)c1c2O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To crude 1,5-diamino-4,8-dihydroxyanthraquinone (11 g, 0.041 mol) was added NaOH (2.5 M, 200 mL) and the suspension was refluxed gently for 3 hours before it was allowed to cool down to room temperature. Sodium hydrogen sulphite (31.74 g, 0.182 mol) was added portionwise and the reaction mixture was refluxed again for 3 hours. It was cooled down to room temperature and was acidified with concentrated hydrochloric acid until pH 3. The precipitate was isolated by filtration and washed successively with cold water and then hot water. After lyophilisation overnight, the title compound was afforded as a crude brown solid (8 g, 73%). FAB MS, m/z(M+H)+ 251.
Reaction SMILES: CC#N.[OH2:4].[CH2:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(Cl)Cl.OF>CC#N>[CH2:7]([CH:6]1[CH2:5][O:4]1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=CCCCCCCCCCC
Reactant: O
Agent: OF
Solvent: CC#N
Solvent: ClCCl
Product: CCCCCCCCCCC1CO1
Yield: 85 %

Procedure:
Under a flow of F2 (10% in N2) of 8.9 ml min−1 (1.49 mmol h−1) fed through conduit 12, MeCN:H2O (4:1, 5.50 ml) was added to conduit 16 at a rate of 5.50 ml −1 (60.4 mmol h−1). A solution of dodec-1-ene 24 (0.25 g, 1.49 mmol) (in a 1:1 mixture of DCM:MeCN) was added to pot reactor 22 prior to reaction. The HOF.MeCN thus generated was passed via conduit 20 into the pot reactor 22. Following reaction and purging with nitrogen, the reaction mixture was then transferred from pot reactor 22 to a vessel containing 100 ml of sodium bicarbonate solution, washed with DCM (3×75 ml), dried over MgSO4 and filtered. The solvent was removed under reduced pressure to yield 2-decyloxirane (0.233 g, 1.27 mmol, 85%) as a pale yellow oil, with no further purification required.
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]3[NH:14][C:13]4[CH:18]([CH2:21][C:22]([OH:24])=[O:23])[CH2:19][CH2:20][C:12]=4[C:11]=3[CH:10]=2)=[CH:5][C:4]=1[C:27]([F:30])([F:29])[F:28])#[N:2].[Li+].[OH-:32].Cl>O1CCOCC1>[C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]3[NH:14][C:13]4[CH:18]([CH2:21][C:22]([OH:24])=[O:23])[CH2:19][CH2:20][C:12]=4[C:11]=3[CH:10]=2)=[CH:5][C:4]=1[C:27]([F:29])([F:30])[F:28])(=[O:32])[NH2:2]
Reactant: N#Cc1ccc(COc2ccc3[nH]c4c(c3c2)CCC4CC(=O)O)cc1C(F)(F)F
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Solvent: C1COCCO1
Product: NC(=O)c1ccc(COc2ccc3[nH]c4c(c3c2)CCC4CC(=O)O)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 48 h

Procedure:
To a solution of 2-(7-(4-cyano-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid (9.0 mg, 0.022 mmol) in dioxane (1 mL) was added 1M LiOH (aq) (3.0 mL). The reaction was stirred at 50° C. for 48 h. 1M HCl (aq) was added to adjust pH to 3. The mixture was extracted with EtOAc. The EtOAc extract was dried over MgSO4 and the residue was purified by preparative HPLC/MS to give the title compound as a solid (2.1 mg). LCMS m/z=433.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.01-2.14 (m, 1H), 2.32-2.42 (m, 1H), 2.57-2.78 (m, 4H), 5.20 (s, 2H), 6.72 (d, J=11.37 Hz, 1H), 6.93 (d, J=2.40 Hz, 1H), 7.20 (d, J=8.72 Hz, 1H), 7.50-7.59 (m, 2H), 7.76 (d, J=7.58 Hz, 1H), 7.82 (s, 1H), 7.91 (s, 1H), 10.47 (s, 1H), 12.17 (bs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[C:13](=[O:18])[NH:14][CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:26][CH3:27].O>CN(C=O)C>[CH2:26]([N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:4]2[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=2[O:2][CH3:1])[C:13]1=[O:18])[CH3:27]
Reactant: CCI
Reactant: COc1cc([N+](=O)[O-])ccc1-c1ccc[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1cccc(-c2ccc([N+](=O)[O-])cc2OC)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
350 mg (1.42 mmol) of the product from example 55A are suspended in 3.5 ml of DMF. To this are added 393 mg (2.84 mmol) of potassium carbonate and 266 mg (1.71 mmol) of iodoethane, and the mixture is left to stir at RT for 3 h. Then it is admixed with water and extracted with dichloromethane. The organic solution is dried over sodium sulfate, concentrated and purified by preparative HPLC. This affords 224 mg (57% of theory) of the title compound.