Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:59][CH:60]1[NH:64][C:63](=[O:65])[CH2:62][CH2:61]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[N:64]1[C:63](=[O:65])[CH2:62][CH2:61][CH:60]1[CH3:59]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: CC1CCC(=O)N1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC1CCC(=O)N1c1cc(C=O)ccc1F
Temperature: 100 °C

Procedure:
A 100 mL round bottom flask was charged with 3-bromo-4-fluorobenzaldehyde (1.0 g, 4.93 mmol), tris(dibenzylideneacetone)dipalladium(0) (450 mg, 0.493 mmol), Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) (428 mg, 0.739 mmol), and cesium carbonate (2.4 g, 7.39 mmol). The mixture was purged with nitrogen, and anhydrous dioxane (15 mL), and 5-methylpyrrolidinone (0.586 g, 5.91 mmol) were added. The reaction mixture was purged with nitrogen again, and heated at 100° C. for 20 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and brine. The organic phase was dried over MgSO4, filtered and concentrated. The residue was separated by flash chromatography (50% ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 222 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=[CH:4][N:3]=1.CN(CCN(C)C)C.C([Li])CCC.[NH4+].[Cl-].C1C[O:34][CH2:33]C1>CCCCCC.CCOC(C)=O.CN(C=O)C>[Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[C:6]([CH:33]=[O:34])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cccnc1Cl
Reactant: C1CCOC1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)Nc1c(C=O)ccnc1Cl
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (2-chloropyridin-3-yl)carbamate (7-2) (3.01 g, 13.2 mmol) and TMEDA (3.37 g, 29 mmol) in THF (50 mL) at −78° C. was added a 2.5 M solution of n-butyllithium in hexane (11.6 mL) dropwise over 10 minutes and the mixture was stirred for 1 hour. The mixture was warmed up to −10° C. and then cooled to −78° C. DMF (3.06 mL) was added to the mixture and then the mixture was warmed to ambient temperature over 3 hours. Saturated aq. NH4Cl and EtOAc were added to the mixture and the organic layer was washed with H2O and brine, dried over MgSO4, filtered, concentrated in vacuo, and purified by silica gel chromatography (0-80% EtOAc/hexane) to give tert-butyl (2-chloro-4-formylpyridin-3-yl)carbamate (7-3) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:12])[NH:6][C:7](=[O:11])[N:8]([CH3:10])[CH:9]=1)([O-:3])=[O:2].Br[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>O>[C:18]([O:17][C:15](=[O:16])[CH2:14][N:6]1[C:5](=[O:12])[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]([CH3:10])[C:7]1=[O:11])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cn1cc([N+](=O)[O-])c(=O)[nH]c1=O
Reactant: CC(C)(C)OC(=O)CBr
Solvent: O
Product: Cn1cc([N+](=O)[O-])c(=O)n(CC(=O)OC(C)(C)C)c1=O
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
Sodium hydride (0.51 g of a 60% dispersion in mineral oil, 13 mmol) was washed with pentane three times (4 mL each). The compound of Example 109 (2.00 g, 12 mmole) was added portionwise. After the addition was complete, the reaction mixture was stirred for 30 minutes under a nitrogen atmosphere. t-Butyl bromoacetate (1.73 g, 12 mmole) was added in one portion, and the solution was stirred for 3 hours. The reaction mixture was diluted with water (200 mL), and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water (3×50 mL), then brine, dried over magnesium sulfate. The solvent was concentrated, hexanes were added and the solvent was removed in vacuo to afford the title compound (1.97 g) in 59% yield. Rf=0.38 (silica gel, 20% ethyl acetate in dichloromethane.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[C:9]([CH2:10][C:11]([O:13]C)=[O:12])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:15][CH2:16][S:17]C(=O)C.[OH-].[K+]>CCO>[C:11]([CH2:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:15][CH2:16][SH:17])[C:4]=1[C:3]([OH:21])=[O:2])([OH:13])=[O:12]
Reactant: COC(=O)Cc1cccc(CCSC(C)=O)c1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1cccc(CCS)c1C(=O)O
Temperature: 25 °C
Yield: 72.9 %

Procedure:
A deoxygenated mixture of 2-(2-acetylsulfanyl-ethyl)-6-methoxycarbonylmethyl-benzoic acid methyl ester (0.555 g, 1.77 mmol) and 6 N KOH (3 mL) in EtOH (7 mL) was heated at reflux for 18 h. After allowing to cool to rt, the mixture was partitioned between 1 N HCl (75 mL) and EtOAc (100 mL). The organic layer was washed with H2O (100 mL), brine (100 mL), dried over MgSO4 and concentrated in vacuo. The crude product was dissolved in ether (100 mL), filtered to remove some unidentified solid material, and concentrated to give 2-Carboxymethyl-6-(2-mercapto-ethyl)-benzoic acid as a white solid (0.310 g, 73%): 1H NMR (CDCl3) δ 1.37 (t, J=8.2 Hz, 1H), 2.76 (m, 2H), 3.06 (m, 2H), 3.90 (s, 2H), 7.10 (d, J=7.6 Hz, 1H), 7.21 (d, J=6.9 Hz, 1H), 7.34 (t, J=7.8 Hz, 1H): 13C NMR (CDCl3) δ 27.25, 40.43, 41.83, 131.58, 131.64, 132.45, 132.55, 134.66, 141.41, 176.14, 179.40. Anal. Calcd for C11H12O4S: C, 54.99; H, 5.03; S, 13.35. Found: C, 55.20; H, 5.26; S, 13.32.
Reaction SMILES: Cl.[CH3:2][N:3]([CH:11]1[CH2:15][CH2:14][N:13](S(C2C=CC=CC=2)(=O)=O)[CH2:12]1)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])O.[Na+]>C(O)C>[CH3:7][C:6]([O:5][C:4]([N:3]1[CH2:2][CH2:14][NH:13][CH2:12][C@@H:11]1[CH3:15])=[O:10])([CH3:9])[CH3:8]
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(S(=O)(=O)c2ccccc2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 49.7 %

Procedure:
2M HCl (50 ml) was added drop wise to a solution of the product of part (b) (31.8 g) in ethanol (1500 ml), the reaction was stirred for 1.5 h. Solid sodium hydrogen carbonate (8.4 g) was added and stirred for 1 h, then concentrated in vacuo. The residue was purified by chromatography (silica, 0-2-5% MeOH/DCM as eluent) to remove the by-products, then eluted with 10% MeOH/DCM to give the sub-title compound (9.3 g).
Reaction SMILES: C(OC([NH:8][C:9]1[N:10]=[CH:11][C:12]([O:15][C:16]2[CH:17]=[C:18]([CH3:30])[C:19]3[CH:23]([CH2:24][C:25]([OH:27])=[O:26])[O:22][B:21]([OH:28])[C:20]=3[CH:29]=2)=[N:13][CH:14]=1)=O)(C)(C)C.Cl.O1CCOCC1>>[NH2:8][C:9]1[N:10]=[CH:11][C:12]([O:15][C:16]2[CH:17]=[C:18]([CH3:30])[C:19]3[CH:23]([CH2:24][C:25]([OH:27])=[O:26])[O:22][B:21]([OH:28])[C:20]=3[CH:29]=2)=[N:13][CH:14]=1
Reactant: Cc1cc(Oc2cnc(NC(=O)OC(C)(C)C)cn2)cc2c1C(CC(=O)O)OB2O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Oc2cnc(N)cn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.7 %

Procedure:
[6-(5-tert-Butoxycarbonylamino-pyrazin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid (70 mg, 0.17 mmol) was treated with 4M HCl in dioxane (1 mL, 4 mmol) and stirred at room temperature for 3 h. The reaction mixture was concentrated under vacuum and purified by HPLC affording the title compound (40 mg, 75%) as a white solid. 1H NMR (CD3OD) δ 7.79 (s, 1H), 7.64 (s, 1H), 7.02 (d, 1H), 6.98 (d, 1H), 5.65 (dd, 1H), 3.35 (m, 1H), 3.20 (dd, 1H), 2.36 (s, 3H). MS found: (M+H)+: 316.05.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][NH:24][CH:25]=3)=[CH:17][CH:16]=2)[CH2:10][C:11]([NH:13]C)=[O:12])[CH:5]=[CH:6][C:7]=1F.[Cl:26]C1C=CC([Mg]Br)=CC=1>>[Cl:26][C:7]1[CH:6]=[CH:5][C:4]([CH:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][NH:24][CH:25]=3)=[CH:17][CH:16]=2)[CH2:10][C:11]([NH2:13])=[O:12])=[CH:3][CH:2]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CNC(=O)CC(c1ccc(-c2cn[nH]c2)cc1)c1ccc(F)c(F)c1
Product: NC(=O)CC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1

Procedure:
By following the procedure described in Example 9A and 9B but substituting 3,4-difluorophenylmagnesium bromide for 4-chlorophenylmagnesium bromide, the title compound was obtained. LC/MS: (PS-A2) Rt 2.54 [M+H]+ 326. 1H NMR (Me-d3-OD) δ 2.95 (2H, d), 4.53 (1H, t), 7.27 (6H, m), 7.50 (2H, d), 7.91 (2H, s).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH2:13][CH3:14])[N:5]=[CH:4][N:3]=1.[CH3:15][Si:16]([CH3:25])([CH3:24])[C@@H:17]1[CH2:22][CH2:21][C@H:20]([NH2:23])[CH2:19][CH2:18]1.C(N(CC)CC)C>O.CCl>[CH2:11]([O:10][C:8]([C:7]1[C:2]([NH:23][C@H:20]2[CH2:19][CH2:18][C@@H:17]([Si:16]([CH3:25])([CH3:24])[CH3:15])[CH2:22][CH2:21]2)=[N:3][CH:4]=[N:5][C:6]=1[CH2:13][CH3:14])=[O:9])[CH3:12]
Reactant: C[Si](C)(C)[C@H]1CC[C@@H](N)CC1
Reactant: CCOC(=O)c1c(Cl)ncnc1CC
Agent: CCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(CC)ncnc1N[C@H]1CC[C@@H]([Si](C)(C)C)CC1

Procedure:
1.00 g (4.66 mmol) of 4-chloro-5-ethoxycarbonyl-6-ethylpyrimidine (EP 606 011), 0.84 g (4.89 mmol) of cis-4-trimethylsilylcyclohexylamine and 0.94 g (9.29 mmol) of triethylamine were heated at 70° C. for 5 hours without solvent. After cooling, the mixture was taken up in water/methyl chloride and the organic phase was dried and concentrated. The residue was purified by chromatography on silica gel using petroleum ether/ethyl acetate (4:1), to give 1.1 g (67% of theory) of a colorless oil.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42]>ClCCl>[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42].[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42].[F:30][C:26]1[CH:25]=[C:24]([N:13]([C@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:16][CH:15]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: Fc1cccc(N(c2ccc(C(F)(F)F)cc2)[C@H]2CCN(Cc3ccccc3)C2)c1
Agent: CC(Cl)OC(=O)Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: ClCCl
Product: Fc1cccc(N(c2ccc(C(F)(F)F)cc2)[C@H]2CCNC2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.4 %

Procedure:
To a 1,2-dichloromethane solution (1 ml) containing ((S)-1-benzylpyrrolidin-3-yl)-(3-fluorophenyl)-(4-trifluoromethylphenyl)amine (0.48 g, 1.1 mmol) was added 1-chloroethyl chloroformate (0.82 g, 5.8 mmol). The mixture was stirred at room temperature for 15 hours and heated under reflux for 3 hours. The solvent was distilled off under reduced pressure, and 5 ml methanol was then added to the residue and heated under reflux for 3 hours. After distilling the solvent off under reduced pressure, the residue was then dissolved in dichloromethane and washed with an aqueous saturated sodium hydrogencarbonate solution. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in ethanol, fumaric acid (128 mg, 1.1 mmol) was then added thereto, giving a uniform solution. The solvent was distilled off under reduced pressure, and the crystals produced by adding dichloromethane to the residue were separated by filtration and dried, giving 0.24 g of light brown powdery (3-fluorophenyl)-(S)-pyrrolidin-3-yl-(4-trifluoromethylphenyl)amine difumarate.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([CH:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)=[CH:3][CH:2]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:8]2[CH2:9][CH2:10][CH2:11][CH:7]2[C:4]2[CH:5]=[CH:6][C:1]([CH3:12])=[CH:2][CH:3]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(C2CCCN2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: Cc1ccc(C2CCCN2S(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The title compound, white solid, m.p. 129° C. and MS: m/e=335 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-p-tolyl-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:23][OH:24]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([CH2:23][OH:24])[CH:25]=[CH:26][C:27]=1[F:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: OCc1ccc(F)c(Br)c1
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1cc(CO)ccc1F

Procedure:
Following the general method as outlined in Intermediate 19, starting from tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3) and 3-bromo-4-fluorobenzyl alcohol (Oakwood), the title compound was obtained as a dark brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[S:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[S:19])[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1
Reactant: Cc1ccc(C(=S)CBr)cc1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Product: CCOC(=O)n1c(C(=S)c2ccc(C)cc2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromo-4′-methylthioacetophenone (Cutler et al., J. Am. Chem. Soc., 1952, 74, 5475). 1H-NMR (CDCl3) δ: 8.25 (1H, d, J=1.8 Hz), 7.67 (2H, d, J=8.4 Hz), 7.53 (1H, d, J=8.4 Hz), 7.31-7.23 (3H, m), 5.75 (2H, br s), 3.82 (2H, q, J=7.0 Hz), 2.51 (3H, s), 0.89 (3H, t, J=7.0 Hz)
Reaction SMILES: C([BH3-])#N.[Na+].[Cl:5][C:6]1[C:7]([CH3:19])=[CH:8][C:9]2[CH:10]=[C:11]3[CH2:18][NH:17][CH2:16][CH2:15][N:12]3[C:13]=2[CH:14]=1.C(=O)([O-])O.[Na+].C(O)(=O)/C=C/C(O)=O>C(O)(=O)C.CC(O)C>[Cl:5][C:6]1[C:7]([CH3:19])=[CH:8][C:9]2[CH2:10][CH:11]3[CH2:18][NH:17][CH2:16][CH2:15][N:12]3[C:13]=2[CH:14]=1
Reactant: Cc1cc2cc3n(c2cc1Cl)CCNC3
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CC(C)O
Solvent: CC(=O)O
Product: Cc1cc2c(cc1Cl)N1CCNCC1C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.3 %

Procedure:
Sodium cyanoborohydride (95%, 0.24 g, 3.6 mmol) was added in 1 portion to a stirred solution of 7-chloro-8-methyl-1,2,3,4-tetrahydropyrazino[1,2-a]indole (0.25 g, 1.1 mmol) in acetic acid (10 mL) at 10° C. under Ar. The reaction was then allowed to warm to room temperature and stirred for 4 h. The mixture was then poured into saturated aqueous sodium hydrogen carbonate solution (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine (1×50 mL), dried (magnesium sulfate), filtered and the solvent removed under vacuum to leave a crude oil. The oil was purified by flash column chromatography [SiO2; ethyl acetate-methanol-ammonium hydroxide (9:1:0)→(90:9:1)] to give an oil (022 g, 87%). The oil was dissolved in boiling 2-propanol (5 mL) and a solution of fumaric acid (0.05 g) in hot 2-propanol (5 mL) was added. The solvent was removed under vacuum and the residue triturated with ether to give the product as an off-white solid (40 mg, 10%). mp 180-182° C. IR νmax (Nujol)/cm−1 4331, 2924, 2854, 1702, 1618, 1459, 1377, 1274, 1176, 1103, 1008, 969, 868, 834, 786, 722, 676, 642 and 537; NMR δH (400 MHz; DMSO-d6) 7.02 (1H, s), 6.60 (1H, s), 6.54 (3H, s), 3.63-3.67 (1H, m), 3.47-3.57 (2H, m), 2.88-3.10 (5H, m), 2.72-2.79 (1H, m), 2.19 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=O)[CH:5]=[C:4]([CH3:11])[CH:3]=1.[BH4-].[Na+].[NH3:14]>CCC[O-].CCC[O-].CCC[O-].CCC[O-].[Ti+4]>[CH3:1][C:2]1[CH:7]=[C:6]([CH:8]([NH2:14])[CH3:10])[CH:5]=[C:4]([CH3:11])[CH:3]=1
Reactant: CC(=O)c1cc(C)cc(C)c1
Reactant: N
Agent: [Ti+4]
Agent: CCC[O-]
Agent: [BH4-]
Product: Cc1cc(C)cc(C(C)N)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 43 %

Procedure:
3,5-Dimethylacetophenone (3.0 g, 20.2 mmol) was dissolved in ethanolic NH3 solution (2 M in ethanol, 50 ml), tetrapropylorthotitanate (11 ml, 40.4 ml) was added and the mixture was stirred for 6 h at room temperature. NaBH4 (1.16 g, 30.4 mmol) was then added carefully to the reaction solution and the mixture was stirred overnight at room temperature. The reaction mixture was poured into aqueous ammonia solution and filtered. The solid was washed twice more with ethyl acetate (50 ml). The phases were separated and the aqueous phase was extracted twice more with ethyl acetate. The combined organic phases were washed with HCl solution (2 N, 60 ml), the aqueous phase was adjusted to pH 11 with NaOH solution and extracted three times with ethyl acetate (100 ml). The organic phase was washed with saturated NaCl solution (100 ml), dried over MgSO4 and concentrated to small volume. The resulting crude product was used without further purification. Yield: 43%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].C(OC([N:33]1[CH2:38][CH2:37][N:36]([S:39]([C:42]2[S:43][C:44](Br)=[CH:45][CH:46]=2)(=[O:41])=[O:40])[CH2:35][CH2:34]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[N:36]1([S:39]([C:42]2[S:43][C:44]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]4[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]5[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=5)=[N:8][C:7]=34)=[CH:45][CH:46]=2)(=[O:41])=[O:40])[CH2:35][CH2:34][NH:33][CH2:38][CH2:37]1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Br)s2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1)N1CCNCC1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (178 mg, 0.5 mmol) and 4-(5-bromo-thiophene-2-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (example B.52) (206 mg, 0.5 mmol) according to general procedure II and subsequent cleavage of the protecting group with TFA in dichloromethane at 0° C. Obtained as an orange solid (145 mg, 50%). MS (ISP) 586.1 [(M+H)+]; mp 223° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.C([Li])CCC.CON(C)[C:16](=[O:18])[CH3:17]>O1CCCC1>[CH3:7][C:5]1[N:6]=[C:2]([CH2:1][C:16](=[O:18])[CH3:17])[S:3][CH:4]=1
Reactant: Cc1csc(C)n1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)Cc1nc(C)cs1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
To a solution of 2,4 dimethylthiazole (2 g) in dry tetrahydrofuran (20 ml) at −70° C. under argon was added 1.6M n-butyllithium in hexanes (12 ml) dropwise, keeping the temperature below −70° C. After stirring at −60° C. for 30 minutes, N-methoxy-N-methylacetamide (1.9 ml) was added. The mixture was allowed to warm to ambient temperature and was then partitioned between water and ethyl acetate The organic phase was dried (MgSO4) and the solvent removed under reduced pressure to yield a yellow oil. This was purified by column chromatography using a isohexane to 40% ethyl acetate/isohexane gradient as the eluent to yield the product as a yellow oil (630 mg, 23%).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].[ClH:10].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([NH:19][NH2:20])[CH:16]=[CH:17][CH:18]=1.C(O)(=O)C>C(O)C>[ClH:10].[C:2]([C:3]1[CH:4]=[C:5]([NH2:6])[N:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH3:11])[CH:14]=2)[N:20]=1)([CH3:9])([CH3:8])[CH3:1]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: COc1cccc(NN)c1
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.4 %

Procedure:
To a solution of 4,4-dimethyl-3-oxo-pentanenitrile (5.0 g, 40 mmol) and 3-methoxy-phenylhydrazine hydrochloride (7.0 g, 40 mmol) in anhydrous ethanol (200 mL) was added acetic acid (1.2 mL). The reaction mixture was heated at reflux overnight, then cooled to room temperature and concentrated at reduced pressure. The residue was combined with ethyl acetate (200 mL), and washed with saturated aq NaHCO3, water, and brine. The solution was dried over Na2SO4, evaporated at reduced pressure and the solid residue was re-dissolved in ethanol (100 mL). A solution of 2M HCl in ether was added and the mixture was stirred for 30 min. The solvent was removed at reduced pressure, the solid residue was triturated and washed with hexane (50 mL) and then dried in a vacuum oven overnight to give the product 5-tert-butyl-2-(3-methoxy-phenyl)-2H-pyrazol-3-ylamine hydrochloride (5.46 g, 56%) as an off-white solid. 1H-NMR (DMSO-d6) δ 7.50 (t, 1H), 7.10 (m, 3H), 5.60 (s, 1H), 3.80 (s, 3H), 1.30 (s, 9H); MS LC-MS [M+H]+=246.2, RT=1.90 min.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:18]=[CH:17][C:10]([CH:11]=[CH:12][C:13]([O:15][CH3:16])=[O:14])=[CH:9][C:8]=1[O:19][CH2:20][C:21]12[CH2:28][CH2:27][C:24]([CH3:29])([CH2:25][CH2:26]1)[O:23][C:22]2=[O:30].[Cl-].[NH4+]>C(Cl)Cl>[OH:6][C:7]1[CH:18]=[CH:17][C:10]([CH:11]=[CH:12][C:13]([O:15][CH3:16])=[O:14])=[CH:9][C:8]=1[O:19][CH2:20][C:21]12[CH2:28][CH2:27][C:24]([CH3:29])([CH2:25][CH2:26]1)[O:23][C:22]2=[O:30]
Reactant: COC(=O)C=Cc1ccc(OC)c(OCC23CCC(C)(CC2)OC3=O)c1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: COC(=O)C=Cc1ccc(O)c(OCC23CCC(C)(CC2)OC3=O)c1
Yield: 32.1 %

Procedure:
At -78° C., 0.3 ml of boron tribromide was added to a solution of 0.68 g of methyl 4-methoxy-3-[1-(4-methyl-2-oxo-3-oxabicyclo[2.2.2]octanyl)methoxy]cinnamate (Example 50) in 10 ml of methylene chloride. The solution was reacted for 15 minutes, as it was. After reaction, 30 ml of an aqueous ammonium chloride solution was added to the reaction solution. The solution was extracted three times with 30 ml of ethyl acetate. The organic layer obtained was washed three times with an aqueous sodium chloride solution and was dried over magnesium sulfate. Thereafter, the solvent was removed in vacuo, yielding 0.21 g of methyl 4-hydroxy-3-[1-(4-methyl-2-oxo-3-oxabicyclo[2.2.2]octanyl)methoxy]cinnamate (a compound of the present invention) as a pale yellow oil, which had the following physiochemical properties:
Reaction SMILES: [N:1]([C:4]1[S:8][C:7]2[CH2:9][CH2:10][CH2:11][C:6]=2[C:5]=1[C:12]([O:14]C)=O)=[C:2]=[S:3].[N:16]1([CH2:21][CH2:22][CH2:23][NH2:24])[CH:20]=[CH:19][N:18]=[CH:17]1>>[N:16]1([CH2:21][CH2:22][CH2:23][N:24]2[C:12](=[O:14])[C:5]3[C:6]4[CH2:11][CH2:10][CH2:9][C:7]=4[S:8][C:4]=3[NH:1][C:2]2=[S:3])[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: NCCCn1ccnc1
Reactant: COC(=O)c1c(N=C=S)sc2c1CCC2
Product: O=c1c2c3c(sc2[nH]c(=S)n1CCCn1ccnc1)CCC3

Procedure:
The compound was synthesized starting from methyl 5,6-dihydro-2-isothiocyanato-4H-cyclopenta[b]thiophene-3-carboxylate (0.018 g.0.08 mmol) and 3-(1H-imidazol-1-yl)propan-1-amine (0.009 g, 0.08 mmol) as described above.
Reaction SMILES: [F:1][S:2]([F:15])([F:14])([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.[Br-:16].[Br-].[Br-].C[N+](C)(C)C1C=CC=CC=1.C[N+](C1C=CC=CC=1)(C)C.C[N+](C1C=CC=CC=1)(C)C>C1COCC1>[Br:16][CH2:10][C:9]([C:6]1[CH:5]=[CH:4][C:3]([S:2]([F:12])([F:13])([F:14])([F:15])[F:1])=[CH:8][CH:7]=1)=[O:11]
Reactant: CC(=O)c1ccc(S(F)(F)(F)(F)F)cc1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc(S(F)(F)(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 1-[4-(pentafluoro-λ6-sulfanyl)phenyl]ethanone (Preparation 41, 0.6 g, 2.44 mmol) in THF (20 mL) at 0° C. was added trimethylphenylammonium tribromide (0.962 g, 2.56 mmol). After stirring for 2 hours at 0° C. the reaction was quenched with a saturated aqueous solution of sodium hydrogen carbonate. The reaction was extracted with ethyl acetate and dried over MgSO4 before concentrating in vacuo to afford the title compound that was used without further purification.