Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH:13]=O)=[O:9])[CH2:4][CH2:3]1.[CH2:18]([CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([CH:25]1[CH2:30][CH2:29][N:28]([CH2:13][C:12]2[CH:11]=[C:10]([C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:9])[CH:17]=[CH:16][CH:15]=2)[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN1CCN(C(=O)c2cccc(C=O)c2)CC1
Reactant: c1ccc(CC2CCNCC2)cc1
Product: CN1CCN(C(=O)c2cccc(CN3CCC(Cc4ccccc4)CC3)c2)CC1

Procedure:
Prepared from the product of Example 17 and 4-benzylpiperidine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
On the other hand, 4-fluorobenzoic acid (0.01 mol) (1.4 g) was reacted with thionyl chloride (10 ml) at 60° C. for 30 minutes and then at 80° C. for 2 hours to obtain a uniform solution, which was then allowed to stand for one hour, followed by distilling off excess thionyl chloride to obtain 4-fluorobenzoyl chloride as residue.
Reaction SMILES: [F:1][C@@H:2]1[C@H:6]([N:7]=[N+]=[N-])[C@@H:5]([CH2:10][O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:4][C@H:3]1[N:20]1[CH:27]=[CH:26][C:24](=O)[NH:23][C:21]1=[O:22].[C:28]([NH:36]C1C=CN([C@@H]2O[C@H](CO[Si](C(C)(C)C)(C)C)[C@@H](NC(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)C2)C(=O)N=1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.N1C=CC(=O)NC1=O.N1C=CC(N)=NC1=O>>[C:28]([NH:36][C:24]1[CH:26]=[CH:27][N:20]([C@@H:3]2[O:4][C@H:5]([CH2:10][O:11][C:12](=[O:19])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C@@H:6]([NH2:7])[C@H:2]2[F:1])[C:21](=[O:22])[N:23]=1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(NC(=O)c3ccccc3)nc2=O)C[C@@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=N[C@H]1[C@@H](F)[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COC(=O)c1ccccc1
Agent: Nc1cc[nH]c(=O)n1
Agent: O=c1cc[nH]c(=O)[nH]1
Product: N[C@H]1[C@@H](F)[C@H](n2ccc(NC(=O)c3ccccc3)nc2=O)O[C@@H]1COC(=O)c1ccccc1

Procedure:
Crude intermediate 10 was used for preparation of the appropriately protected cytidine phosphoramidite 2c as shown in Scheme VI below. The uracil base of 10 was converted to cytosine by adaptation of the method of Divakar and Reese, J. Chem. Soc., Perkin. Trans. 1 1982, 1171-1176. Subsequent 4-N benzoylation and reduction of the 3'-azido to an amino group gave compound 13, which was separable from its regioisomer by silica gel chromatography. Protection of the 3'-amine with an MMT group, followed by selective 5'-O-debenzoylation produced intermediate 15. Subsequent 5'-phosphitylation lead to desired phosphoramidite 2c in a 10% overall yield based on anhydronucleoside 8. ##STR12## More particularly, the steps were carried out as follows: N4,5'-O-dibenzoyl-2'-fluoro-3'-amino-2',3'-dideoxycytidine 13 was prepared as follows: To 6.9 g (18.4 mmol) of crude 10 (containing 35% 10i) in 50 mL anhydrous CH3CN was added an ice-cold solution of 11.7 g (169 mmol) 1,2,4-triazole and 3.35 mL (36.1 mmol) POCl3 in 90 mL anhydrous CH3CN. The mixture was cooled in an ice bath and anhydrous triethylamine (23 mL, 165 mmol) was added, then the reaction allowed to warm to room temperature with stirring. After 90 min, 15 mL (108 mmol) triethylamine and 4 mL water were added and the mixture stirred for 10 min. The solvent was removed in vacuo, then 250 mL ethyl acetate was added, and the solution was TLC indicated a fluorescent intermediate with the same mobility as the starting material.
Reaction SMILES: [C:1](/[C:4](/[CH3:29])=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:15])[CH:10]=[C:9]2[CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]=1[O:27][CH3:28])([OH:3])=[O:2]>[Pd].O1CCCC1>[C:1]([CH:4]([CH3:29])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:15])[CH:10]=[C:9]2[CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]=1[O:27][CH3:28])([OH:3])=[O:2]
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(/C=C(\C)C(=O)O)cc23)c(OC)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(CC(C)C(=O)O)cc23)c(OC)c1
Reaction time: 4 h
Yield: 91.8 %

Procedure:
Palladium on carbon (10% w/w, 0.3 g) was added to a solution of methyl E-4-[5-(2-carboxy-1-propenyl)-1-methylindol-3-ylmethyl]-3-methoxybenzoate (4.14 g) in redistilled tetrahydrofuran (75 ml) in a hydrogenation bottle. The mixture was hydrogenated at 2.7 bar for 4 hr. The catalyst was removed by filtration through diatomaceous earth, the filter pad was washed with tetrahydrofuran, and the filtrate evaporated. The residue was crystallized from methanol to give methyl 4-[5-(2-carboxypropyl)-1-methylindol-3-ylmethyl]-3-methoxybenzoate (3.82 g, 92%) as white crystals; mp 149°-151°; partial NMR (250 MHz, DMSO-d6) 1.0(d, CHCH3), 2.60(m, 2H, CHCH2Ar), 3.34(m, 1H, CHCH2), 3.67(s, 3H), 3.83(s, 3H), 3.91(s, 3H), 3.99(s, 2H, ArCH2Ar'), 12.05(s, 1H, COOH).
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].C([Li])CCC.CCCCCC.[Cl:19][C:20](=[CH2:29])[CH2:21][CH:22]([CH2:27][CH3:28])[C:23]([O:25][CH3:26])=[O:24].C(I)C>C1COCC1>[Cl:19][C:20](=[CH2:29])[CH2:21][C:22]([CH2:1][CH3:2])([CH2:27][CH3:28])[C:23]([O:25][CH3:26])=[O:24]
Reactant: CC(C)NC(C)C
Reactant: C=C(Cl)CC(CC)C(=O)OC
Agent: [Li]CCCC
Solvent: CCI
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C(Cl)CC(CC)(CC)C(=O)OC
Reaction time: 0.75 h

Procedure:
To a cold solution (0° C.) of diisopropylamine (0.80 mL, 5.7 mmol) in THF (5 mL) was added a 1.6M solution of butyllithium in hexane (3.4 mL, 5.4 mmol) over a 5 minute period and stirring was continued for an additional 45 min. Then a solution of methyl 4-chloro-2-ethyl-4-pentenoate (800 mg, 5 mmol) from Example 27, Step A, in THF (2 mL) was added and the reaction was stirred at 0° C. for another 30 minutes. Then ethyl iodide (440 μL, 5.5 mmol) was added and the reaction was allowed to proceed at room temperature for 2 hours. The reaction was quenched with NH4OAc buffer (50 mL of 25% w/v) and extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered and concentrated. The crude product was purified by Kugelrohr distillation (b.p. 120° C. at 0.1 mm Hg) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.O1CCCC1.[NH:15]1[CH2:20][CH2:19][S:18](=[O:22])(=[O:21])[CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:15]2[CH2:20][CH2:19][S:18](=[O:22])(=[O:21])[CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCNCC1
Reactant: O=Cc1ccc(Br)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S1(=O)CCN(Cc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-bromobenzaldehyde (150 mg, 0.811 mmol) was placed in a flask that was subsequently evacuated and backfilled with nitrogen (3×). Tetrahydrofuran (8107 μl) and thiomorpholine 1,1-dioxide (110 mg, 0.811 mmol) were then added and the reaction was allowed to stir at room temperature for 1 hour. Sodium triacetoxyborohydride (258 mg, 1.216 mmol) was weighed and quickly added to the solution (flask was uncapped during addition). The reaction was stirred at room temperature overnight. The reaction was diluted in ethyl acetate and washed with aqueous sodium bicarbonate. The organic layer was extracted and the aqueous layer was extracted 3× with ethyl acetate. All organics were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was purified via HPLC to yield the title compound. LRMS (APCI) calc'd for C11H15BrNO2S [M+H]+: 304. Found: 304.
Reaction SMILES: [ClH:1].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:14][S:13][C:12]3=[N:15][CH:16]=[C:17]([C:18]([OH:20])=O)[N:11]23)=[CH:6][CH:5]=1)#[N:3].Cl.[C:22]1([S:28]([CH2:31][CH2:32][NH2:33])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>>[ClH:1].[C:22]1([S:28]([CH2:31][CH2:32][NH:33][C:18]([C:17]2[N:11]3[C:12]([S:13][CH2:14][CH:10]3[C:7]3[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:9][CH:8]=3)=[N:15][CH:16]=2)=[O:20])(=[O:29])=[O:30])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: N#Cc1ccc(C2CSc3ncc(C(=O)O)n32)cc1
Reactant: NCCS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(C2CSc3ncc(C(=O)NCCS(=O)(=O)c4ccccc4)n32)cc1
Reaction time: 0.25 h

Procedure:
The carboxylic acid from Step D (60.0 mg, 0.188 mmol), amine from Step G (41.6 mg, 0.188 mmol), EDC hydrochloride (43.2 mg, 0.225 mmol), HOBT (30.4 mg, 0.225 mmol), and N,N-diisopropylethylamine (0.163 mL, 0.938 mmol) were stirred in dry, degassed DMF (1 mL) at 25° C. for 16 hours. The crude product was purified by preparative HPLC using a gradient of 5%-95% acetonitrile/0.1% TFA; 95%-5%/0.1% aqueous TFA over 15 min. The title compound was isolated after conversion to the HCl salt. MS (es) m+1=439. 1H-NMR (CD3OD): δ7.87 (d, 2H, J=7.8 Hz); 7.71 (d, 2H, J=8.5 Hz); 7.70 (t, 1H, J=7.8 Hz); 7.59 (t, 2H, J=7.7 Hz); 7.49 (s, 1H); 7.17 (d, 2H, J=8.0 Hz); 6.24 (bd, 1H, J=7.7 Hz); 4.64 (dd, 1H, J=12.3, 8.9 Hz); 3.74 (d, 1H, J=12.3 Hz), 3.28-3.57 (m, 4H).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([CH:18]=O)[CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CC(O)=O>[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][NH:10][C@@H:8]2[CH2:9][C@H:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:14][CH2:13]1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: CN1CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CN1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.1 %

Procedure:
A mixture of [trans-2-phenylcyclopropyl]amine (540 mg, 4.05 mmol), 1-methyl-4-piperidinecarbaldehyde (506 mg, 3.98 mmol) and AcOH (1 mL, 0.017 mmol) in chloroform (15 mL) was stirred at room temperature for 18 hours. Sodium triacetoxyborohydride (947 mg, 4.47 mmol) was added and stirring continued for 18 hours. Upon completion, saturated NaHCO3 was added to the reaction mixture and the mixture was extracted with THF—CHCl3 (2×50 mL). The organics were combined, dried over Na2SO4 and concentrated. The residue was adsorbed onto silica and purified via column chromatography on the ISCO Companion (gradient 0-100% 80:20:2 [CHCl3/MeOH/NH4OH]/CHCl3; 40 g column) to obtain pure final compound (166 mg, 13% yield) as an off white solid: LC-MS (ES) m/z=245 (M+H)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.17-7.27 (m, 2H), 7.06-7.15 (m, 1H), 6.97-7.06 (m, 2H), 2.64-2.77 (m, 2H), 2.41-2.49 (m, 2H), 2.27 (br. s., 1H), 2.18 (ddd, J=3.28, 4.23, 7.14 Hz, 1H), 2.08-2.15 (m, 3H), 1.70-1.83 (m, 2H), 1.57-1.70 (m, 2H), 1.30 (ddd, J=4.29, 7.26, 10.93 Hz, 1H), 1.01-1.16 (m, 2H), 0.86-0.98 (m, 2H).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:27])([F:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[NH:22][N:21]=[C:20]([C:23]([OH:25])=O)[CH:19]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:50][CH2:51][C:52]([N:54]1[CH2:59][CH2:58][N:57]([C:60](=[O:72])[C:61]2[CH:66]=[C:65]([F:67])[CH:64]=[CH:63][C:62]=2[C:68]([F:71])([F:70])[F:69])[CH2:56][CH2:55]1)=[O:53]>CN(C=O)C.O>[F:67][C:65]1[CH:64]=[CH:63][C:62]([C:68]([F:70])([F:69])[F:71])=[C:61]([CH:66]=1)[C:60]([N:57]1[CH2:58][CH2:59][N:54]([C:52](=[O:53])[CH2:51][NH:50][C:23]([C:20]2[CH:19]=[C:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11]([F:10])([F:27])[F:26])[NH:22][N:21]=2)=[O:25])[CH2:55][CH2:56]1)=[O:72]
Reactant: NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Reactant: O=C(O)c1cc(-c2ccccc2C(F)(F)F)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)c1cc(-c2ccccc2C(F)(F)F)[nH]n1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 36.9 %

Procedure:
DIPEA (124 mg, 0.16 mL, 0.95 mmol) was added to a stirred solution of 5-(2-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid (70 mg, 0.27 mmol) in DMF (2 mL). HOBT (43 mg, 0.31 mmol) and EDCI (60 mg, 0.31 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (101 mg, 0.27 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, filtered the solid precipitate. The solid was purified by dissolving in DCM and washed with 1.2N HCl. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 57 mg (36.77% yield) of 5-(2-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 93.30%. 1H NMR (DMSO-d6): δ 13.6 (s, 1H), 8.1 (m, 1H), 7.9 (m, 2H), 7.5 (m, 21H), 7.5 (m, 6H), 6.79 (s, 1H), 4.1 (d, 2H), 3.5 (m, 7H), 3.0 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N:19]1([C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[C:34]=2[N:33]=[CH:32][CH:31]=[CH:30]3)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH:15]([N:22]3[CH2:23][CH2:24][N:19]([C:25]4[CH:26]=[CH:27][CH:28]=[C:29]5[C:34]=4[N:33]=[CH:32][CH:31]=[CH:30]5)[CH2:20][CH2:21]3)[CH2:14][CH2:13]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: c1cnc2c(N3CCNCC3)cccc2c1
Reactant: O=C1CCN(c2ccc(F)c3cccnc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: Fc1ccc(N2CCC(N3CCN(c4cccc5cccnc45)CC3)CC2)c2ncccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 138.3 %

Procedure:
To a solution of 0.120 g of 1-(5-fluoro-quinolin-8-yl)-piperidin-4-one (Step 3, 0.22 g) and 8-piperazin-1-ylquinoline (Oruz, et al., J. Med. Chem. 45:4128 (2002), 0.19 g) was added of 0.19 g sodium triacetoxyborohydride and 0.1 mL acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2Cl2. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 75 ml of silica gel using 100% Ethyl acetate, to give 0.30 g of the desired product. Mp: 224° C.; MS (ES) m/z (relative intensity): 442 (M++−H, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([OH:19])[C:13]=1[OH:20])=[O:11].[C:21]1(C)C=C(C)C=C(C)C=1Cl>CN(C=O)C>[OH:18][C:15]1[C:14]([OH:19])=[C:13]2[C:12]([C:10](=[O:11])[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[CH:21][O:20]2)=[CH:17][CH:16]=1
Reactant: COc1ccccc1CC(=O)c1ccc(O)c(O)c1O
Reactant: Cc1cc(C)c(Cl)c(C)c1
Solvent: CN(C)C=O
Product: COc1ccccc1-c1coc2c(O)c(O)ccc2c1=O
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 24.6 %

Procedure:
BF3—OEt2 complex (7 ml, 56 mmol) was gradually added to a solution of 2-(2-methoxy-phenyl)-1-(2,3,4-trihydroxy-phenyl)-ethanone (3.8 gm, 14 mmol) in DMF at 0° C. The resulting solution was stirred for 30 min. Mesityl chloride (1.5 ml, 42 mmol) was then gradually added to it at 50° C. The solution was then heated up to 110° C. for 5 hours. The mixture was then concentrated. The residue was treated with ice and the solid obtained was purified with silica gel column chromatography using hexane-chloroform as the eluent to give 7,8-dihydroxy-3-(2-methoxy-phenyl)-chromen-4-one (0.98 gm, 25%) as white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[NH:10][S:9]1(=[O:19])=[O:18].[Br:20][CH:21](CC)[CH2:22]O>>[Br:20][CH2:21][CH2:22][N:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[CH2:13][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[S:9]1(=[O:19])=[O:18]
Reactant: CCC(Br)CO
Reactant: O=S1(=O)Nc2ccccc2CN1c1ccccc1F
Product: O=S1(=O)N(c2ccccc2F)Cc2ccccc2N1CCBr
Yield: 48.3 %

Procedure:
In an analogous manner to example 25, step 4, 3-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.24 g, 0.86 mmol) was treated with 2-bromobutanol (0.073 mL g, 1.0 mmol) to give 1-(2-bromoethyl)-3-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.16 g, 48%).
Reaction SMILES: N#N.[CH3:3][O:4][C:5]([C:7]1[O:8][C:9]([CH2:12][N:13]2[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[N:14]2)=[CH:10][CH:11]=1)=[O:6]>CO.[Pd]>[CH3:3][O:4][C:5]([C:7]1[O:8][C:9]([CH2:12][N:13]2[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]2)=[CH:10][CH:11]=1)=[O:6]
Reactant: COC(=O)c1ccc(Cn2cc([N+](=O)[O-])cn2)o1
Agent: [Pd]
Agent: N#N
Solvent: CO
Product: COC(=O)c1ccc(Cn2cc(N)cn2)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(4-nitro-pyrazol-1-ylmethyl)-furan-2-carboxylic acid methyl ester (4.45 g, 17.7 mmol) in MeOH (100 mL) was treated with Pd/C (445 mg, 10% Pd). The N2 atmosphere was replaced by an H2 atmosphere (H2 balloon) and the reaction mixture was stirred at rt for 4 h before being filtered through Celite and the solvent was removed under reduced pressure to give the title compound as an oil. LC-MS-conditions 02: tR=0.50 min; [M+H]+=222.27. 1H NMR (400 MHz, DMSO-d6) 1H NMR 83.79 (s, 3H), 3.88 (s, 2H), 5.24 (s, 2H), 6.54 (d, J=3.3 Hz, 1H), 6.96 (s, 1H), 7.08 (s, 1H), 7.25 (d, J=3.5 Hz, 1H).
Reaction SMILES: [C:1](#[N:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:10]1[CH:14]2[CH2:15][C:16](=O)[CH:12]([CH2:13]2)[CH2:11]1.C([N-]C(C)C)(C)C.[Li+]>C1C=CC=CC=1.O1CCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[NH2:9][C:1]1[C:2]2[C:3]([N:4]=[C:11]3[C:10]=1[CH:14]1[CH2:13][CH:12]3[CH2:16][CH2:15]1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: N#Cc1ccccc1N
Reactant: O=C1CC2CCC1C2
Agent: CC(C)[N-]C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Li+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: Nc1c2c(nc3ccccc13)C1CCC2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.4 %

Procedure:
A solution of anthranilonitrile (3.6 g, 30.0 mmole), norcamphor (3.3 g, 30.0 mmole) and para-toluenesulfonic acid (50 mg) in benzene (50 ml) was heated to reflux using a Dean Stark apparatus. After heating for 18 hours, the reaction mixture was then cooled (25° C.) and the separated water (about 1.5 ml) was withdrawn. The excess benzene was then removed under vacuum (1 mm Hg, 15 minutes). The oily residue thus obtained was dissolved in tetrahydrofuran (THF, 10 ml) and was cooled to 0° C. and a solution of lithium diisopropylamide in THF (1M, 36 ml, 36 mmole) was then added. This reaction mixture was then stirred at 0° C. for 3 hours. At the end of this period, the reaction mixture was quenched with 40 ml of water and was extracted with methylene chloride (200 ml). The resulting organic phase was washed with water (2×50 ml) and dried (anhydrous MgSO4). The methylene chloride was removed under vaccum to afford a residue which was loaded on a silica gel flash chromatography column. Elution with 5% methanol in methylene chloride containing 1% triethylamine afforded the title compound 1.6 g, 25%) as an oil which solidified on standing (m.p. 185°-186° C.). 1H-NMR (CDCl3, 300 MHz, δ): 2H, m, 1.22-1.42 ppm; 1H, d, 1.64 ppm (J=7.0 Hz); 1H, d, 1.86 ppm (J=6.0 Hz); 2H, m, 1.9-2.04 ppm; 2H, bd, 3.46 ppm; 2H, bs, 4.49 ppm; 1H, t, 7.38 ppm (J=6.0 Hz); 1H, t, 7.55 ppm (J=6.0 Hz); 1H, d, 7.67 ppm (J=6.0 Hz); 1H, d, 7.92 ppm (J=6.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[O:5][CH2:6][CH2:7][NH:8]C(=O)C.FC1C=CC(C(C2C=CC(F)=CC=2)OCCNC(=O)C)=CC=1.[C:45]([OH:52])(=[O:51])/[CH:46]=[CH:47]\[C:48]([OH:50])=[O:49].Cl>>[C:45]([OH:52])(=[O:51])/[CH:46]=[CH:47]\[C:48]([OH:50])=[O:49].[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[O:5][CH2:6][CH2:7][NH2:8]
Reactant: CC(=O)NCCOC(c1ccc(F)cc1)c1ccccc1Cl
Agent: CC(=O)NCCOC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Product: NCCOC(c1ccc(F)cc1)c1ccccc1Cl

Procedure:
Using the procedure described in Example IV but substituting an equivalent amount of N-{2-[o-chloro-α(p-fluorophenyl)benzyloxy]ethyl}acetamide for the N-{2-[bis(p-fluorophenyl)methoxy]ethyl}acetamide and maleic acid for the hydrogen chloride, there is obtained 2-[o-chloro-α-(p-fluorophenyl)benzyloxy]ethylamine hydrogen maleate, which is crystallised from ethanol. Its melting point is 123°-123.5° C.
Reaction SMILES: C1(C([C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)=[CH:10][S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=O)CCCCC1.[CH3:26][O:27][C:28](=[O:33])/[CH:29]=[C:30](\[NH2:32])/[CH3:31]>C(O)(C)C>[CH3:26][O:27][C:28](=[O:33])[C:29]1[CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:10]([S:11](=[O:13])(=[O:12])[N:14]([CH3:16])[CH3:15])=[C:9]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[NH:32][C:30]=1[CH3:31]
Reactant: CN(C)S(=O)(=O)C=C(C(=O)C1CCCCC1)c1cccc([N+](=O)[O-])c1
Reactant: COC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C2CCCCC2)=C(S(=O)(=O)N(C)C)C1c1cccc([N+](=O)[O-])c1
Yield: 64.7 %

Procedure:
A solution of 3.67 g (0.01 mol) of α-(cyclohexyl- carbonyl)-N,N-dimethyl-3 -nitrostyrenesulfonamide in 30 ml of isopropanol is treated with 1.15 g (0.01 mol) of 3-aminocrotonic acid methyl ester and 1.16 g (0.005 mol) of DL-camphor-10-sulfonic acid in accordance with the procedure described in Example 1. After chromatography on silica gel with methylene chloride/ethyl acetate (9:1) as the elution agent the crude product is recrystallized from acetonitrile. There are obtained 1.5 g (32%) of 6-cyclohexyl-5-(dimethylsulfamoyl)-1,4 -dihydro-2-methyl-4-(3-nitrophenyl)nicotinic acid methyl ester, m.p 185°-188°, as a colorless crystalline powder.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])[C:3]=1[CH3:30].[CH3:31][N:32]([CH2:34][C:35]#[CH:36])[CH3:33].C1COCC1.CCO>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O>[C:26]([O:25][CH:19]([C:4]1[C:3]([CH3:30])=[C:2]([C:36]#[C:35][CH2:34][N:32]([CH3:33])[CH3:31])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:20]([OH:22])=[O:21])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)c(Br)c2ccccc2c1-c1ccc(Cl)cc1
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1C#CCN(C)C
Temperature: 100 °C
Yield: 17.9 %

Procedure:
A solution of ethyl 2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate (40 mg, 81.7 μmol), N,N-dimethylpropargylamine (26 μL, 0.245 mmol), PdCl2(PPh3)2 (5.7 mg, 16.3 μmol), CuI (3.1 mg, 16.3 μmol) and THF (1.00 mL) was heated to 70° C. for 18 h in a sealed vessel. Conversion was incomplete, so the vessel was charged with more PdCl2(PPh3)2 (5.7 mg, 16.3 μmol) and CuI (3.1 mg, 16.3 μmol) and heated to 100° C. for an additional 26 h. The reaction was cooled to 23° C. THF (1.0 mL), EtOH (absolute, 500 μL), and H2O (500 μL) were added followed by LiOH monohydrate (100 mg, 2.37 mmol). The reaction was heated to 100° C. for 4 h. After cooling to 23° C., the crude reaction was filtered through a 0.45 micron filter, and directly purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA). The product-containing fractions were combined and lyophilized, giving the title compound (mono trifluoroacetic acid salt) (6.8 mg, 15%). 1H NMR (400 MHz, DMSO-d6) δ 12.92 (s, broad, 1H), 10.26 (s, broad, 1H), 8.30 (d, J=8.6 Hz, 1H), 7.71-7.62 (m, 3H), 7.47-7.43 (m, 2H), 7.34 (d, J=8.2 Hz, 1H), 7.22 (d, J=8.6 Hz, 1H), 5.03 (s, 1H), 4.56 (s, 2H), 2.96 (s, 6H), 2.72 (s, 3H), 0.90 (s, 9H). 19F NMR (377 MHz, DMSO-d6) δ−74.1 (s) LCMS-ESI+ (m/z): [M+H]+ calcd for C28H31ClNO3: 464.2; Found: 464.0.