Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[CH2:22][CH2:21][CH2:20]3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[CH2:22][CH2:21][CH2:20]3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:23]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(N2CCN(CC3CCC3)CC2)c1[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(CC5CCC5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 85 °C

Procedure:
To a mixture of 5-bromo-4-(4-(cyclobutylmethyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.036 g, 0.097 mmol) and EtOH (1 mL) was added p-anisaldehyde (0.015 g, 0.11 mmol) in EtOH (1.2 mL) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.29 mL, 0.29 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and purified by column chromatography on a Biotage SP1 system eluting with methanol (2-10%) in dichloromethane. The title compound was isolated as a pale yellow solid after trituration with diethyl ether (0.016 g, 37%); 1H-NMR (500 Mz, DMSO-d6): δ 1.63-1.73 (m, 2H), 1.77-1.93 (m, 2H), 2.00-2.10 (m, 2H), 2.42 (d, J=7.0 Hz, 2H, NCH2), 2.52-2.60 (m, 4H, piperazine N(CH2)2), 3.62 (m, 4H, piperazine N(CH2)2), 3.84 (s, 3H, OMe), 7.10 (d, J=9.0 Hz, 2H, ArH, C6H4—OMe), 8.13 (d, J=8.5 Hz, 2H, ArH, C6H4—OMe), 8.20 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.34 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 3.29 min—456/458 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 456.1395, calculated for C22H27BrN5O (M+H)+: 456.1399.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][N:9]([C:11]([C:13]3[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:14]=3[O:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])=[O:12])[CH2:8][C:5]2=[N:6][CH:7]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:3]=[C:4]3[CH2:10][N:9]([C:11]([C:13]4[CH:18]=[C:17]([S:19]([CH3:22])(=[O:20])=[O:21])[CH:16]=[CH:15][C:14]=4[O:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:26])[F:27])=[O:12])[CH2:8][C:5]3=[N:6][CH:7]=2)=[CH:33][CH:32]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2cc(Br)cnc2C1)C(F)(F)F
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2cc(-c3ccc(F)cc3)cnc2C1)C(F)(F)F

Procedure:
Prepared in analogy to Example 321 from (3-Bromo-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone (example 22) and 4-fluorophenyl boronic acid. White solid. MS (m/e): 509.2 [M+H]+, 100%).
Reaction SMILES: CS(C)=O.[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:31])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH2:14][CH:13]1[CH2:32][OH:33])=[O:11])([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>C(Cl)Cl>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:31])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH2:14][CH:13]1[CH:32]=[O:33])=[O:11])([CH3:7])([CH3:8])[CH3:6]
Reactant: COc1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)C(CO)C2)cc(OC)c1OC
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)C(C=O)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.4 %

Procedure:
methylene chloride (50 ml) is added dropwise at -78° C. a solution of dimethyl sulfoxide (2.86 g) in methylene chloride (20 ml). The mixture is stirred for 10 minutes. To the resulting reaction mixture is added dropwise a solution of 1-tertbutoxycarbonyl-4-(3,4,5-trimethoxybenzoyl)piperazine-2-methanol (5.0 g) obtained in Reference Example 4 in methylene chloride (10 ml). The mixture is stirred for 20 minutes. To the mixture is added triethylamine (7.4 g), followed by raising the reaction temperature up to room temperature. The reaction mixture is poured into ice water, followed by extraction with methylene chloride. The organic layer is washed with water, dried and concentrated under reduced pressure. The concentrate is recrystallized from ethyl acetate to give 1-tert-butoxycarbonyl-4-(3,4,5-trimethoxybenzoyl)piperazine-2-carbaldehyde as colorless prisms (4.1 g), m.p. 160-161° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]2[C:11](=[O:12])[N:10]([CH3:13])[C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[NH:7][C:6]=2[N:18]=1.[H-].[Na+].[CH2:22]([N:24]([CH2:32][CH2:33][CH2:34]Cl)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:23]>CN(C)C=O>[CH2:22]([N:24]([CH2:32][CH2:33][CH2:34][N:7]1[C:8]2[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=2[N:10]([CH3:13])[C:11](=[O:12])[C:5]2[C:4]([CH3:19])=[CH:3][C:2]([CH3:1])=[N:18][C:6]1=2)[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH3:23]
Reactant: CCN(CCCCl)Cc1ccccc1
Reactant: Cc1cc(C)c2c(n1)Nc1ccccc1N(C)C2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CCCN1c2ccccc2N(C)C(=O)c2c(C)cc(C)nc21)Cc1ccccc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture consisting of 12.3 gm of 6,11-dihydro-2,4,6-trimethyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, 120 ml of dimethyl formamide and 3.05 gm of 50% sodium hydride in mineral oil was stirred at 60° C. for 2 hours. Thereafter, 17 gm of 3-(N-ethyl-N-benzyl-amino)-propyl chloride were added dropwise, and the solution was stirred at 120° C. for 2 hours. After evaporating the solution in vacuo, the residue was distilled, yielding 68% of theory of 11-[3-(N-ethyl-N-benzyl-amino)-propyl]-6,11-dihydro-2,4,6-trimethyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one having a b.p. of 236°-238° C. at 0.3 mm Hg.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[C:17]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(CCCCCO)OCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: O=C(CCCCCOC(=O)c1ccccc1)OCc1ccccc1

Procedure:
To a solution of benzyl 6-hydroxyhexanoate (b) (27.37 g) in methylene chloride were added 4-dimethyl amino pyridine (19.5 g) and benzoyl chloride (19.53 g), and the resultant mixture was stirred for 2 hours. The reaction mixture was treated in the conventional manner and was distilled under reduced pressure (1 mmHg, 190°-215° C.) to give the title compound (c). Yield: 38.09 g (95%)
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:21]C)=[C:17]([F:20])[CH:18]=3)[C:13]([C:23]#[N:24])=[CH:12]2)=[CH:7][CH:6]=1)C.B(Br)(Br)Br.O>ClCCl>[C:23]([C:13]1[C:14]2[C:19](=[CH:18][C:17]([F:20])=[C:16]([OH:21])[CH:15]=2)[N:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:25])=[O:3])=[CH:6][CH:7]=2)[CH:12]=1)#[N:24]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(OC)c(F)cc32)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: N#Cc1cn(-c2ccc(C(=O)O)cc2)c2cc(F)c(O)cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 41.9 %

Procedure:
To a solution of 4-(3-cyano-6-fluoro-5-methoxyindol-1-yl)benzoic acid ethyl ester (1.2 g) in dichloromethane (20 mL) was added boron tribromide (1.0 mol/L dichloromethane solution) (10 mL) in a dropwise manner under ice cooling, and this mixture was stirred at room temperature for 12 hours. This reaction mixture was poured into water, and this mixture was extracted with ethyl acetate, concentrated under reduced pressure to give the title compound (0.44 g).
Reaction SMILES: [CH3:1][C:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14](=[O:16])[CH3:15])[CH2:4][O:3]1.[Cl:17][C:18]1[CH:29]=[CH:28][C:21]([O:22][CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)=[CH:20][CH:19]=1>>[ClH:17].[Cl:17][C:18]1[CH:29]=[CH:28][C:21]([O:22][CH:23]2[CH2:27][CH2:26][N:25]([CH2:4][C:2]([OH:3])([CH3:1])[CH2:5][O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:13][C:14](=[O:16])[CH3:15])[CH2:24]2)=[CH:20][CH:19]=1
Reactant: CC(=O)Nc1ccccc1OCC1(C)CO1
Reactant: Clc1ccc(OC2CCNC2)cc1
Product: CC(=O)Nc1ccccc1OCC(C)(O)CN1CCC(Oc2ccc(Cl)cc2)C1
Product: Cl
Yield: 221.3 %

Procedure:
The title compound (255 mg, 110%) was prepared from N-{2-[(2-methyl-2-oxiranyl)methoxy]phenyl}acetamide (123 mg, 0.557 mmol) and 3-(4-chlorophenoxy)pyrrolidine (100 mg, 0.506 mmol) analogously to that described in Example 1 (iii).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.Cl[C:26]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].[Cl:36]CCl>>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][C:33]([Cl:35])=[C:34]([Cl:36])[CH:26]=4)=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
As described for Example 9, 0.111 g (1.1 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine in 8 ml of dichloromethane is reacted with 0.230 g of (1.1 mmol) of 2,4-dichlorobenzoyl chloride. The product is recrystallized from hexane-dichloromethane to give 0.24 g of crystals, m.p. 212°-215° C.
Reaction SMILES: [CH2:1]([Si:9](OC)(OC)OC)[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].COCC(O)C>>[CH2:1]([SiH3:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: CO[Si](CCCCCC(C)C)(OC)OC
Solvent: COCC(C)O
Product: CC(C)CCCCC[SiH3]
Reaction time: 8 h

Procedure:
Silica nanoparticles surface modified with isooctyltrimethoxysilane were prepared as follows: 61.42 g BS1316 isooctyltrimethoxysilane (Wacker Silicones Corp., Adrian, Mich.), 1940 g 1-methoxy-2-propanol and 1000 g NALCO 2326 colloidal silica were combined in a 1 gallon glass jar. The mixture was shaken to ensure mixing and then placed in an oven at 80° C. overnight. The mixture was then dried in a flow through oven at 150° C. to produce a white particulate solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:20][CH2:21][CH:22]=[CH:23][CH3:24])=[C:4](I)[C:5]2[CH2:11][CH2:10][N:9]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:8][CH2:7][C:6]=2[CH:18]=1.[PH2](O)=O.CC(N=NC(C#N)(C)C)(C#N)C>CCO>[Br:1][C:2]1[C:3]2[O:20][CH2:21][CH:22]([CH2:23][CH3:24])[C:4]=2[C:5]2[CH2:11][CH2:10][N:9]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:8][CH2:7][C:6]=2[CH:18]=1
Reactant: CC=CCOc1c(Br)cc2c(c1I)CCN(C(=O)C(F)(F)F)CC2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=[PH2]O
Solvent: CCO
Product: CCC1COc2c(Br)cc3c(c21)CCN(C(=O)C(F)(F)F)CC3
Temperature: 90 °C

Procedure:
Into a 100 ml flask containing the product of step (g) (642 mg, 1.24 mmol) dissolved in EtOH (20 ml), TEA (1.7 ml, 12.4 mmol), hypophosphorous acid (2.3 ml, 12.4 mmol), and AIBN (407 mg, 2.48 mmol) were added. The reaction mixture was heated to 90° C. for 30 minutes, and then the volatiles were evaporated in vacuo. The resulting residue was diluted with water (100 ml) and extracted with DCM (3×). The combined DCM extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the crude product. Purification by silica-gel chromatography (gradient elution: 0 to 30% EtOAc in hexanes) gave the sub-title compound as a white solid that was contaminated with AIBN. This material was used as obtained in the next step. MS: ESI (positive): 392, 394 (M+H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22].[C:25]([N:29]=[C:30]=[O:31])([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[C:25]([NH:29][C:30]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([C:2]([F:23])([F:1])[F:24])=[CH:11][CH:10]=2)[C:6]([N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[N:7]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C1c2ccccc2C(=O)N1c1n[nH]c2ccc(C(F)(F)F)cc12
Reactant: CC(C)(C)N=C=O
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)n1nc(N2C(=O)c3ccccc3C2=O)c2cc(C(F)(F)F)ccc21

Procedure:
2-(5-Trifluoromethyl-1H-indazol-3-yl)-isoindole-1,3-dione (1.56 g, 4.71 mmol) in DMF (5 mL) was treated with t-butyl-isocyanate (513 mg, 5.18 mmol) at room temperature overnight. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude material. Purification by silica gel column (hexanes:ethyl acetate 2:1) afforded the title compound as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:28])[C:11]([C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23](=[O:25])[N:22]([CH3:26])[C:21]=2[CH:27]=1)([OH:16])[C:12]([F:15])([F:14])[F:13]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:28])[C:11]([C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23](=[O:25])[N:22]([CH3:26])[C:21]=2[CH:27]=1)([OH:16])[C:12]([F:13])([F:14])[F:15]
Reactant: COc1ccc(C(C)C(O)(c2ccc3oc(=O)n(C)c3c2)C(F)(F)F)c(Cl)c1
Solvent: ClCCl
Product: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
5-[2-(2-Chloro-4-methoxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (766 mg) was dissolved in CH2Cl2 (25 mL) and cooled to −78° C. Borontribromide (1M in CH2Cl2, 7.37 mL) was added over a period of 20 minutes. Stirring was continued for 1.5 hours at −78° C. The cooling bath was removed and the mixture was allowed to warm to 0° C. Stirring was continued for 2 hours at 0° C. The reaction mixture was poured into ice and basified with sat. NaHCO3 and extracted three times with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The title compound was obtained as a colorless foam (740 mg, 99%) and was used without further purification. MS (m/e)=402.2 [M+H+].
Reaction SMILES: [CH3:1][Si:2]([CH3:16])([CH3:15])[O:3][CH2:4][CH2:5][C-:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.[Li+].[Cl-:18].[Cl-].[Cl-].[CH3:21][Zr:22]([CH3:31])([CH3:30])([CH3:29])([CH3:28])[CH:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1>CCOCC>[Cl-:18].[Cl-:18].[CH3:16][Si:2]([CH3:15])([CH3:1])[O:3][CH2:4][CH2:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[Zr:22]([CH3:31])([CH3:30])([CH3:29])([CH3:28])([CH3:21])[CH:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1
Reactant: C[Si](C)(C)OCC[c-]1ccc2ccccc21
Reactant: C[Zr](C)(C)(C)(C)C1C=CC=C1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Product: C[Si](C)(C)OCCC1C([Zr](C)(C)(C)(C)(C)C2C=CC=C2)=Cc2ccccc21
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
A suspension of 1.5 g (6.5 mmol) of lithium [1-(2-trimethylsiloxyethyl)indenide] in ether was added to a suspension of 2.2 g (6.5 mmol) of pentamethylcyclopentadienyl zirconium trichloride in 100 ml of ether at 0° C. After 30 minutes, the formation of a white solid was the volatiles were removed under vacuum to give a yellow oily-solid. This solid was recrystallized in hexane to give a mycrocristalline yellow solid, which was characterized as [1-(2-trimethylsiloxyethyl)indenyl]pentamethylcyclopentadienyl zirconium dichloride (1.7 g, 3.2 mmol, yield: 49%). 1H-NMR (CDCl3): 7.65 (m, 1H); 7.33 (m, 1H); 7.25 (m, 2H); 6.08 (m, 1H); 5.92 (m, 1H); 3.72 (dm, 2H); 3.28 (m, 1H); 2.72 (m, 1H); 2.04 (s, 15H); 0.03 (s, 9H). 13C-NMR (CDCl3): 131.4; 127.1; 126.7; 125.2; 125.1; 124.2; 123.5; 122.6; 116.1; 97.0; 62.6; 32.1; 12.5; −0.6.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[CH:18]=[O:19].[F-:20].[Cs+].O>CN(C)C=O>[F:20][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[CH:18]=[O:19]
Reactant: [F-]
Reactant: O=CC1=C(Cl)c2ccccc2OC1c1ccccc1
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=CC1=C(F)c2ccccc2OC1c1ccccc1

Procedure:
A solution of 1.35 g 4-chloro-3-formyl-flav-3-ene and 7.6 g cesium fluoride in 10 ml dimethylformamide is stirred at 110° C. over 40 minutes. After cooling to room temperature water is added and the solution is extracted with methylene chloride. The organic phase is washed with water, and dried over magnesium sulfate. The solid residue is purified by column chromatography and the best fractions are crystallised in hexane. Pure 4-fluoro-3-formyl-flav-3-ene is obtained as yellow crystals; m.p. 114°-115° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[C:13]([C:15]([C:18]1[CH:19]=[C:20]([CH:31]=[CH:32][CH:33]=1)[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=1)=[O:22])([CH3:17])[CH3:16])#[N:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:13]([C:15]([C:18]1[CH:19]=[C:20]([CH:31]=[CH:32][CH:33]=1)[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:8]2[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=2[C:1]#[N:2])[CH:25]=1)=[O:22])([CH3:17])[CH3:16])#[N:14]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(O)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc([N+](=O)[O-])cc3C#N)c2)c1
Temperature: 70 °C
Reaction time: 12 h
Yield: 94 %

Procedure:
To a solution of 3-cyano-4-fluoronitrobenzene (1.76 g, 10.5 mmol) and 3-(1-cyano-1-methylethyl)-N-(3-hydroxyphenyl)benzamide (2.97 g, 10.5 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (2.17 g, 15.7 mmol), and the mixture was stirred at 70° C. for 12 hr. The reaction mixture was cooled to room temperature, insoluble material was filtered off, water (100 ml) was added to the filtrate, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate, and insoluble material was filtered off. The obtained organic layer was purified by basic silica gel column chromatography (eluate: ethyl acetate), and the obtained solution was concentrated under reduced pressure to give the title compound (4.21 g, 94%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:31])[C:14]([C:15]([NH:17][C@H:18]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[O:16])=[C:10]2[CH:9]=[C:8]([CH3:32])[CH:7]=1.Cl>C(OCC)C>[F:1][C:2]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:31])[C:14]([C:15]([NH:17][C@H:18]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:19][C:20]([OH:22])=[O:21])=[O:16])=[C:10]2[CH:9]=[C:8]([CH3:32])[CH:7]=1
Reactant: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)N[C@@H](CC(=O)OC(C)(C)C)CC(C)C)c2c1
Agent: Cl
Solvent: CCOCC
Product: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)N[C@@H](CC(=O)O)CC(C)C)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
88 mg (0.17 mmol) of tert-butyl (3R)-3-[({7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl}carbonyl)amino]-5-methylhexanoate from Example 37 were suspended in 2 ml of diethyl ether and admixed with 2.56 ml of 2 N hydrogen chloride solution, and the mixture was stirred at RT overnight. Subsequently, 2 ml of 2 N hydrogen chloride solution in diethyl ether were added and the mixture was stirred at RT for 4 h. The reaction mixture was concentrated, admixed with water and TFA and purified by means of preparative HPLC (RP18 column, eluent:acetonitrile/water gradient with addition of 0.1% TFA). The product fractions were combined, concentrated and lyophilized. 57 mg of the target compound were obtained (73% of theory).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([F:27])[C:5]=1[O:6][C:7]1[CH:18]=[CH:17][C:10]2[NH:11][C:12](=[O:16])[C@@H:13]([CH3:15])[O:14][C:9]=2[CH:8]=1.O.[CH3:29]I>CN(C)C=O>[Cl:3][C:4]1[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[C:19]([F:27])[C:5]=1[O:6][C:7]1[CH:18]=[CH:17][C:10]2[N:11]([CH3:29])[C:12](=[O:16])[C@@H:13]([CH3:15])[O:14][C:9]=2[CH:8]=1
Reactant: C[C@H]1Oc2cc(Oc3c(F)cc(C(F)(F)F)cc3Cl)ccc2NC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H]1Oc2cc(Oc3c(F)cc(C(F)(F)F)cc3Cl)ccc2N(C)C1=O
Reaction time: 0.17 h

Procedure:
Then, 60% sodium hydride (0.03 g) was suspended in dimethylformamide (5 ml), and a solution of the abovedescribed 7-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)-2(R)-methyl-2H-1,4-benzoxazine-3 (4H)-one (0.3 g) in dimethylformamide (5 ml) was dropwise added thereto while cooling with water. The mixture was stirred for 10 min, methyl iodide (0.1 g) was added thereto, and the mixture was stirred for an additional 10 min. Water (10 ml) was added thereto to terminate the reaction, and the reaction mixture was extracted with ethyl acetate (20 ml×2), washed with water and a saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo, and the residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate=3/1) to prepare the title compound (0.3 g) as a colorless crystal. The compound thus prepared was subjected to HPLC analysis for chiral separation and found to be in agreement with the first eluted fraction in the case of racemate (Example 26) modification and have an optical purity of 80%.
Reaction SMILES: O=C1NC2[CH:8]=[CH:9][C:10]([C:12](=[O:19])[CH:13]([CH3:18])[CH2:14][C:15]([OH:17])=[O:16])=[CH:11][C:5]=2[S:4][CH2:3]1.[H-].[Na+].[CH3:22]I.[CH3:24][N:25]([CH3:28])[CH:26]=[O:27]>>[CH3:24][N:25]1[C:28]2[CH:8]=[CH:9][C:10]([C:12](=[O:19])[CH:13]([CH3:18])[CH2:14][C:15]([O:17][CH3:22])=[O:16])=[CH:11][C:5]=2[S:4][CH2:3][C:26]1=[O:27]
Reactant: CC(CC(=O)O)C(=O)c1ccc2c(c1)SCC(=O)N2
Reactant: CI
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COC(=O)CC(C)C(=O)c1ccc2c(c1)SCC(=O)N2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(3,4-Dihydro-3-oxo-1,4[2H]-benzothiazin-7-yl)-3-methyl-4-oxobutyric acid (1.7 g) was dissolved in 50 ml of dimethylformamide and 0.23 g of 60% sodium hydride was added. After 30 minutes, 0.7 ml of methyl iodide was added and the mixture stirred at room temperature for three hours, then poured into 100 ml of ice water and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate and evaporated. The residue was chromatographed on a silica gel column eluted with 5% methanol in methylene chloride. The solvent was removed and the oil obtained was used in Example 56.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH:10]([O:12][Si](C(C)(C)C)(C)C)[CH2:9][CH:8]1[CH:20]=[C:21]([CH3:25])[C:22](=[O:24])[CH3:23])=[O:6])[CH:2]=[CH2:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.O>O1CCCC1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH:20]=[C:21]([CH3:25])[C:22](=[O:24])[CH3:23])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1C=C(C)C(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1C=C(C)C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
To a solution of 2S,4R)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (9.9 g) in tetrahydrofuran (99 ml) was added 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (32.3 ml) at 0° C. After stirring at room temperature for 1 hour, the reaction mixture was poured into a mixture of ethyl acetate (200 ml) and water (100 ml). The aqueous layer was separated and extracted with ethyl acetate. The combined organic layer was washed twice with 1N hydrochloric acid (25 ml) and then with saturated aqueous sodium bicarbonate, water and brine successively, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (100 ml) eluting with a mixture of n-hexane and ethyl acetate (1:1-1:2 V/V) to give (2S,4R)-1-allyloxycarbonyl-4-hydroxy-2-(2-methyl-3oxo-1-butenyl)pyrrolidine (5.65 g).