Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][O:15][NH:14][C:13]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([CH:25]([C:42]([O-])=[O:43])[CH2:26][C:27](=[O:41])[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1CCC(N=C=NC2CCCCC2)CC1.C(OCC)(=O)C>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][O:15][N:14]([C:27]2([C:28]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=3)=[O:29])[CH2:26][CH:25]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:42](=[O:43])[O:41]2)[C:13]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@H]1CONC1=O)OCc1ccccc1
Reactant: O=C(CC(Cc1ccccc1)C(=O)[O-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(N[C@H]1CON(C2(C(=O)OCc3ccc([N+](=O)[O-])cc3)CC(Cc3ccccc3)C(=O)O2)C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
In 6 ml of dichloromethane were dissolved 286 mg of (4S)-4-benzyloxycarbonylamino-3-isoxazolidinone and 540 mg of the Compound (73) obtained in Example 73. To the solution was added 325 mg of DCC dissolved in 2 ml of dichloromethane. The mixture was stirred at room temperature for 2 hours. To the reaction solution was added ethyl acetate, and the crystals which separated out were filtered off. The filtrate was washed with water and dried (Na2SO4), followed by evaporating off the solvent. The residue was subjected to a silica gel column chromatography, followed by elution with hexane-ethyl acetate (2:1) to give 553 mg of the subject Compound (75) as a pale yellow oily product.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[N+:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-:9])=[O:7]
Reactant: c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccccc1

Procedure:
A sulfuric acid stream (11), a nitric acid stream (12), a fresh benzene stream (13) and a recycle benzene stream (21) are fed into a reactor (1). The benzene is used in 5 to 10% excess, based on nitric acid. The amount of recycle benzene obtained depends on this excess and the quality of the starting benzene. Once all the nitric acid has reacted with the benzene to give nitrobenzene under adiabatic reaction conditions, the reaction product (14), now at a temperature of approx. 130° C., is fed into a phase separation apparatus (2), in which the reaction product (14) separates into an organic phase ((15)=crude nitrobenzene, comprising benzene and low boilers in addition to nitrobenzene) and an aqueous phase ((16)=waste acid, still comprising small proportions of nitrobenzene and benzene in addition to sulfuric acid). The aqueous phase (16), comprising mainly sulfuric acid, is subjected to a flash evaporation of water in the evaporator (3) by sudden pressure reduction, and is thereby concentrated. The concentrated sulfuric acid (17) is stored in the sulfuric acid tank (4) until it is re-used. After separation in the phase separation apparatus, the crude nitrobenzene (15) is cooled to approx. 50° C. in the crude nitrobenzene cooler (5) and fed into the wash (6). The resulting stream of purified crude nitrobenzene (18), substantially freed of nitrophenols and salts, is heated again and, in a distillation column (7), freed of water, benzene and other low boilers, which are separated off (19) overhead, to give dried pure nitrobenzene (20), which is stored in a tank (8). The condensed head product (19) of the distillation column (7) is fed into a phase separation apparatus (9), in which the head product separates into an organic phase ((21), comprising benzene and low boilers) and an aqueous phase (22). The organic phase (21) is temporarily stored in a buffer tank (10) and from there, as already described above, is returned into the inlet of the reactor (1) for reaction. Nitrobenzene prepared in this way typically has a purity of approx. 99.96% (GC), a residual benzene content of 0.0028% (GC), a 1,3-dinitrobenzene content of 0.0273% (GC) and a nitrophenole content of <5 ppm (HPLC). Furthermore, the nitrobenzene has a water content of 0.0079% (Karl-Fischer).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:11])[CH:7]=[C:8]([Br:10])[CH:9]=1)=[O:4].[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:11]=[CH:18][C:17]2[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:22])[F:23])=[CH:21][CH:20]=2)[CH:7]=[C:8]([Br:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(Br)cn1N
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Product: COC(=O)c1cc(Br)cn1N=Cc1ccc(C(F)(F)F)cc1

Procedure:
Prepared according to the imine formation condition used in Example 18 step b) from 1-amino-4-bromo-1H-pyrrole-2-carboxylic acid methyl ester and 4-trifluoromethylbenzaldehyde. 1H NMR (CDCl3, δ in ppm): 8.44 (s, 1H), 7.96 (d, 2H, J=7.8 Hz), 7.70 (d, 2H, J=7.8 Hz), 7.27 (d, 1H, J=1.8 Hz), 6.99 (d, 1H, J=1.6 Hz), 3.85 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][CH2:15][C:11]2([CH2:14][NH:13][CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH2:28][CH2:27][N:26]([CH2:29][C:30](O)=[O:31])[C:25]2=[O:33])=[CH:20][CH:19]=1.C(N=C=NCCCN(C)C)C.CN1CCOCC1>ClCCl>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]2([CH2:14][N:13]([C:30](=[O:31])[CH2:29][N:26]3[CH2:27][CH2:28][C:24]([C:21]4[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=4)([C:34]4[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=4)[C:25]3=[O:33])[CH2:12]2)[CH2:15][CH2:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCC3(CC2)CNC3)cc1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CC2(CCN(Cc3ccccc3)CC2)C1
Reaction time: 8 h

Procedure:
7-Benzyl-2,7-diazaspiro[3.5]nonane (0.237 g, 0.749 mmol), 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (0.248 g, 0.749 mmol; Example 58D), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.199 mL, 1.123 mmol) and N-methylmorpholine (0.247 mL, 2.247 mmol) were stirred together in dichloromethane (2 mL). After stirring overnight, the reaction was diluted with dichloromethane (20 mL) and washed with 1 N HCl (10 mL) and brine (10 mL), dried over magnesium sulfate and concentrated. The residue was loaded onto a GraceResolv™ 40 g silica gel column (Grace Davison Discovery Sciences) and the title compound eluted with a gradient of 0.4% methanol/dichloromethane containing 0.2 N NH3 to 6% methanol/dichloromethane containing 0.2 N NH3 (Flow=40 mL/minute) over 40 minutes. 1H NMR (300 MHz, CDCl3) δ 7.39-7.15 (m, 9H), 6.99 (t, J=8.2, 4H), 3.97 (s, 2H), 3.72 (d, J=20.0, 4H), 3.53 (t, J=6.5, 2H), 3.46 (s, 2H), 2.75 (t, J=6.4, 2H), 2.32 (s, 4H), 1.73 (s, 4H); MS (ESI+) m/z 530.2 (M+H)+.
Reaction SMILES: Cl[SiH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH2:4][CH2:3]1.[Cl-].[CH2:27]([Zn+])[CH2:28][CH3:29].Cl[SiH]1CCC(CC[C@H]2CC[C@H](C3C=CC(F)=CC=3)CC2)CC1.[Cl-].C([Zn+])CCCC>>[F:23][C:22]([F:25])([F:24])[C:19]1[CH:20]=[CH:21][C:16]([C@H:13]2[CH2:14][CH2:15][C@H:10]([CH2:9][CH2:8][C@H:5]3[CH2:6][CH2:7][Si@H:2]([CH2:27][CH2:28][CH3:29])[CH2:3][CH2:4]3)[CH2:11][CH2:12]2)=[CH:17][CH:18]=1
Reactant: FC(F)(F)c1ccc([C@H]2CC[C@H](CCC3CC[SiH](Cl)CC3)CC2)cc1
Reactant: CCC[Zn+]
Agent: CCCCC[Zn+]
Agent: Fc1ccc([C@H]2CC[C@H](CCC3CC[SiH](Cl)CC3)CC2)cc1
Agent: [Cl-]
Product: CCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(C(F)(F)F)cc3)CC2)CC1

Procedure:
The preparation was conducted in the same manner as in Example 6, except that 8.2 g (21 mmol) of 1-chloro-4-(2-(trans-4-(p-trifluoromethylphenyl)cyclohexyl)ethyl)-1-silacyclohexane and n-propylzinc chloride were used instead of 7.0 g (21 mmol) of 1-chloro-4-(2-(trans-4-(p-fluorophenyl)cyclohexyl)ethyl)-1-silacyclohexane and n-pentylzinc chloride.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4].[Br:17]NC(=O)CCC(N)=O>CN(C)C=O.CCOC(C)=O>[Br:17][C:11]1[C:10]([O:14][CH3:15])=[CH:9][CH:8]=[C:7]2[C:12]=1[CH2:13][CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]2=[O:16]
Reactant: CCCCC1Cc2cc(OC)ccc2C1=O
Reactant: NC(=O)CCC(=O)NBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCC1Cc2c(ccc(OC)c2Br)C1=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 2-butyl-5-methoxy-1-indanone (1.869 g, 8.56 mmol) in anhydrous dimethylformamide (8.6 mL) was treated with N-bromosuccinamide (1.676 g, 9.42 mmol). The resulting mixture was stirred under a nitrogen atmosphere and at room temperature for 14 hours, and then heated in an oil bath at 50° C. for 4 hours. After cooling to room temperature, the mixture was diluted with EtOAc (100 mL), washed with water (4×50 mL) and brine (50 mL), dried over MgSO4, and evaporated under vacuum to a dark amber oil (2.468 g). The crude product was purified by column chromatography on EM silica gel 60 (230-400 mesh, 620 mL dry, packed under CH2Cl2), using CH2Cl2 as eluting solvent, to afford 4-bromo-2-butyl-5-methoxy-1-indanone (1.267 g, contains approx. 3% of the 6-bromo isomer) as a pale tan solid. Earlier fractions afforded the 6-bromo isomer.
Reaction SMILES: [CH2:1]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([N:9]1[CH2:14][CH2:13][CH:12]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][CH2:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1CCN(CCc2ccccc2)CC1
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: c1ccc(CCN2CCC(Nc3ccccc3)CC2)cc1

Procedure:
The title compound was prepared by the method outlined in Example 1 using 1-phenethyl-4-piperidone (5.3 g, 0.026 mol), aniline (5.01 ml, 0.55 mol), acetic acid (3 ml) 1,2-dichloroethane (100 ml) and sodium triacetoxyborohydride (5.82 g, 0.027 mol). The title compound was obtained as a white solid (74% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@@H:16]([CH3:44])[C:17]([N:19]1[C@H:27]([C:28]([O:30]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:29])[CH2:26][C:21]2([S:25][CH2:24][CH2:23][S:22]2)[CH2:20]1)=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2]>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@@H:16]([CH3:44])[C:17]([N:19]1[C@H:27]([C:28]([OH:30])=[O:29])[CH2:26][C:21]2([S:22][CH2:23][CH2:24][S:25]2)[CH2:20]1)=[O:18])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1CC2(C[C@H]1C(=O)OC(c1ccccc1)c1ccccc1)SCCS2
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1CC2(C[C@H]1C(=O)O)SCCS2
Reaction time: 0.5 h

Procedure:
A solution of (S,S,S)-7-[2-[(1-ethoxycarbonyl-3-phenylpropyl)amino]-1-oxopropyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid, diphenylmethyl ester (800 mg.) in a mixture of trifluoroacetic acid (15 ml.) and anisole (3 ml.) is stirred at 0° for 30 minutes. The solvent is removed at reduced pressure and the residue applied to an AG 50W-X2(H+) column. After washing with water, the column is eluted with aqueous pyridine. The fractions containing the product are combined and lyophilized to yield (S,S,S)-7-[2-[(1-ethoxycarbonyl-3-phenylpropyl)amino]-1-oxopropyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([Cl:9])[CH:3]=1.[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:10])=[C:4]([Cl:9])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Br)cc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(Br)ccc1CBr
Yield: 65.6 %

Procedure:
4-Bromo-2-chloro-1-methylbenzene (CAS 89794-02-5, 30 g, 0.15 mol) and N-bromosuccinimide (26 g, 0.15 mol) were mixed in CCl4 (300 mL). Azobis(2-methylpropionitrile) (˜0.3 g) was added in portions under vigorous stirring and refluxing. The mixture was refluxed for 30 min and cooled. The precipitate was filtered off and discarded. The filtrate was evaporated. The residue was distilled at 1 mmHg, bp 75° C. to give the title compound (28 g, 65%). 1H NMR data (CDCl3): δ 7.57 (d, J=1.9 Hz, 1H ArH), 7.39 (dd, 1H, J1=1.9 Hz, J2=8.1 Hz, ArH), 7.31 (d, 1H, J=1.9 Hz, ArH), 4.53 (s, 2H, ArCH2).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][Si:11]([CH3:27])([CH3:26])[CH2:12][CH2:13][O:14][CH2:15][N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][C:17]1=[O:25].Br[CH2:29][C:30]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:31]=1[C:32](Cl)=[O:33]>C1COCC1>[N+:39]([C:36]1[CH:35]=[C:31]2[C:30]([CH2:29][C:18]3([C:32]2=[O:33])[C:19]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[N:16]([CH2:15][O:14][CH2:13][CH2:12][Si:11]([CH3:27])([CH3:26])[CH3:10])[C:17]3=[O:25])=[CH:38][CH:37]=1)([O-:41])=[O:40]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1CBr
Reactant: C[Si](C)(C)CCOCN1C(=O)Cc2cccnc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCN1C(=O)C2(Cc3ccc([N+](=O)[O-])cc3C2=O)c2cccnc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N,N-Diisopropylethylamine (3.64 mL, 22 mmol) is added to a stirred solution of 1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (prepared according to the procedures described in WO2008/020902) (2.64 g, 10 mmol) in THF (75 mL) at ambient temperature. To the stirred mixture is added dropwise a solution of 2-(bromomethyl)-5-nitrobenzoyl chloride (3.06 g, 11 mmol) [Pifferi et al. (1966) Tetrahedron 22, 2107] in THF (75 mL) and the mixture is then stirred at ambient temperature for 18 h. The mixture is then partitioned between EtOAc and saturated aqueous NaHCO3. The layers are separated and the aqueous layer further extracted with EtOAc. The combined organic extracts are washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue is purified by silica gel chromatography (gradient elution with hexanes-EtOAc) to afford the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]2[N:12]=[C:13]([CH2:16]O)[S:14][CH:15]=2)[CH:8]=[C:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[OH:22])([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:24].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>ClCCl>[Br:24][CH2:16][C:13]1[S:14][CH:15]=[C:11]([C:9]2[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:22])=[C:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=2)[N:12]=1
Reactant: CC(C)(C)c1cc(-c2csc(CO)n2)cc(C(C)(C)C)c1O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1cc(-c2csc(CBr)n2)cc(C(C)(C)C)c1O
Temperature: 0 °C
Yield: 92 %

Procedure:
1.5 g (4.70 mmol) of intermediate 334.2, (2,6-ditert-butyl-4-[2-(hydroxymethyl)-1,3-thiazol-4-yl]phenol is dissolved in dichloromethane (30 ml). After adding CBr4 (2.02 g; 6.10 mmol), the reaction medium is cooled down to 0° C. PPh3 (1.48 g; 5.63 mmol) is added by fractions then the mixture is left to return to ambient temperature. The reaction medium is then poured into ice-cooled water before being extracted with dichloromethane. The organic phase is washed with salt water before being dried over magnesium sulphate, filtered and concentrated under vacuum. The expected product is obtained after chromatography on a silica column (eluent: 30% of ethyl acetate in heptane), in order to produce a brown oil with a yield of 92%. This product is sufficiently pure to be used directly in the following stage.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[C:9]([C:12]([OH:14])=O)[C:8]3[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>C(OCC)(=O)C.CCCCCC>[CH:1]1[C:11]2[CH:10]=[C:9]([C:12]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:14])[C:8]3[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1=Cc2ccccc2Oc2ccccc21
Reactant: C1COCCN1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(C1=Cc2ccccc2Oc2ccccc21)N1CCOCC1
Yield: 62 %

Procedure:
Preparation analogous to Example 10a from dibenz[b,f]oxepine-10-carboxylic acid and morpholine; yield: 62%; yellow oil; 1H-NMR (CDCl3, 200 MHz): 3.30 (mbr, 4H); 3.62 (mbr, 4H); 6.90-7.28 (m, 9H); MS: 307 (M+), 221, 193, 165; TLC (silica gel; ethyl acetate/hexane=1:1; UV): Rf =0.17.
Reaction SMILES: [CH2:1]([NH:10][C:11](=[O:15])[CH2:12][CH2:13]Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH2:1]([NH:10][C:11](=[O:15])[CH2:12][CH2:13][N:25]1[CH2:26][CH2:27][N:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:23][CH2:24]1)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: O=C(CCBr)NCC(=O)c1ccccc1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CCN1CCN(c2ccccc2)CC1)NCC(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A solution of N-phenacyl-3-bromopropanamide (10.2 g; 0.038 mole) and N-phenylpiperazine (12.0 g; 0.074 mole) in dry DMF (100 ml) was stirred with anhydrous, finely-powdered sodium carbonate (15.0 g) for 18 hours at room temperature. The temperature was then increased to 80° C. and held for 12 hours to complete the reaction. The DMF was evaporated off under vacuum and the residue diluted with water (100 ml). The mixture was extracted with chloroform (3 × 100 ml). The extracts were shaken with 2 × 100 ml 2N HCl and the organic layer discarded. The aqueous layer was basified with NaOH solution to pH 9 and extracted with 3 × 75 ml CHCl3. The extracts were washed with water and dried. After removal of the solvent the remaining viscous gum triturated with ether to give a buff-coloured solid. After recrystallisation from isopropanol the product weighed 6.0 g and melted at 126° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[CH3:22][NH2:23]>>[CH:19]([N:12]1[C:13]2[N:14]=[CH:15][N:16]=[CH:17][C:18]=2[C:10]([C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([NH:23][CH3:22])[CH:3]=2)=[O:9])=[CH:11]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1cc(C(=O)c2cncc(Br)c2)c2cncnc21
Reactant: CN
Product: CNc1cncc(C(=O)c2cn(C(C)C)c3ncncc23)c1
Yield: 13 %

Procedure:
The title compound was prepared according to the method described for Preparation 31 using (5-bromopyridin-3-yl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Preparation 94) and methylamine (20 mL) in 13% yield, 78 mg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:19]([O-:21])=[O:20])[C:5]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])=[N:6][C:7]=1F.CCN(C(C)C)C(C)C.[CH3:31][C:32]1[NH:36][N:35]=[C:34]([NH2:37])[CH:33]=1>C1COCC1>[F:1][C:2]1[C:7]([NH:37][C:34]2[CH:33]=[C:32]([CH3:31])[NH:36][N:35]=2)=[N:6][C:5]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])=[C:4]([N+:19]([O-:21])=[O:20])[CH:3]=1
Reactant: C[C@H](Nc1nc(F)c(F)cc1[N+](=O)[O-])c1ccc(F)cc1
Reactant: Cc1cc(N)n[nH]1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)c([N+](=O)[O-])cc2F)n[nH]1
Temperature: 55 °C
Yield: 69.7 %

Procedure:
To a solution of (S)-5,6-difluoro-N-(1-(4-fluorophenyl)ethyl)-3-nitropyridin-2-amine (Method 53, 0.70 g, 2.3 mmol) in THF (12 ml) was added DIEA (0.39 g, 3.0 mmol) and 5-methyl-1H-pyrazol-3-amine (0.45 g, 4.7 mmol). The reaction was heated to 55° C. for 24 hours, cooled to room temperature, and quenched with water. The reaction was extracted with DCM (2×75 ml), and the combined organic fractions were dried over Na2SO4, filtered, and concentrated. The resulting oil was purified by column chromatography (DCM-MeOH=100:1) to give the title compound (0.60 g, 68%). MS: Calcd.: 374. Found: [M+H]+ 375.
Reaction SMILES: [C:1]1(C)[CH:6]=CC(S(O)(=O)=O)=C[CH:2]=1.[OH:12][C@:13]([CH3:21])([CH2:19][OH:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[CH3:2][C:1]1([CH3:6])[O:12][C@@:13]([CH3:21])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:19][O:20]1
Reactant: CCOC(=O)[C@](C)(O)CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)[C@@]1(C)COC(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 2049.4 %

Procedure:
500 mg of p-toluenesulfonic acid were added to 10.7 g of ethyl (R)-2,3-dihydroxy-2-methylpropionate, dissolved in 35 ml of dry, freshly distilled 2,2-dimethoxypropane, and the mixture was stirred at room temperature overnight. The excess dimethoxypropane was removed at 45°/12 mmHg and the residue was vigorously stirred for 30 minutes with 5 ml of 1-N sodium bicarbonate. Then, 150 ml of ether were added thereto and the aqueous phase was separated. The ether solution was washed with saturated brine and then dried over sodium sulfate. After evaporation of the solvent, the product was distilled and there were obtained 11.2 g of ethyl (R)-2,2,4-trimethyl-1,3-dioxolan-4-carboxylate in the form of a colorless liquid; boiling point 81°/15 mmHg.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([NH:21][CH3:22])[C@@H:17]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl[CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37].CCN(C(C)C)C(C)C>C(#N)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([N:21]([CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH3:22])[C@@H:17]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:8]=1
Reactant: CN[C@@H]1CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Reactant: COC(=O)CCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)CCCN(C)[C@@H]1CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 60 h

Procedure:
To a solution of 40 mg of 1-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-2-(S)-(4-fluorophenyl)-3-(R)-(methylamino)cyclopentane from Example 15 in 1 mL of acetonitrile was added 0.011 mL of methyl 4-chlorobutyrate and 0.046 mL of DIPEA. The reaction was heated at 50° C. for 24 hours, then an additional 0.022 mL of methyl 4-chlorobutyrate, 0.030 mL of DIPEA and 3 mg of tetrabutylammonium iodide were added and heating continued at 80° C. for 60 hours. The reaction was evaporated under a stream of nitrogen and the residue purified by prep TLC (5% methanol in methylene chloride) to give 27 mg of title compound. Mass spec (ESI): 550 (M+1).