Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]3([C:32]#[N:33])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][S:20][C:19]4[CH:28]=[CH:29][CH:30]=[CH:31][C:18]3=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.ClCCl.[H-].C([Al+]CC(C)C)C(C)C.O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]3([CH:32]=[NH:33])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][S:20][C:19]4[CH:28]=[CH:29][CH:30]=[CH:31][C:18]3=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#CC1(CCCN2CCC(O)(c3ccc(Cl)cc3)CC2)c2ccccc2CSc2ccccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: O
Product: N=CC1(CCCN2CCC(O)(c3ccc(Cl)cc3)CC2)c2ccccc2CSc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
To a solution of 4-(4-chlorophenyl)-1-[3-(11-cyano-6,11-dihydrodibenzo[b,e]thiepin-11-yl)propyl]piperidin-4-ol (1.92 g) in dichloromethane (30 ml) at −78° C. was added 1M diisobutyl aluminum hydride dichloromethane solution (10 ml). The reaction mixture was warmed to room temperature, and stirred for 30 minutes. Water and dichloromethane were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate to give the titled compound (1.16 g).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:26][C:27]1([F:38])[O:31][C:30]2[CH:32]=[CH:33][C:34]([NH:36][NH2:37])=[CH:35][C:29]=2[O:28]1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[F:38][C:27]1([F:26])[O:31][C:30]2[CH:32]=[CH:33][C:34]([N:36]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:16][CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:37]3)=[CH:35][C:29]=2[O:28]1
Reactant: NNc1ccc2c(c1)OC(F)(F)O2
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Agent: [Na+]
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1ccc2c(c1)OC(F)(F)O2

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and 2,2-difluoro-benzo[1,3]dioxol-5-yl-hydrazine (prepared from the corresponding amino derivative using sodium nitrite and tin(II) chloride as described in J. Med. Chem. 2003, 46, 4676-4686) according to the method described for example 91. MS: M=479.0 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]1([F:16])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[CH3:21][N:22]([CH3:27])[CH2:23][C:24](Cl)=[O:25].Cl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]1([F:16])[CH2:15][CH2:14][N:13]([C:24](=[O:25])[CH2:23][N:22]([CH3:27])[CH3:21])[CH2:12][CH2:11]1
Reactant: NS(=O)(=O)c1cnc(OCC2(F)CCNCC2)c(Cl)c1
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CCC(F)(COc2ncc(S(N)(=O)=O)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-chloro-6-((4-fluoropiperidin-4-yl)methoxy)pyridine-3-sulfonamide, 2•trifluoroacetic acid (0.131 g), 2-(dimethylamino)acetyl chloride, hydrochloric acid (0.139 g), and sodium carbonate (0.048 g) were combined in a 5-mL vial with N,N-dimethylformamide (3 mL) and stirred overnight at room temperature. Additional sodium carbonate (0.048 g) was added followed by 2-(dimethylamino)acetyl chloride, hydrochloric acid (0.139 g) and stirring was continued over a second night. The reaction mixture was concentrated under high vacuum, slurried in CH2Cl2, filtered, concentrated, chromatographed on amine functionalized silica gel with 0 to 4% methanol in CH2Cl2 as the eluent and dried in a vacuum oven at 80° C.
Reaction SMILES: CC1C=CC(S(O[CH:12]([CH2:29][CH3:30])[C@@H:13]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[CH:15]1([CH2:14][C@H:13]([NH:21][C:22](=[O:23])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:12]([NH:32][CH3:31])[CH2:29][CH3:30])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCC(OS(=O)(=O)c1ccc(C)cc1)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reactant: CN
Product: CCC(NC)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C

Procedure:
A solution of (S)-2-(tert-butoxycarbonylamino)-1-cyclohexylpentan-3-yl 4-methylbenzenesulfonate (640 mg, 1.46 mmol) in 33% MeNH2 (in EtOH) (0.02 M) was heated to 60° C. for 1 h in a pressure sealed vessel. The solvent was removed under reduced pressure to give (S)-tert-butyl 1-cyclohexyl-3-(methylamino)pentan-2-ylcarbamate. MS ESI +ve m/z 299 (M+H).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]([CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([OH:10])=[O:9].C1(C)C=CC=CC=1>CO>[CH3:1][O:9][C:8]([CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCCC1CC(=O)O
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)CC1CCCN1C(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
Trimethylsilyldiazomethane (2 M solution in hexane, 1.5 ml) was added dropwise to a mixed solution of tert-butyl 2-carboxymethylpyrrolidine-1-carboxylate (CAS No. 194154-91-1, 500 mg) in methanol (1 ml)-toluene (1 ml) under ice-cooling, and the reaction solution was stirred at the same temperature for three hours. The reaction solution was concentrated. The resulting residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 506 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9].[CH3:32][N:33]1[CH2:37][CH2:36][CH:35]([CH2:38][NH2:39])[CH2:34]1>>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:39][CH2:38][CH:35]4[CH2:36][CH2:37][N:33]([CH3:32])[CH2:34]4)=[O:28])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CN1CCC(CN)C1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCC3CCN(C)C3)cn2)c1O

Procedure:
The title compound, as a TFA salt, was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (1-methylpyrrolidin-3-yl)methanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.61-1.97 (m, 1H) 1.98-2.29 (m, 1H) 2.40-2.47 (m, 3H) 2.54-2.65 (m, 1H) 2.73-2.91 (m, 4H) 2.97-3.25 (m, 1H) 3.40 (dt, J=18.51, 6.28 Hz, 2H) 3.50-3.78 (m, 2H) 7.67 (d, J=7.33 Hz, 1H) 7.70-7.89 (m, 2H) 8.12-8.32 (m, 1H) 8.33-8.74 (m, 2H) 8.77-8.98 (m, 2H) 9.66-9.94 (m, 1H) 12.62-13.68 (m, 1H). MS m/z [M+H]+ 417.2.
Reaction SMILES: C(N)C1C=CC=CC=1.[CH2:9]1[CH2:11][CH:10]1[CH2:12][NH2:13].[CH3:14][C:15]1[N:16]=[C:17]([N:23]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=3)[C:24]2=[O:40])[S:18][C:19]=1[C:20](O)=[O:21]>>[CH:10]1([CH2:12][NH:13][C:20]([C:19]2[S:18][C:17]([N:23]3[CH2:27][CH2:26][N:25]([CH2:28][C:29]4[CH:30]=[CH:31][C:32]([O:35][C:36]([F:37])([F:38])[F:39])=[CH:33][CH:34]=4)[C:24]3=[O:40])=[N:16][C:15]=2[CH3:14])=[O:21])[CH2:11][CH2:9]1
Reactant: NCC1CC1
Reactant: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)O
Solvent: NCc1ccccc1
Product: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)NCC1CC1
Yield: 15 %

Procedure:
Following the procedure as describe in Example 8, making variations as required to replace benzylamine with 2-cyclopropylmethylamine to react with 4-methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid, the title compound was obtained as a white powder in 15% yield: mp 184-186° C.: 1H NMR (300 MHz, CDCl3) δ 7.32 (d, J=8.4 Hz, 2H), 7.18 (d, J=8.4 Hz, 2H), 5.70 (s, 1H), 4.48 (s, 2H), 4.08 (t, J=8.4 Hz, 2H), 3.46 (t, J=8.4 Hz, 2H), 3.24-3.20 (m, 2H), 2.58 (s, 3H), 1.03-0.92 (m, 1H), 0.55-0.44 (m, 2H), 0.29-0.27 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.3, 156.9, 155.5, 152.7, 148.9, 134.4, 129.7, 121.4, 120.4, 117.6, 47.3, 44.8, 42.0, 41.8, 17.1, 10.6, 3.5: MS (ES+) m/z 455.3 (M+1).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=1)[CH:2]([CH3:4])[CH3:3].Br[CH2:19][C:20]([O:22]C(C)(C)C)=[O:21]>>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:19][C:20]([OH:22])=[O:21])=[CH:7][C:8]=1[C:14]([F:15])([F:16])[F:17])#[N:11]
Reactant: CC(C)CNc1ccc(C#N)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)CN(CC(=O)O)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 70B using 4-(isobutylamino)-2-(trifluoromethyl)benzonitrile and 1,1-dimethylethyl bromoacetate: 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J=9.0 Hz, 1H), 6.90 (d, J=2.6 Hz, 1H), 6.72 (dd, J=9.0, 2.7 Hz, 1H), 4.19 (s, 2H), 3.26 (d, J=7.5 Hz, 2H), 2.04 (m, 1H), 0.97 (d, J=6.6 Hz,
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[CH:5][C:4]=1[O:13][CH3:14])#[N:2].[BH4-].[Li+].CCOC(C)=O>C1COCC1.Cl>[C:1]([C:3]1[CH:12]=[CH:11][C:6]([CH2:7][OH:8])=[CH:5][C:4]=1[O:13][CH3:14])#[N:2]
Reactant: COC(=O)c1ccc(C#N)c(OC)c1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1C#N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.2 %

Procedure:
To a solution of the ester from Step D (48.8 g, 255 mmol) in 400 mL of dry THF under argon at room temperature was added lithium borohydride (255 mL, 510 mmol, 2M THF) over 5 minutes. After 1.5 hours, the reaction was warmed to reflux for 0.5 hours, then cooled to room temperature. The solution was poured into EtOAc/IN HCl soln. [CAUTION], and the layers were separated. The organic layer was washed with water, sat Na2CO3 soln. and brine (4x), dried (Na2SO4), and concentrated in vacuo to provide the titled product (36.3 g, 87% yield).
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([CH2:24][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([S:34][CH3:35])=[CH:30][CH:29]=4)[CH:26]=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].[C:36]1([Mg]Cl)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl.[Cl-].[NH4+].C(OCC)(=O)C>[CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([CH2:24][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([S:34][CH3:35])=[CH:30][CH:29]=4)[CH:26]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[OH:27])[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:3])=[O:4]
Reactant: CSc1ccc(C(C=O)Cc2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)cc1
Reactant: Cl[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CSc1ccc(C(Cc2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)C(O)c2ccccc2)cc1
Temperature: 21 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methylsulfanyl-phenyl)-propionaldehyde from Step 2 (150 mg, 0.3 mmol) in CH2Cl2 (6 mL) at 21° C. was added phenylmagnesium chloride (2M, TBF, 0.45 mL, 0.9 mmol) dropwise. The resulting reaction mixture was stirred 0.5 h at 21° C. then diluted with a saturated ammonium chloride solution and ethyl acetate. The organic extracts were washed (H2O), (brine), dried (MgSO4), filtered and concentrated. The crude oil was used as such in the next step.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([O:21][CH:22]([CH3:24])[CH3:23])=[N:14][C:13]([NH:25][C:26]1[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=1)=[CH:12]2)C1C=CC=CC=1.[H][H]>[Pd].CO>[CH:22]([O:21][C:15]1[C:16]2[C:11](=[CH:10][C:9]([OH:8])=[C:18]([O:19][CH3:20])[CH:17]=2)[CH:12]=[C:13]([NH:25][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)[N:14]=1)([CH3:24])[CH3:23]
Reactant: COc1cc2c(OC(C)C)nc(Nc3cc(C)[nH]n3)cc2cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(OC(C)C)nc(Nc3cc(C)[nH]n3)cc2cc1O
Yield: 106.2 %

Procedure:
A mixture of (6-benzyloxy-1-isopropoxy-7-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (300 mg), 10% Pd/C (50 mg) and MeOH (80 ml) was shaken in Parr apparatus for 5 hs under 30-40 psi of hydrogen at room temperature. Then the mixture was passed through a celite pad and the filtrate was concentrated and dried to give 1-Isopropoxy-7-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol (250 mg). LC-MS: m/e 329 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Cl.Cl[CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cnn(CCN2CCCC2)c1
Temperature: 80 °C

Procedure:
A mixture of 4-nitro-1H-pyrazole (5.00 g, 44.22 mmol), 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (8.86 g, 52.42 mmol), acetonitrile (50 mL) and potassium carbonate (19.00 g, 137.50 mmol) was heated at 80° C. under an argon atmosphere for 16 hours. The reaction mixture was evaporated in vacuo and partitioned between water and dichloromethane. The aqueous phase was extracted twice with dichloromethane and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. 4-Nitro-1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazole was isolated as an orange solid (8.50 g, 91%). MP=39-41° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.29 (s, 1H), 8.06 (s, 1H), 4.27 (t, J=6.22 Hz, 2H), 2.95 (t, J=6.17 Hz, 2H), 2.55 (s, 4H), 1.80 (s, 4H). MS=211 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([C:13]2[CH:14]=[N:15][C:16](F)=[CH:17][CH:18]=2)=[CH:10]OC)[C:5]([NH2:8])=[N:6][CH:7]=1.Cl(O)(=O)(=O)=[O:21]>O1CCOCC1.O.[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([C:13]3[CH:18]=[CH:17][C:16]([OH:21])=[N:15][CH:14]=3)=[CH:10][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: [O-][Cl+3]([O-])([O-])O
Reactant: COC=C(c1ccc(F)nc1)c1cc(Br)cnc1N
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Oc1ccc(-c2c[nH]c3ncc(Br)cc23)cn1
Yield: 77 %

Procedure:
To a solution of 5-bromo-3-[1-(6-fluoro-pyridin-3-yl)-2-methoxy-vinyl]-pyridin-2-ylamine (220 mg, 0.678 mmol) in 1,4-dioxane (3 ml) in a Smith process vial was added 0.3 ml of 70% aqueous perchloric acid. The reaction was irradiated in a Personal Chemistry® microwave to 150° C. for 300 s. The reaction mixture was diluted with water and neutralized to pH 7 by addition of an aqueous solution of sodium hydroxide. The resulting precipitate was filtered, washed with water, and dried in vacuo to yield the title compound as a beige solid (152 mg, 77% yield). 1H NMR (DMSO-d6): δ 12.1 (broad s, 1H), 11.7 (broad s, 1H), 8.32 (d, J=2.5 Hz, 1H), 8.30 (d, J=2.5 Hz, 1H), 7.83 (dd, J=2.5, 11.5 Hz, 1H), 7.82 (s, 2H), 7.67 (s, 1H), 6.43 (d, J=11.5 Hz, 1H); MS: m/z 290 [MH]+.
Reaction SMILES: [C:1]([Si:5]([CH3:21])([CH3:20])[O:6][C@H:7]1[CH2:15][CH2:14][CH2:13][C@@:12]2([CH3:16])[C@H:8]1[CH2:9][CH2:10][C@@H:11]2[C@@H:17](O)[CH3:18])([CH3:4])([CH3:3])[CH3:2].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]([Si:5]([CH3:21])([CH3:20])[O:6][C@H:7]1[CH2:15][CH2:14][CH2:13][C@@:12]2([CH3:16])[C@H:8]1[CH2:9][CH2:10]/[C:11]/2=[CH:17]\[CH3:18])([CH3:3])([CH3:4])[CH3:2].[C:1]([Si:5]([CH3:21])([CH3:20])[O:6][C@H:7]1[CH2:15][CH2:14][CH2:13][C@@:12]2([CH3:16])[C@H:8]1[CH2:9][CH2:10]/[C:11]/2=[CH:17]\[CH3:18])([CH3:3])([CH3:4])[CH3:2]
Reactant: C[C@H](O)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: C/C=C1\CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Temperature: 0 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
1.43 g (4.58 mmol) of (S)-1-[(1S,3aR,4S,7aR)-4-(tert-Butyldimethyl-silanyloxy)7a-methyl-octahydro-inden-1-yl]ethanol was dissolved in 15 ml pyridine and cooled to 0° C. 420 μl of POCl3 were added slowly. The reaction mixture was stirred at room temperature overnight then poured into a buffer at pH 4, extracted with n-hexane. The organic solution was washed with brine, dried over sodium sulfate and evaporated to dryness. The residue was purified by column chromatography (eluent: n-hexane) to yield 516 mg (39%) of (E)-(3aR,4S,7aS)-4-(tert-Butyl-dimethyl-silanyloxy)-1-ethylidene-7a-methyl-octahydro-indene (E)-(3aR,4S,7aS)-4-(tert-Butyldimethyl-silanyloxy)-1-ethylidene-7a-methyl-octahydro-indene as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4]([O:8][CH3:9])[C:5](O)=[O:6].[F:11][C:12]([F:19])([C:15]([F:18])([F:17])[F:16])[CH2:13][NH2:14]>>[CH3:1][O:2][C:3](=[O:10])[CH:4]([O:8][CH3:9])[C:5]([NH:14][CH2:13][C:12]([F:19])([F:11])[C:15]([F:18])([F:17])[F:16])=[O:6]
Reactant: NCC(F)(F)C(F)(F)F
Reactant: COC(=O)C(OC)C(=O)O
Product: COC(=O)C(OC)C(=O)NCC(F)(F)C(F)(F)F

Procedure:
2-Methoxy-malonic acid monomethyl ester was coupled with 2,2,3,3,3-pentafluoro-propylamine in analogy to the description in Example 73 to yield 2-methoxy-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid methyl ester as colourless oil,
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:34]3[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=3)=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN2CCOC2=O)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(-c3cnn(C)c3)cc2CN2CCOC2=O)c1

Procedure:
Prepared according to the procedure described in Example 84, Step 1, using the following starting materials: {3-[4-bromo-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and 1-methylpyrazole-4-boronic acid pinacol ester.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[C:15]3[C:10]([C:11](=[O:23])[C:12]([C:20]([OH:22])=[O:21])=[C:13]4[S:18][CH:17]([CH3:19])[N:14]43)=[CH:9][C:8]=2[F:24])[CH2:3]1.II.[Cl:27]S(O)(=O)=O>>[NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]([Cl:27])=[C:15]3[C:10]([C:11](=[O:23])[C:12]([C:20]([OH:22])=[O:21])=[C:13]4[S:18][CH:17]([CH3:19])[N:14]43)=[CH:9][C:8]=2[F:24])[CH2:3]1
Reactant: O=S(=O)(O)Cl
Reactant: CC1Sc2c(C(=O)O)c(=O)c3cc(F)c(N4CCC(N)C4)cc3n21
Agent: II
Product: CC1Sc2c(C(=O)O)c(=O)c3cc(F)c(N4CCC(N)C4)c(Cl)c3n21

Procedure:
To a solution of 1.80 g of 7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-methyl-4-oxo-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid in 10 ml of chlorosulfonic acid, a trace of iodine was added, and the mixture was bubbled with chlorine gas for 3.5 hours under ice-cooling with stirring. The reaction mixture was poured into ice-water and neutralized to pH 8 with 10% aqueous sodium hydroxide. The precipitate obtained was collected by filtration and converted to the methanesulfonate. The salt was dissolved into water and filtered. The filtrate was neutralized to pH 8 with 10% aqueous sodium hydroxide. The precipitate was collected by filtration to give 1.50 g of pale yellowish-brown crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.C([Li])(C)(C)C.[P:14](Cl)([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15]>O1CCCC1.CCCCC>[CH3:8][C:4]1[CH:3]=[C:2]([P:14]([O:19][CH2:20][CH3:21])(=[O:15])[O:16][CH2:17][CH3:18])[CH:7]=[CH:6][CH:5]=1
Reactant: CCOP(=O)(Cl)OCC
Reactant: Cc1cccc(Br)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCOP(=O)(OCC)c1cccc(C)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromotoluene (5 g) in tetrahydrofuran at −78° C. was added tert-butyllithium (35 ml of a 1.7 M solution in pentane). The mixture was stirred at −78° C. for 1 hour and diethl chlorophosphate (5.1 ml) was added. After 2 hours the mixture was warmed to 0° C., quenched with aqueous ammonium chloride and partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. Purified by chromatography eluting with 40% ethyl acetate in isohexane. Yield 2.7 g.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=O)=[N:6][C:7]=1[C:8]([NH:10][CH3:11])=[O:9].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:55][CH2:56][C:57]1[CH:62]=[CH:61][C:60]([NH2:63])=[CH:59][CH:58]=1>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[N:6][C:5]([C:12]2[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([NH:55][CH2:56][C:57]3[CH:62]=[CH:61][C:60]([NH2:63])=[CH:59][CH:58]=3)=[O:17])[CH:13]=2)=[CH:4][N:3]=1
Reactant: CNC(=O)c1nc(-c2cccc(C(=O)O)c2)cnc1N
Reactant: NCc1ccc(N)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CNC(=O)c1nc(-c2cccc(C(=O)NCc3ccc(N)cc3)c2)cnc1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 25.1 %

Procedure:
A solution of 3-{5-amino-6-[(methylamino)carbonyl]pyrazin-2-yl}benzoic acid (0.10 g, 0.37 mmol), HOBt (0.055 g, 0.41 mmol) and HBTU (0.15 g, 0.41 mmol) in DMF (1.2 mL) was stirred at r.t. for 10 min. A solution of [4-(aminomethyl)phenyl]amine (0.050 mL, 0.44 mmol) in DMF (1.0 mL) was added and the resulting solution was stirred for 12 h at r.t. The solution was concentrated in vacuo and the crude mixture was partitioned between EtOAc (100 mL) and brine (50 mL). The organic layer was washed with brine (2×50 mL) and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified via column chromatography (SiO2, 5% MeOH/CH2Cl2) and trituration of the product gave 0.035 g (39% yield) of product: 1H NMR (400 MHz, d6-DMSO): 8.95 (t, 1H), 8.91 (s, 1H), 8.84 (m, 1H), 8.50 (m, 1H), 8.37 (dt, 1H), 7.87 (dt, 1H), 7.56 (t, 1H), 7.01 (d, 2H), 6.52 (m, 2H), 4.97 (s, 2H), 4.35 (d, 2H), 2.85 (d, 3H); MS (EI) for C20H20N6O2: 377 (MH+).
Reaction SMILES: C([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][N:11]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH2:12]2)C1C=CC=CC=1.[ClH:23].CO>>[ClH:23].[F:22][C:19]1[CH:20]=[CH:21][C:16]([N:11]2[CH2:10][CH:9]3[NH:8][CH:13]([CH2:14][CH2:15]3)[CH2:12]2)=[CH:17][CH:18]=1
Reactant: Fc1ccc(N2CC3CCC(C2)N3Cc2ccccc2)cc1
Agent: Cl
Solvent: CO
Product: Fc1ccc(N2CC3CCC(C2)N3)cc1
Reaction time: 2 h
Yield: 100 %

Procedure:
8-Benzyl-3-(4-fluoro-phenyl)-3,8-diaza-bicyclo[3.2.1]octane (2.7 g, 9.11 mmol) was dissolved in 1N hydrochloric acid/methanol (150 mL) and under nitrogen 10% palladium on carbon (1.4 g) was added. The reaction was hydrogenated at 1 atmosphere for 2 hours. The reaction was filtered through Celite and concentrated to yield 3-(4-Fluoro-phenyl)-3,8-diaza-bicyclo[3.2.1]octane, hydrochoride salt (2.2 g, 100%) as a white solid which had the following properties: Mp. 129-131° C.; 1H NMR CDCl3 δ: 9.69 (brd s, 1H), 7.07-6.95 (m, 2H), 6.90-6.80 (m, 2H), 4.05 (brd s, 2H), 3.49 (d, J=10.4 Hz, 2H), 3.08 (d, J=11.2 Hz, 2H), 2.00-1.84 (m, 2H).