Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH:5]=[CH:4][C:3]=1[S:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.C([C:28]1[C:29]([N:34]=[CH:35][N:36]([CH3:38])C)=[N:30][CH:31]=[CH:32][CH:33]=1)#N.NC1C=C(OCC2C=CC=C(F)C=2)C=CC=1SC1C=CC(O)=CC=1>>[CH3:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([S:18][C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)=[C:2]([NH:1][C:38]2[C:28]3[CH:33]=[CH:32][CH:31]=[N:30][C:29]=3[N:34]=[CH:35][N:36]=2)[CH:7]=1
Reactant: COc1ccccc1COc1ccc(Sc2ccc(O)cc2)c(N)c1
Reactant: CN(C)C=Nc1ncccc1C#N
Agent: Nc1cc(OCc2cccc(F)c2)ccc1Sc1ccc(O)cc1
Product: COc1ccccc1COc1ccc(Sc2ccc(O)cc2)c(Nc2ncnc3ncccc23)c1
Yield: 56 %

Procedure:
The product of Example 37A was reacted with the product of Example 57A using the procedure of Example 57E substituting the product of Example 37A for the product of Example 57D to provide a solid which was triturated with methanol to provide the title compound (47 mg, 56%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 10.08 (s, 1H), 9.63 (s, 1H), 9.07 (s, 1H), 8.85 (d, J=6.62 Hz, 1H), 8.59 (s, 1H), 7.64 (s, 1H), 7.41 (dd, J=7.35, 1.47 Hz, 1H), 7.30-7.38 (m, 1H), 7.24 (s, 1H), 7.16 (d, J=8.46 Hz, 1H), 7.08-7.14 (m, 2H), 7.05 (d, J=8.09 Hz, 1H), 6.89-7.01 (m, J=7.54, 7.54 Hz, 2H), 6.61-6.71 (m, 2H), 5.05 (s, 2H), 3.80 (s, 3H); MS (ESI+) m/z 483.2 (M+H)+, (ESI−) m/z 481.2 (M−H)−.
Reaction SMILES: [I:1][C:2]1[S:10][C:9]2[C:8]([C:11]#[N:12])=[CH:7][N:6]=[C:5]([NH:13]CC3C=CC(OC)=CC=3)[C:4]=2[CH:3]=1.[OH:23]S(O)(=O)=O>>[NH2:13][C:5]1[C:4]2[CH:3]=[C:2]([I:1])[S:10][C:9]=2[C:8]([C:11]([NH2:12])=[O:23])=[CH:7][N:6]=1
Reactant: COc1ccc(CNc2ncc(C#N)c3sc(I)cc23)cc1
Reactant: O=S(=O)(O)O
Product: NC(=O)c1cnc(N)c2cc(I)sc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2-iodo-4-(4-methoxy-benzylamino)-thieno[3,2-c]pyridine-7-carbonitrile 27 (3.88 g, 9.21 mmol) was added conc. H2SO4 (9.75 mL). The reaction was stirred for 1 h at room temperature, then quenched by the addition of ice (20 g). The filtered precipitate was washed with H2O, then suspended in 30% MeOH—CH2Cl2 (30 mL). Triethylamine was added dropwise until the solids dissolved. The solution was purified by silica gel column chromatography (eluent: 10 to 20% MeOH in CH2Cl2 with 1% NH4OH additive) to yield 2.6 g of 28. 1H NMR (400 MHz, d6-DMSO) δ 8.46 (s, 1H), 7.94 (m, 2H), 7.31 (bs, 1H), 7.18 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(C(O[NH:30][C@H:31]([C:36](O)=[O:37])[CH2:32][CH:33]([CH3:35])[CH3:34])C1C=CC=CC=1)(O)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]([C:36](=[O:37])[C@H:31]([CH2:32][CH:33]([CH3:35])[CH3:34])[NH2:30])[CH:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CNC1Cc2ccccc2C1
Reactant: CC(C)C[C@H](NOC(C(=O)O)c1ccccc1)C(=O)O
Product: CC(C)C[C@H](N)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Yield: 34.3 %

Procedure:
By reacting 7 g of N-(indan-2-yl)glycine tert-butyl ester with 8.5 g of N-(carboxybenzoxy)-L-leucine and treating the reaction mixture as in Reference Example 5, there is obtained 3.5 g of L-leucyl-N-(indan-2-yl)glycine tert-butyl ester as colorless amorphous powder.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:12]1(O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C([O-])=O)=NC([O-])=O>C(Cl)Cl>[O:11]([CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ccccc1
Reactant: OC1CCC2(CC1)OCCO2
Agent: O=C([O-])N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: c1ccc(OC2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decan-8-ol (1.05 g, 6.63 mmol), phenol (0.75 g, 7.95 mmol), triphenylphosphine (1.91 g, 7.29 mmol) in CH2Cl2 (20 mL) was added disopropyl azodicarboxylate (1.57 mL, 7.95 mmol). After being stirred overnight at room temperature under N2, the reaction mixture was concentrated. The residue was flash chromatographed using 10:90 hexane-EtOAc to give 1.09 g of 8-phenoxy-1,4-dioxaspiro[4.5]decane. MS (EI) calcd: (M+H)+=235.1; found: 235.0.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([O:26][C:27](=[O:28])[C:5]=2[CH:4]=1)[CH2:13][CH2:12][N:11]([C:14]([C:16]1([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH2:18][CH2:17]1)=[O:15])[CH2:10]3.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>O1CCCC1.O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([O:26][C:27](=[O:28])[C:5]=2[CH:4]=1)[CH2:13][CH2:12][N:11]([C:14]([C:16]1([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)[CH2:17][CH2:18]1)=[O:15])[CH2:10]3
Reactant: COc1ccc2c(c1)C(=O)OC21CCN(C(=O)C2(c3ccc(C)cc3)CC2)C1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C2(C(=O)N3CCC4(C3)OC(=O)c3cc(O)ccc34)CC2)cc1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a solution of 5-methoxy-1′-{[1-(4-methylphenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (40 mg, 0.0001 mol) in tetrahydrofuran (2 mL, 0.02 mol) was added L-Selectride® in tetrahydrofuran (1.0 M, 0.53 mL) and the resulting solution was heated to 120° C. for 50 minutes using microwave irradiation. To the reaction mixture was added a few drops of water to quench the reaction. Then the reaction mixture was concentrated and about. 3 mL of concentrated HCl aqueous solution was added to dissolve the residue. The resulting solution was stirred at rt for 2 h. The crude product was purified using prep-HPLC. LCMS: m/z 364.2 (M+H)+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][O:10][C:9]2=[O:18])[CH2:4][CH2:3]1.Cl[C:20]1[CH:36]=[CH:35][C:23]([C:24]([C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28]([OH:30])=[O:29])=[O:25])=[CH:22][C:21]=1[N+:37]([O-:39])=[O:38].C(N(CC)CC)C>CN(C)C=O>[N+:37]([C:21]1[CH:22]=[C:23]([C:24]([C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28]([OH:30])=[O:29])=[O:25])[CH:35]=[CH:36][C:20]=1[N:2]1[CH2:3][CH2:4][CH:5]([N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][O:10][C:9]2=[O:18])[CH2:6][CH2:7]1)([O-:39])=[O:38]
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=C1OCc2ccccc2N1C1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)c1ccccc1C(=O)c1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c([N+](=O)[O-])c1

Procedure:
A solution of 1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride (J.Med. Chem. 1998, 2157) (0.8 g), 2-(4-chloro-3-nitrobenzoyl)benzoic acid (0.9 g) and triethylamine (0.8 ml) in N,N-dimethylformamide (5 ml) was stirred at room temperature for 72 h. The mixture was partitioned between ethyl acetate and dilute hydrochloric acid, the organic layer was evaporated under reduced pressure. Purification was by chromatography eluting with 4% methanol/dichloromethane. The residue was triturated from methanol, yield 0.4 g as a solid.
Reaction SMILES: [OH-:1].[K+].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH2:13]Br>C(O)/C=C/C>[CH2:9]([O:1][CH2:13][C:5]1[C:6]([N+:10]([O-:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=1[Br:3])/[CH:4]=[CH:5]/[CH3:6]
Reactant: O=[N+]([O-])c1cccc(Br)c1CBr
Reactant: [OH-]
Agent: C/C=C/CO
Agent: [K+]
Product: C/C=C/COCc1c(Br)cccc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a solution of KOH (0.57 g, 0.099 mol) in (2E)-but-2-en-1-ol (100 mL) was added 1-bromo-2-(bromomethyl)-3-nitrobenzene (10 g, 0.033 mol), and the mixture was stirred at r.t for 30 min. Then the mixture was washed with water (200 mL*4), extracted with EtOAc, dried over Na2SO4, concentrated in vacuo. The residue was purified via chromatography (petrol ether) to give 2-bromo-6-nitrobenzyl (2E)-but-2-en-1-yl ether. 1H-NMR (400 MHz, CDCl3) δ 7.76 (d, J=8.0 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.25˜7.30 (m, 1H), 5.68˜5.77 (m, 1H), 5.51˜5.58 (m, 1H), 4.82 (s, 2H), 1.69 (d, J=6.0 Hz, 3H).
Reaction SMILES: [N+:1]([CH:3]([CH3:11])[C:4]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5])#[C-:2].C(C(CCCC)CN(CC(CC)CCCC)CC(CC)CCCC)C>>[CH3:11][C:3]1[N:1]=[CH:2][O:5][C:4]=1[O:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: [C-]#[N+]C(C)C(=O)OCCCC
Agent: CCCCC(CC)CN(CC(CC)CCCC)CC(CC)CCCC
Product: CCCCOc1ocnc1C

Procedure:
Example 3 was repeated, except that a mixture of 13.14% by weight of n-butyl α-isocyanopropionate and 86.86% by weight of tris(2-ethylhexyl)amine was continuously added via inlet (A).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[CH3:14][N:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]#[N:21]>>[CH3:10][C:9]([CH3:12])([CH3:11])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:19]2[N:15]([CH3:14])[C:16]([C:20]#[N:21])=[CH:17][CH:18]=2)=[CH:3][CH:4]=1)=[O:13]
Reactant: CC(C)(C)C(=O)c1ccc(Br)cc1
Reactant: Cn1cccc1C#N
Product: Cn1c(C#N)ccc1-c1ccc(C(=O)C(C)(C)C)cc1

Procedure:
The title compound was prepared from 1-(4-bromophenyl)-2,2-dimethylpropan-1-one and 1-methyl-2-cyanopyrrole according to the coupling procedure described in example 1. MS m/z 267; HRMS: calcd for C17H18N2O+H+, 267.14919; found (ESI, [M+H]+), 267.1494.
Reaction SMILES: [F:1][CH:2]([F:14])[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.[Br:15]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:15][C:4]1[CH:5]=[C:6]([C:10]([O:12][CH3:13])=[O:11])[C:7](=[O:9])[NH:8][C:3]=1[CH:2]([F:1])[F:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C(F)F)[nH]c1=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(C(F)F)[nH]c1=O
Reaction time: 2 h

Procedure:
4.1 g (20 mmol) of methyl 6-(difluoromethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate were dissolved in 20 ml of N,N-dimethylformamide, and 5.35 g (30 mmol) of N-bromosuccinimide were added at room temperature. After 2 hours of stirring, the reaction mixture was added to water and extracted with tert-butyl methyl ether. The extract was subsequently washed repeatedly with water. Drying and concentration finally gave 3.7 g (65% of theory) of the product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([CH2:20][CH:21]=O)[CH:16]=[CH:17][C:18]=1[F:19].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH:10][CH2:21][CH2:20][C:15]1[CH:16]=[CH:17][C:18]([F:19])=[C:13]([F:12])[CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=CCc1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCNCCc1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
To a solution of tert-butyl-N-(2-aminoethyl)carbamate (718 mg, 4.5 mmol) in MeOH (40 mL) at 0° C., under nitrogen, was added (3,4-difluorophenyl)acetaldehyde (0.7 g, 4.5 mmol) in MeOH (10 mL), acetic acid (0.78 mL, 13.5 mmol) and sodium cyanoborohydride (564 mg, 9.0 mmol). After stirring at 0° C. for 15 min the cooling bath was removed and the mixture stirred at room temperature for 3 h. Saturated K2CO3 solution (50 mL) was added and the mixture stirred for a further 15 min. The solvents were removed in vacuo and the residue partitioned between water (50 mL) and EtOAc (2×50 mL). The combined organic layers were dried (Na2SO4), and evaporated. The residue was chromatographed on silica gel, eluting with CH2Cl2 :MeOH:NH3 (90:10:1) to give the amine (473 mg, 35%) as a yellow oil. 1H NMR (250 MHz, CDCl3) δ 1.44 (9H, s), 2.72-2.78 (4H, m), 2.83-2.90 (2H, m), 3.18-3.28 (2H, m), 4.87 (1H, br s), 6.87-7.13 (3H, m). MS (ES+) (301, M+1).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27](Cl)=[N:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CC(C)([O-])C.[K+].C(O)(C)(C)C.[Cl:42][C:43]1[CH:48]=[C:47]([CH2:49][OH:50])[CH:46]=[CH:45][N:44]=1>CO>[F:29][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([O:50][CH2:49][C:47]4[CH:46]=[CH:45][N:44]=[C:43]([Cl:42])[CH:48]=4)=[N:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nccnc2Cl)CC1
Reactant: OCc1ccnc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CO
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nccnc2OCc2ccnc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 21 %

Procedure:
To a solution of 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide (115 mg, 0.254 mmol) and 1M solution of potassium tert-butoxide in tert-butanol (0.80 mL, 0.80 mmol) was added 2-Chloro-4-pyridinemethanol (81.8 mg, 0.568 mmol). The resulting suspension was stirred at room temperature for 15 h. The crude reaction mixture was diluted with methanol and purified by preparative HPLC (50 mM NH4OAc(aq), Acetonitrile system). The product was isolated by lyophilization of pure fractions yielding N-[3,5-bis(trifluoromethyl)phenyl]-4-(3-{[(2-chloropyridin-4-yl)methyl]oxy}pyrazin-2-yl)piperazine-1-carboxamide (29.9 mg, 21% yield). 1H NMR (CDCl3) 8.41 (d, 1H), 7.91 (s, 2H), 7.82 (d, 1H), 7.61 (d, 1H), 7.54 (s, 1H), 7.39 (s, 1H), 6.70 (s, 1H), 5.47 (s, 2H), 3.70-3.65 (m, 8H) ppm.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:10]([CH3:23])=[C:11]([CH3:22])[C:12]3[O:17][C:16]([CH3:19])(O)[CH2:15][CH2:14][C:13]=3[C:20]=2[CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:24]>CCOCC>[Cl:24][C:16]1([CH3:19])[CH2:15][CH2:14][C:13]2[C:20]([CH3:21])=[C:9]([O:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:10]([CH3:23])=[C:11]([CH3:22])[C:12]=2[O:17]1
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(O)O2
Reactant: Cl
Solvent: CCOCC
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(Cl)O2
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
To a solution of 5 g (16 mmol) of rac-3,4-dihydro-6-(phenylmethoxy)-2,5,7,8-tetramethyl-2H-1-benzopyran-2-ol in 50 mL of anhydrous ether was added 5 g of 4 A molecular sieves. The mixture was stirred mechanically with ice-bath cooling while HCl gas was bubbled in for 30 min. Stirring was continued at 0° C. for 30 min and then the solvent was removed in vacuo. The residue was treated with 500 mL of hexane and the solution was decanted. The hexane solution was then treated with 10 g of anhydrous CaCl2 and the mixture stirred for 2 hr. The solids were filtered and the filtrate was concentrated in vacuo to a volume of ca. 20 mL. Crystallization was induced by cooling to -10° C. and stirring, then the remaining solvent was removed in vacuo giving 4.9 g (92.8% yield) of rac-2-chloro-3,4-dihydro-2,5,7,8-tetramethyl-6-(phenylmethoxy)-2H-1-benzopyran as a colorless solid. The chlorochroman decomposed upon attempted column or thin layer chromatography. It was stored at 0° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[NH:10]N.[CH2:12]1[CH2:19][C:17](=O)[C:15](=[O:16])[CH2:14][CH2:13]1>CO.CC(O)=O.Cl>[Cl:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]2[C:4]=1[NH:10][C:14]1[C:15](=[O:16])[CH2:17][CH2:19][CH2:12][C:13]2=1
Reactant: O=C1CCCCC1=O
Reactant: NNc1ccc(F)cc1Cl
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: O=C1CCCc2c1[nH]c1c(Cl)cc(F)cc21
Temperature: 60 °C
Reaction time: 12 h
Yield: 56.1 %

Procedure:
To 2-chloro-4-fluoro phenyl hydrazine hydrochloride (0.3 g, 1.5 mmol) in MeOH (2.5 mL), a solution of 1,2-cyclohexadione (0.17 g, 1.5 mmol) in AcOH (2.5 mL) and conc. HCl (1 mL) were added. The resulting mixture was stirred at 60° C. for 12 h, then cooled to room temperature and MeOH was removed in vacuo. Water (25 mL) was added and the reaction mixture was basified with NaHCO3 (pH 8). The crude residue was extracted with EtOAc (2×30 mL). The combined organic extracts were washed with water (50 mL), dried over Na2SO4 and concentrated in vacuo to give the crude material which was purified by silica gel chromatography [EtOAc-hexane (1:19) as eluant] to afford the title compound (0.2 g, 55%). 1H NMR (200 MHz, CDCl3, δ in ppm) 8.84 (bs, 1H), 7.26-7.17 (m, 2H), 2.99-2.93 (t, J=6.0 Hz, 2H), 2.70-2.64 (q, J=7.4, 5.8 Hz, 2H), 2.34-2.21 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([OH:17])[CH2:15][CH:14]2[NH:16][CH:11]([CH2:12][CH2:13]2)[CH2:10]1.[CH3:18][O:19][C:20]1[C:25]2[O:26][C@H:27]([CH2:30]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:28][O:29][C:24]=2[CH:23]=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[C:25]2[O:26][C@@H:27]([CH2:30][N:16]3[CH:11]4[CH2:12][CH2:13][CH:14]3[CH2:15][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])([OH:17])[CH2:10]4)[CH2:28][O:29][C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: COc1cccc2c1O[C@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Reactant: COc1ccccc1C1(O)CC2CCC(C1)N2
Product: COc1ccccc1C1(O)CC2CCC(C1)N2C[C@H]1COc2cccc(OC)c2O1
Yield: 70 %

Procedure:
The title compound was prepared by the same procedure described in Example 1, Step 4 using 3-(2-methoxyphenyl)-8-azabicyclo[3.2.1]octan-3-ol in place of 3-naphthalen-2-yl-8-aza-bicyclo[3.2.1]octan-3-ol, and (S)-toluene-4-sulfonic acid 8-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester in place of (S)-toluene-4-sulfonic acid 8-ethoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester. Yield: 70%, white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[Na+].[I-].[CH3:19][NH2:20]>>[CH3:19][NH:20][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCl)CC1
Reactant: CN
Agent: [I-]
Agent: [Na+]
Product: CNCCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
Into a 50-mL sealed tube, was placed tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate (300 mg, 1.21 mmol, 1.00 equiv), methylamine (in ethanol) (10 mL), and NaI (100 mg). The resulting solution was stirred for 12 h at 70° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 3 mL of water and adjusted to pH 7-8 with sodium bicarbonate (5%). The resulting solution was extracted with 2×5 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 1×3 mL of water and 1×3 mL of brine. The resulting mixture was concentrated under vacuum. This resulted in 180 mg (crude) of tert-butyl 4-(2-(methylamino)ethyl)piperazine-1-carboxylate as brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.Cl[C:15]1[C:19]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=2[S:17](=[O:26])(=[O:25])[N:16]=1.C(#N)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:15]2[C:19]3[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=3[S:17](=[O:25])(=[O:26])[N:16]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1CCCCN
Reactant: O=S1(=O)N=C(Cl)c2cc(Cl)ccc21
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: Cc1cc(Br)cnc1CCCCNC1=NS(=O)(=O)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a refluxing solution of 4-(5-bromo-3-methyl-2-pyridinyl)butylamine (300 mg, 1.23 mmol) in chloroform (20 ml, purified as in previous example) was added over 10 minutes a solution of 3,5-dichloro-1,2-benzisothiazole 1,1-dioxide (U.S. Pat. No. 4,490,527) (400 mg, 1.69 mmol) in chloroform (20 ml)/acetonitrile (10 ml). Since a precipitate formed during the addition, another 10 ml of acetonitrile was added to give almost complete solution. Heating at 65°-70° C. was continued for 60 minutes giving a slightly cloudy mixture. Cooling to room temperature, filtration and evaporation of the filtrate in vacuo gave a solid residue. Recrystallization from methanol/methylene chloride/2-propanol gave 0.410 g of the title compound as an off-white solid hydrochloride: m.p. 231°-235° C., IR(KBr) 3005, 2500 (broad), 1620, 1278, 1160 cm-1. 1H NMR (Me2SO-d6) 9.87 (1H, t), 8.68 (1H, s), 8.60 (1H, s), 8.25 (1H, s), 7.90 (2H, m), 3.42 (2H, m), 2.83 (2H, m), 2.37 (3H, s), 1.68 (4H, m).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C(=O)N([I:25])C(=O)C1>CN(C)C=O>[Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[I:25])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ncc2c1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]nc(I)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of 5-[(tert-butyldimethylsilyl)oxy]-1H-indazole (13 g, 52.34 mmol, 1.00 equiv) in N,N-dimethylformamide (550 mL) maintained under nitrogen was added NIS (28.6 g, 104.76 mmol, 2.00 equiv) in portions. The reaction mixture was stirred at room temperature overnight and then concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-10% of ethyl acetate in petroleum ether to give 19.2 g (98%) of 5-(tert-butyldimethylsilyloxy)-3-iodo-1H-indazole as an off-white solid. 1H NMR (300 MHz, CDCl3): δ 7.50-7.45 (m, 1H), 7.09 (dd, J=9.0 Hz, 2.1 Hz, 1H), 6.98-6.70 (m, 1H), 1.10 (s, 9H), 0.24 (s, 6H) ppm. LCMS (method A, ESI): RT=1.80 min, m/z=374.9 [M+H]+.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[OH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:23][OH:24].[OH-].[K+]>O.O1CCCC1>[OH:24][CH2:23][C:10]1[C:9](=[O:8])[C:18]2[C:13](=[CH:14][C:15]([C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=2)[N:12]([CH3:5])[CH:11]=1
Reactant: OCc1cnc2cc(C(F)(F)F)ccc2c1O
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(CO)c(=O)c2ccc(C(F)(F)F)cc21
Reaction time: 3 h

Procedure:
Dimethyl sulphate (24.4 g.) was added over 5 minutes to a stirring solution of 4-hydroxy-3-hydroxymethyl-7-trifluoromethylquinoline (23.6 g.) and potassium hydroxide (16.3 g.) in a mixture of water (50 ml.) and tetrahydrofuran (50 ml.) at room temperature. After stirring for a further 3 hours at this temperature the solid product was collected. The filtrate was extracted with dichloromethane (3×200 ml.). The combined extracts were dried over anhydrous magnesium sulphate and evaporated to give a second crop of the solid. The combined solids were purified by high pressure liquid chromatography over silica gel, eluting with isopropanol: dichloromethane 10:90 at a flow rate of 200 ml. per minute. The same solvent was used for applying the product to silica gel. This procedure gave the novel 3-hydroxymethyl-1-methyl-7-trifluoromethyl-4-quinolone, m.p. 172°-175°.