Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CO[CH:9](OC)[CH2:10]Br.[Br:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[SH:22].[C:23]([O:26][CH2:27][CH3:28])(=[O:25])[CH3:24]>CN(C=O)C.O>[Br:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[S:22][CH2:24][CH:23]([O:25][CH2:9][CH3:10])[O:26][CH2:27][CH3:28]
Reactant: CCOC(C)=O
Reactant: COC(CBr)OC
Reactant: Sc1ccc(Cl)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(CSc1ccc(Cl)cc1Br)OCC
Temperature: 70 °C

Procedure:
Potassium carbonate (0.926 g, 9.34 mmol) then bromoacetaldehyde dimethyl acetal (1.35 g, 6.85 mmol) were added to a solution of 2-bromo-4-chlorobenzenethiol (1.397 g, 6.23 mmol) in anhydrous DMF (11 mL). The mixture was heated at 70° C. for 3 hours. After being allowed to cool to room temperature, the mixture was diluted with ethyl acetate and water. The resulting layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organics were washed with water then saturated NaCl (aq), dried over Na2SO4, filtered, then concentrated. The resulting light yellow oil was used directly for the following step. 1H NMR (500 MHz, CDCl3) δ 7.57 (d, J=2.0 Hz, 1H); 7.33 (d, J=8.5 Hz, 1H); 7.26 (dd, J=8.5, 2.0 Hz, 1H); 4.70 (t, J=5.5 Hz, 1H); 3.75-3.68 (m, 2H); 3.61-3.55 (m, 2H); 3.15 (d, J=5.5 Hz, 2H); 1.23 (t, 7.0 Hz, 6H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]1[CH2:12]C1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.CO>[CH2:1]([NH:8][CH:9]1[CH2:10][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CNCC2CC2)cc1
Solvent: CO
Solvent: ClCCl
Product: c1ccc(CNC2CC2)cc1

Procedure:
The title compound is prepared analogously as described for benzyl-cyclopropylmethylamine. TLC, Rf (CH2Cl2/MeOH 95:5)=0.1, MS (LC-MS): 148.2 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:11][CH:12]=1.[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:22]=1)=[O:19]>>[C:13]([C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:30]1[CH2:31][CH2:32][CH:27]([C:23]2[CH:22]=[C:21]([NH:20][C:18](=[O:19])[CH:17]([CH3:16])[CH3:33])[CH:26]=[CH:25][CH:24]=2)[CH2:28][CH2:29]1)(=[O:15])[CH3:14]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: CC(=O)c1cccc(OCCCCCl)c1
Product: CC(=O)c1cccc(OCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-[3-(4-chlorobutoxy)phenyl]ethanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 437.2 (M+H)+.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][C:25]=1[Cl:26])[N:22]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:21]=[C:20]2[NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39].C(OCC)(=O)C>O.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>[C:1]1([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][C:25]=2[Cl:26])[N:22]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:34])[CH3:32])[N:21]=[C:20]3[NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(Br)cc12
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(-c3ccccc3)cc12

Procedure:
821 mg of phenylboronic acid, 1.14 g of sodium carbonate in 30 cm3 of distilled water and finally 347 mg of tetrakis(triphenylphosphine)palladium are added to 2 g of N-[5-bromo-6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described in Example 58, in 180 cm3 of dioxane. The mixture is refluxed for 90 minutes and is then allowed to return to 20° C. to add 100 cm3 of ethyl acetate and 100 cm3 of distilled water. The organic phase is washed with 100 cm3 of saturated aqueous sodium chloride solution and then separated out after settling of the phases has taken place and dried over magnesium sulphate. After filtration, the filtrate is concentrated to dryness under reduced pressure (2 kPa; 50° C.) and the residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4.5 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 45° C.), 2 g of N-[5-phenyl-6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide are thus obtained in the form of a yellow oil.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@H:8]([OH:17])[CH2:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C.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>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@H:8]([OH:17])[CH2:9][CH2:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O[C@H](CCc1cccnc1)COc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O[C@H](CCc1cccnc1)COc1ccc(-c2ccc(Cl)cc2)cc1
Yield: 37.9 %

Procedure:
Prepared according to the method described in Example 65 from (2R)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (0.25 g), 4-chlorobenzeneboronic acid (0.180 g) and tetrakis(triphenylphosphine)palladium(0) (40 mg) in toluene (5 ml), aqueous sodium carbonate (2 M, 1 ml) and ethanol (1 ml) with heating at reflux for 4 hours. The residue obtained after work up was purified by column chromatography over silica eluting with ethyl acetate to give the title compound as a white solid (0.104 g).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCN(C(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(C(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)O)n2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-{3-[(4-methyl-1-piperazinyl)carbonyl]-1,2,4-oxadiazol-5-yl}hexanoate (Preparation 23) (312 mg, 0.70 mmol) in dichloromethane (4 ml) was treated with trifluoroacetic acid (1 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 17 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene to afford the title compound as a white foam (320 mg).
Reaction SMILES: [ClH:1].C[N:3](C)CCCN=C=NCC.O.O.O.OC1C2N=NNC=2C=CC=1.Cl.[N:27]1([CH2:32][C:33]([OH:35])=O)[CH2:31][CH2:30][CH2:29][CH2:28]1.Cl.[C:37]1([C:43]2([CH2:49][O:50][CH:51]([C:54]3[CH:59]=[C:58]([C:60]([F:63])([F:62])[F:61])[CH:57]=[C:56]([C:64]([F:67])([F:66])[F:65])[CH:55]=3)[CH2:52][OH:53])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C)C=O.C(N(CC)CC)C>[ClH:1].[C:37]1([C:43]2([CH2:49][O:50][CH:51]([C:54]3[CH:59]=[C:58]([C:60]([F:61])([F:62])[F:63])[CH:57]=[C:56]([C:64]([F:67])([F:65])[F:66])[CH:55]=3)[CH2:52][OH:53])[CH2:48][CH2:47][N:46]([NH:3][C:33](=[O:35])[CH2:32][N:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)[CH2:45][CH2:44]2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=C(O)CN1CCCC1
Reactant: CCN=C=NCCCN(C)C
Reactant: OCC(OCC1(c2ccccc2)CCNCC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1CCCC1)NN1CCC(COC(CO)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-[3-Dimethylaminopropyl]-3-ethylcarbodiimide hydrochloride (797 mg), hydroxybenzo-triazole trihydrate (475 mg) and triethylamine (0.890 ml) were added to a stirred solution of 2-pyrrolidinyl acetic acid hydrochloride (528 mg) in dry dimethylformamide at room temperature. After 30 minutes a solution of the compound of Example 14 (800 mg) in dry dimethylformamide was added, followed by triethylamine (0.590 ml). The resulting solution was stirred at room temperature for 4 hours. The reaction was quenched with water and extracted into diethyl ether then the organic solution was dried (MgSO4) and evaporated to give a yellow oil. The residue was purified by chromatography on grade 3 neutral alumina (1% methanol/dichloromethane) then treated with ethereal hydrogen chloride to afford the title compound, mp=106°-108° C.;
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([N+:24]([O-:26])=[O:25])=[C:18]([S:20](Cl)(=[O:22])=[O:21])[CH:19]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([N+:24]([O-:26])=[O:25])=[C:18]([S:20]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)(=[O:21])=[O:22])[CH:19]=1
Reactant: Nc1cccc2cccnc12
Reactant: COc1ccc([N+](=O)[O-])c(S(=O)(=O)Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc([N+](=O)[O-])c(S(=O)(=O)Nc2cccc3cccnc23)c1
Yield: 29.1 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoquinoline (950 mg, 6.59 mmol), 5-methoxy-2-nitro-benzenesulfonyl chloride (Intermediate 447) (2.15 g, 8.57 mmol), pyridine (4 ml), DMAP (cat.) and DCM (8 ml) gave the title compound (690 mg, 30%) after purification by column chromatography with n-hexane/EtOAc (80:20) as the eluent.
Reaction SMILES: [OH:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][S:13][C:14]3[N:23]([CH3:24])[C:22](=[O:25])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[CH3:26])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:31]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][S:13][C:14]3[N:23]([CH3:24])[C:22](=[O:25])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[CH3:26])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:29][CH:30]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(O)cc4)cc3)n(C)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCc5ccccc5)cc4)cc3)n(C)c(=O)c12

Procedure:
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (395 mg), benzyl bromide (0.13 ml) and potassium carbonate (408 mg) in DMF (5 ml) was stirred at 60° C. for 1 hour. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The residue was recrystallized from ethyl acetate to provide the title compound as colorless solid (346 mg).
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[CH:12]=[C:11]([NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[N:21][C:20]=23)=[O:15])[C:10]([C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=2[O:32][CH:33]([F:35])[F:34])=[N:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:31][C:29]1[CH:28]=[CH:27][C:26]([O:32][CH:33]([F:35])[F:34])=[C:25]([C:10]2[C:11]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:12][N:8]([CH2:7][C:6]([OH:36])=[O:5])[N:9]=2)[CH:30]=1
Reactant: CC(C)(C)OC(=O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.7 %

Procedure:
To a solution of {3-(5-chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid tert-butyl ester (45.0 g, 86.7 mmol) in dichloromethane (350 mL) was added TFA (100 mL) and the mixture left to stir at room temperature for 18 hours. The solvent was evaporated and the resultant residue triturated with diethyl ether. The resultant solid was collected by filtration, washed with diethyl ether and left to air dry to afford the title compound as a white solid (40.0 g, 99%). LCMS (Method 3) [M+H]+=463.1, RT=2.89 min. 1H NMR (400 MHz, CDCl3) δ: (ppm) 9.86 (s, 1H), 8.78 (dd, 1H), 8.71 (s, 1H), 8.56 (dd, 1H), 8.40 (s, 1H), 7.70 (d, 1H), 7.42 (dd, 1H), 7.30 (s, 1H), 6.99 (dd, 1H), 6.47 (t, 1H), 4.86 (s, 2H), 1.49 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:15]([O-])=O)=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([OH:13])[C:6]([OH:14])=[N:5]2>CN(C)C=O.C(N(CC)CC)C.[Pd]>[NH2:15][C:3]1[C:2]([NH2:1])=[C:11]([Cl:12])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([OH:14])[C:7]([OH:13])=[N:8]2
Reactant: Nc1c(Cl)cc2nc(O)c(O)nc2c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1c(Cl)cc2nc(O)c(O)nc2c1N
Yield: 72.3 %

Procedure:
A solution of 3 g (11,9 mmol) 6-amino-7-chloro-5-nitro-2,3-dihydroxyquinoxaline in a mixture of 80 ml dimethylformamide and 7,5 ml triethylamine was hydrogenated at atm. pressure using 5% Pd-C (0,5 g) as a catalyst. The reaction mixture was filtered and evaporated in vacuo. The residue was stirred with 100 ml water, added 4N hydrochloric acid to pH 5-6, and the precipitate was filtered off to give 2,1 g of a crude product. Recrystallization (dimethylformamide-methanol) gave 1,95 g (74%) 5,6-diamino-7-chloro-2,3-dihydroxy-quinoxaline, m.p.>300° C. NMR (DMSO-d6): 11.6 (1H, broad s), 11.0 (1H, broad m), 6.47 (1H,s), 5.1 (2H, broad s), 4.6 (2H, broad s).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[OH:13])#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:21]1[CH2:24][CH2:23][CH2:22]1>CN(C=O)C>[C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH:21]1[CH2:24][CH2:23][CH2:22]1)#[N:2]
Reactant: COC(=O)c1ccc(C#N)c(O)c1
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C#N)c(OC2CCC2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 62.6 %

Procedure:
To a solution of methyl 4-cyano-3-hydroxybenzoate (0.067 g, 0.38 mmol) in 2 ml of DMF was added cesium carbonate (0.2 g, 0.62 mmol), bromocyclobutane (0.051 g, 0.38 mmol), and the reaction mixture was heated at 60° C. and stirred at this temperature for 3 hrs. The reaction mixture was cooled to RT, poured into ice water, and extracted several times with ethyl acetate (3×20 ml). The organic solution was dried over Na2SO4, filtered, rotary evaporated to dryness then dried in vacuo to provide methyl 4-cyano-3-(cyclobutyloxy)benzoate (0.055 g, 63%). 1H NMR (400 MHz, CD3OD): 7.74 (d, 1H), 7.67 (d, 1H), 7.54 (s, 1H), 3.93 (s, 3H), 2.57-2.52 (m, 2H), 2.26-2.21 (m, 2H), 1.94-1.90 (m, 1H), 1.94-1.78 (m, 2H). MS (EI) for C13H13NO3: 232 (MH+).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]([F:34])([F:33])[F:32])[CH2:4][NH:5][C:6](=[O:24])[CH2:7][N:8]1[C:12](=[O:13])[N:11]([CH2:14][CH2:15][O:16][CH3:17])[C:10]([C:18]2[S:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[N:9]1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>>[Cl:23][C:20]1[S:19][C:18]([C:10]2[N:11]([CH2:14][CH2:15][O:16][CH3:17])[C:12](=[O:13])[N:8]([CH2:7][C:6]([NH:5][CH2:4][CH:3]([NH:2][S:36]([CH3:35])(=[O:38])=[O:37])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:32])([F:33])[F:34])=[O:24])[N:9]=2)=[CH:22][CH:21]=1
Reactant: CS(=O)(=O)Cl
Reactant: COCCn1c(-c2ccc(Cl)s2)nn(CC(=O)NCC(N)c2ccccc2C(F)(F)F)c1=O
Agent: Cl
Product: COCCn1c(-c2ccc(Cl)s2)nn(CC(=O)NCC(NS(C)(=O)=O)c2ccccc2C(F)(F)F)c1=O

Procedure:
Analogously to the procedure of Example 68, 29 mg (46 μmol) of the compound of Example 60A were reacted with methanesulphonyl chloride. This gave 25 mg (92% of theory) of the title compound.
Reaction SMILES: C(OC(=O)[N:7]([C:39]1[CH:40]=[N:41][C:42](Cl)=[CH:43][CH:44]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:16]2[C:24]3[C:23]([CH:25]4[CH2:27][CH2:26]4)=[N:22][CH:21]=[N:20][C:19]=3[N:18]([Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])[CH:17]=2)[OH:15])=[C:10]([F:38])[N:9]=1)(C)(C)C.[CH:47]1([Mg]Br)[CH2:49][CH2:48]1.O>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:47]1([C:42]2[N:41]=[CH:40][C:39]([NH:7][C:8]3[N:9]=[C:10]([F:38])[C:11]([CH:14]([C:16]4[C:24]5[C:23]([CH:25]6[CH2:26][CH2:27]6)=[N:22][CH:21]=[N:20][C:19]=5[N:18]([Si:28]([CH:32]([CH3:33])[CH3:34])([CH:35]([CH3:36])[CH3:37])[CH:29]([CH3:31])[CH3:30])[CH:17]=4)[OH:15])=[CH:12][CH:13]=3)=[CH:44][CH:43]=2)[CH2:49][CH2:48]1
Reactant: Br[Mg]C1CC1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2ccc(N(C(=O)OC(C)(C)C)c3ccc(Cl)nc3)nc2F)c2c(C3CC3)ncnc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2ccc(Nc3ccc(C4CC4)nc3)nc2F)c2c(C3CC3)ncnc21
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 90.7 %

Procedure:
To (6-chloro-pyridin-3-yl)-{5-[(4-cyclopropyl-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-hydroxy-methyl]-6-fluoro-pyridin-2-yl}-carbamic acid tert-butyl ester (81, 0.51 g, 0.77 mmol) in 12 mL of toluene, [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (0.13 g, 0.17 mmol) is added under nitrogen and the reaction stirred for 5 minutes. Cyclopropylmagnesium bromide (17, 15.29 mL, 0.50 M in tetrahydrofuran, 7.65 mmol) is added slowly and the reaction is heated at 65° C. for 2 hours. The reaction is poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (82, 400 mg).
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@@H:20]([C:27](=[O:38])[N:28]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[CH2:29][CH3:30])[CH2:19][C@@H:18]2[CH3:39])=[O:16])=[CH:11][CH:10]=1)C.[OH-].[Li+].C(O)C>O1CCCC1.O>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([N:28]([CH2:29][CH3:30])[C:27]([C@@H:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:17]([C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:40])=[O:3])=[CH:14][CH:13]=3)=[O:16])[C@@H:18]([CH3:39])[CH2:19]2)=[O:38])=[CH:32][CH:33]=1.[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([N:28]([CH2:29][CH3:30])[C:27]([C@H:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:17]([C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:40])=[O:3])=[CH:14][CH:13]=3)=[O:16])[C@@H:18]([CH3:39])[CH2:19]2)=[O:38])=[CH:32][CH:33]=1
Reactant: CCOC(=O)CCCOc1ccc(C(=O)N2c3ccccc3[C@@H](C(=O)N(CC)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCN(C(=O)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCC(=O)O)cc2)c2ccccc21)c1ccc(Cl)cc1
Product: CCN(C(=O)[C@H]1C[C@H](C)N(C(=O)c2ccc(OCCCC(=O)O)cc2)c2ccccc21)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(±)-trans-4-(4-{4-[(4-Chloro-phenyl)-ethyl-carbamoyl]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-butyric acid ethyl ester (520 mg, 0.923 mmol) was dissolved in tetrahydrofuran (15 mL). A solution of lithium hydroxide (77 mg, 1.8 mmol) in water (5 mL) was added. Ethanol was added until the reaction was homogeneous. The resulting solution was allowed to stir at room temperature overnight. The solution was concentrated to remove ethanol and tetrahydrofuran. The resulting aqueous mixture was acidified with concentrated hydrochloric acid until pH=1-2. The heterogeneous mixture was immediately extracted with ethyl acetate (2×75 mL). The extracts were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was a mixture of cis and trans isomers. A portion of the crude residue was purified by HPLC to afford pure (±)-trans-4-(4-{4-[(4-chloro-phenyl)-ethyl-carbamoyl]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-butyric acid and pure (±)-cis-4-(4-{4-[(4-chloro-phenyl)-ethyl-carbamoyl]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-butyric acid. The remainder of the mixture was used without further purification in subsequent reactions. Data for the trans isomer: 1H-NMR (CD3OD) δ: 0.97 (d, 3H), 1.12 (t, 3H), 4.73 (ddd, 1H), 2.00-2.13 (m, 2H), 2.47-2.58 (m, 3H), 3.61-3.99 (m, 5H), 5.02-5.12 (m, 1H), 6.44 (d, 1H), 6.68-6.74 (m, 2H), 6.75-6.83 (m, 2H), 6.85-6.92 (m, 1H), 7.17-7.25 (m, 3H), 7.42-7.51 (m, 4H). MS m/z: 535 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[CH:12]4[CH2:18][CH2:17][NH:16][CH2:15][CH2:14][CH:13]4[N:5]([C:6]=23)[CH2:4][CH2:3]1.Cl[CH2:20][CH2:21][CH2:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)=[O:24].CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[CH:12]4[CH2:18][CH2:17][N:16]([CH2:20][CH2:21][CH2:22][C:23]([C:25]5[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=5)=[O:24])[CH2:15][CH2:14][CH:13]4[N:5]([C:6]=23)[CH2:4][CH2:3]1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: CN1CCN2c3c(cccc31)C1CCNCCC12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN2c3c(cccc31)C1CCN(CCCC(=O)c3ccc(F)cc3)CCC12
Temperature: 96 °C
Reaction time: 18 h
Yield: 30.7 %

Procedure:
3-Methyl-2,3,7,8,9,10,11,11a-octahydro-1H,6bH-azepino[4′,5′:4,5]pyrrolo[1,2,3-de]quinoxaline (72 mg, 0.3 mmol), 4-chloro-4′-flourobutyrophenone (119 mg, 0.6 mmol), KI (49 mg, 0.3 mmol), and DIEA (383 mg, 3 mmol) were added to dioxane (2.5 mL). The suspension was stirred at 96° C. for 18 hrs. The reaction was cooled to rt and then concentrated. The residue was purified by column chromatography (5–10% MeOH/CH2Cl2), to afford the title compound (37.5 mg, 31%) as an oil. The enantiomers of the title compound were separated on a Chiracel OD column using 8% EtOH-Hexane as the eluent. 1H NMR (CDCl3, 300 MHz) δ 7.9–8.1 (2H, m), 7.1–7.2 (2H, m), 6.6–6.7 (1H, m), 6.3–6.5 (2H, m), 2.7–3.8 (19 H, m), 1.9–2.3 (4H, m) ppm. MS (ESI): 408.3 (base, M+H)
Reaction SMILES: [N+]([O-])([O-])=O.[N:5]([O-])=O.[CH:8]1[C:13](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)=[C:12](O)[CH:11]=[C:10]2OC([CH:30]=[CH:31][C:9]=12)=O>>[NH:5]1[C:10]2[C:9](=[CH:8][CH:13]=[CH:12][CH:11]=2)[CH:31]=[CH:30]1
Reactant: O=c1ccc2cc(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(O)cc2o1
Reactant: O=N[O-]
Agent: O=[N+]([O-])[O-]
Product: c1ccc2[nH]ccc2c1

Procedure:
As assayed with the API-NFT test (bioMerieux S.A., Marcy-l′Etiole, France), strain 2.2N can grow at about 41° C., reduce nitrate to nitrite, hydrolyze esculin and gelatin, and form indole. Strain 2.2N cannot produce yellow pigments, urease, arginine dihydrolase and cytochrome oxidase.