Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11](Cl)(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][C@H:16]1[CH2:21][NH:20][CH2:19][C@@H:18]([CH3:22])[NH:17]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:15][C@H:16]1[NH:17][C@@H:18]([CH3:22])[CH2:19][N:20]([S:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)(=[O:13])=[O:12])[CH2:21]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: O=[N+]([O-])c1ccc(CS(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(S(=O)(=O)Cc2ccc([N+](=O)[O-])cc2)C[C@H](C)N1
Yield: 89.7 %

Procedure:
A solution of 250 mg (1.06 mmol) of 4-nitrophenylmethanesulfonyl chloride and 133 mg (1.17 mmol) of cis-2,6-dimethylpiperazine in CH2Cl2 (10 mL) was treated with 325 μL (2.33 mmol) of triethylamine at RT for 20 min. The mixture was diluted with CH2Cl2 (15 mL) and washed with water (1×15 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to afford 298 mg (90%) of the title compound as an off-white solid: 1H-NMR (CDCl3; 400 MHz): δ 8.25 (d, 2H, J=8.8 Hz), 7.87 (d, 2H, J=8.8 Hz), 4.24 (s, 1H), 3.59-3.53 (m, 2H), 2.92-2.82 (m, 2H), 2.30-2.23 (m, 2H), 1.04 (d, 6H, J=6.0 Hz). Mass spectrum (ESI, m/z): Calcd. for C13H19N3O4S, 314.1 (M+H). found 314.1.
Reaction SMILES: BrC1C=CC(O)=CC=1N(CC)CC1C=CC(OCCN2CCCCC2)=C(F)C=1.[C:29]([N:32]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][CH2:53][N:54]2[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]2)=[C:47]([F:60])[CH:46]=1)[C:33]1[CH:34]=[C:35]([O:40][C:41](=[O:43])[CH3:42])[CH:36]=[CH:37][C:38]=1[Br:39])(=O)[CH3:30].C(OC(=O)C)(=O)C.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[Br:39][C:38]1[CH:37]=[CH:36][C:35]([O:40][C:41](=[O:43])[CH3:42])=[CH:34][C:33]=1[N:32]([CH2:29][CH3:30])[CH2:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][CH2:53][N:54]2[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59]2)=[C:47]([F:60])[CH:46]=1
Reactant: CC(=O)Oc1ccc(Br)c(N(Cc2ccc(OCCN3CCCCC3)c(F)c2)C(C)=O)c1
Agent: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(O)ccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(OC(C)=O)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
To the total amount of 4-bromo-3-{ethyl[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]amino}phenol crude product, which was synthesized from acetic acid 3-{acetyl-[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]amino}-4-bromophenyl ester (300 mg) synthesized according to an analogous synthetic method to Example 337 described below, were added pyridine (3 ml) and acetic anhydride (3 ml), and the solution was stirred overnight at room temperature. To reaction mixture was added a saturated aqueous solution of sodium bicarbonate, the solution was extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform-methanol system) to provide the title compound (200 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH2:20]([O:27][C:28](=[O:36])[CH2:29][C@@H:30]([NH2:35])[CH2:31][N:32]([CH3:34])[CH3:33])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:27][C:28](=[O:36])[CH2:29][C@@H:30]([NH:35][C:15](=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:31][N:32]([CH3:33])[CH3:34])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)CCCCCCCCc1ccccc1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: Cl
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCCc1ccccc1

Procedure:
The title compound, m/e=361.5 ([M−H]−), was produced in analogy with intermediate 1, steps 3 and 4. Thus, commercially available 9-phenylnonanoic acid was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-4-dimethylamino-3-(9-phenyl-nonanoylamino)-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>C1COCC1.CCOC(C)=O>[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH:40][S:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:10]3[N:9]=[C:8]([C:6]4[CH:5]=[C:4]([C:24]5[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=5)[CH:3]=[C:2]([CH3:1])[N:7]=4)[CH:13]=[CH:12][CH:11]=3)[CH:15]=2)(=[O:22])=[O:21])=[CH:37][CH:36]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NCc4ccc(F)cc4)c3)n2)n1
Yield: 46.6 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with commercially available 4-fluorobenzylamine (0.23 ml, 2.05 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.110 g, 46%) as a white solid. MS (ISP) 578.2 [(M+H)+]; mp 175° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([O:10][CH2:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[C:6]([CH3:9])=[N:7][CH:8]=1)=O.[NH2:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1>>[C:15]([C:14]1[CH:13]=[C:12]([CH:19]=[CH:18][CH:17]=1)[CH2:11][O:10][C:5]1[CH:4]=[C:3]([CH2:1][NH:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[CH:8]=[N:7][C:6]=1[CH3:9])#[N:16]
Reactant: Cc1ncc(C=O)cc1OCc1cccc(C#N)c1
Reactant: N#Cc1ccc(N)cc1
Product: Cc1ncc(CNc2ccc(C#N)cc2)cc1OCc1cccc(C#N)c1
Yield: 22.4 %

Procedure:
The reductive amination of 3-((5-formyl-2-methylpyridin-3-yloxy)methyl)benzonitrile (134) (300 mg, 1.2 mmol) and 4-aminobenzonitrile (422 mg, 3.6 mmol), as described in Example 21, gave 4-((5-(3-cyanobenzyloxy)-6-methylpyridin-3-yl)methylamino)benzonitrile (135) (95.24 mg, 22.58% yield).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([CH:12]=O)[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1([C:6]2[N:11]=[C:10]([CH:12]=[CH:22][CH:23]=[O:24])[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1cccc(-n2cccn2)n1
Product: O=CC=Cc1cccc(-n2cccn2)n1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 6-(1H-pyrazol-1-yl)-2-pyridinecarboxaldehyde (prepared as described in J. Med. Chem. 1998, 41, 5070) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.C([Li])CCC.[C:14]12([C:24](Cl)=[O:25])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2>C1COCC1.CCCCCC>[C:14]12([C:24]([O:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:25])[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:22]3)[CH2:15]1)[CH2:23]2
Reactant: OCc1cccnc1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(OCc1cccnc1)C12CC3CC(CC(C3)C1)C2
Yield: 77.8 %

Procedure:
The method followed that described in Example 1, but using 3-pyridylcarbinol (240 mg, 2.2 mmol) in THF (10 ml), n-butyllithium (2.5 M; 0.84 ml, 2.1 mmol) in hexane, and 1-adamantanecarbonyl chloride (397 mg, 2.0 mmol) in THF (2 ml). Chromatography, on elution with petrol-ether-triethylamine 200:50:1, gave the title compound (422 mg, 78%) as an oil. IR νmax 1728 cm-1 ; 1H-NMR (CDCl3) δ1.71 and 1.91 (12H, 2s, adamantyl CH2), 2.02 (3H, s, adamantyl CH), 5.11 (2H, s, OCH2), 7.30 (1H, m, Py 5-H), 7.66 (1H, m, Py 4-H), 8.56 (1H, m. Py 6-H), 8.61 (1H, m, Py 2-H). Anal. Calcd: C, 75.24; H, 7.80; N, 5.16. Found: C, 75.09; H, 7.84; N, 5.03%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[NH:13][C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[N:13]=[C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]2[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COc1ccc(OC)c(Sc2nc3c(N)ncnc3[nH]2)c1
Product: COc1ccc(OC)c(Sc2nc3c(N)ncn(Cc4ccc(F)cc4)c-3n2)c1
Yield: 34 %

Procedure:
The title compound was prepared from 8-(2,5-dimethoxy-phenylsulfanyl)-9H-purin-6-ylamine and 1-bromomethyl-4-fluoro-benzene by a procedure similar to examples 1 and 2. The compound was purified by preparative HPLC. 8-(2,5-Dimethoxy-phenylsulfanyl)-3-(4-fluoro-benzyl)-3H-purin-6-ylamine: Yield 34%, 1H NMR (DMSO-d6) δ 8.55 (s, 1H), 8.1 (bs, 2H), 7.51 (m, 2H), 7.15 (m, 2H), 6.97 (m, 2H), 6.76 (dd, J=8.8, 2.8 Hz, 1H), 5.44 (s, 2H), 3.74 (s, 3H), 3.50 (s, 3H); LC-MS [M+H]+ 412.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@H:7]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:6][CH2:5]2.[CH3:17][C:18]1[O:22][C:21]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)=[N:20][C:19]=1[CH2:30][CH2:31]O.CN(C(/N=N/C(N(C)C)=O)=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH3:17][C:18]1[O:22][C:21]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)=[N:20][C:19]=1[CH2:30][CH2:31][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@H:7]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:6][CH2:5]2
Reactant: Cc1ccc(-c2nc(CCO)c(C)o2)cc1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(-c4ccc(C)cc4)oc3C)ccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A suspension of the ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate prepared in Example 135 (507.5 mg, 2.30 mmol), and 2-[5-methyl-2-(4-methylphenyl)-1,3-oxazol-4-yl]ethanol prepared in Example 10 (500 mg, 2.30 mmol), TMAD (792.6 mg, 4.60 mmol), and Ph3P (1.21 g, 4.60 mmol) in 15 mL anhydrous DCM was stirred at rt under Ar for 12 hours. DCM was removed under reduced pressure. Flash chromatograph of the residue over silica gel using 1% CH3CN/CH2Cl2gave ethyl 2-((1S)-5-{2-[5-methyl-2-(4-methylphenyl)(1,3-oxazol-4-yl)]ethoxy}indanyl)acetate (776.3 mg, 1.85 mmol, 80.5%). HPLC/MS (M+H)+ m/z 420.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([OH:17])=O)=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[Cl:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[C:57]1([OH:62])[CH2:61][CH2:60][NH:59][CH2:58]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([N:59]3[CH2:60][CH2:61][C:57]([C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=4[Cl:50])([OH:62])[CH2:58]3)=[O:17])=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: OC1(c2ccccc2Cl)CCNC1
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2nocc2C(=O)N2CCC(O)(c3ccccc3Cl)C2)cc1Cl
Yield: 34.6 %

Procedure:
A solution of 3-(3-chloro-4-methoxyphenyl)isoxazole-4-carboxylic acid (10 mg, 0.04 mmol), N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.08 mmol, 2 equ.) and TBTU (15 mg, 0.046 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 3-(2-chlorophenyl)pyrrolidin-3-ol hydrochloride (9 mg, 0.04 mmol). After 1 h at rt the crude product was purified by RP-HPLC, evaporated and dried in vacuum to yield the title compound (6 mg). MS (ESI, pos. ion) m/z: calcd for C21H18Cl2N2O4: 432.0644, found 432.0645.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([O:28][CH3:29])[CH:22]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([O:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(Cl)Cl>[CH2:30]([O:37][C:38]1[CH:39]=[CH:40][C:41]([C:42]([O:27][C:24]2[CH:25]=[CH:26][C:21]([CH2:20][CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])=[CH:22][C:23]=2[O:28][CH3:29])=[O:43])=[CH:45][CH:46]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: COc1cc(CC(NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)ccc1O
Reactant: CCCCCCCOc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CC(NC(=O)OCc3ccccc3)C(=O)OC(C)(C)C)cc2OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
Prepared using General Procedure 3: To a stirred solution of tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-(4-hydroxy-3-methoxyphenyl)propanoate INT-2 (4.7 g, 11.71 mmol) and TEA (3.05 mL, 21.07 mmol) in DCM (50 mL) at 0° C. was added 4-(heptyloxy)benzoyl chloride (2.95 mL, 12.29 mmol) dropwise. After warming to room temperature and stirring for 10 min, the mixture was quenched with saturated aqueous NaHCO3 (50 mL) and water (50 mL). The organic layer was dried over MgSO4 and concentrated. The product was purified by chromatography (EA/hexanes) to afford 5.46 g (75%) of 4-(2-(((benzyloxy)carbonyl)amino)-3-(tert-butoxy)-3-oxopropyl)-2-methoxyphenyl 4-(heptyloxy)benzoate INT-3. LCMS-ESI (m/z) calculated for C36H45NO8: 619. Found 564 [M+H-tBu]+, tR=3.22 min (Method 4).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2([CH2:13][CH2:12]2)[O:10][C:9](=[O:14])[C:8]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)=[CH:17][CH:16]=1)(=O)=O.[N:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:35]1[CH:40]=[CH:39][C:38]([C:7]2[C:11]3([CH2:12][CH2:13]3)[O:10][C:9](=[O:14])[C:8]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)=[CH:17][CH:16]=2)=[CH:37][CH:36]=1
Reactant: O=C1OC2(CC2)C(OS(=O)(=O)C(F)(F)F)=C1c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1OC2(CC2)C(c2ccncc2)=C1c1ccc(OCc2ccc3ccccc3n2)cc1
Reaction time: 0.5 h
Yield: 17.8 %

Procedure:
To a stirred solution of 5-oxo-6-(4-(quinolin-2-ylmethoxy)phenyl)-4-oxaspiro[2.4]hept-6-en-7-yl trifluoromethanesulfonate (200 mg, 0.4 mmol) in 1,4-dioxane (10 mL) were added pyridin-4-ylboronic acid (74 mg, 0.6 mmol), Na2CO3 (102 mg, 1.2 mmol) and water (4 mL) at RT under an inert atmosphere. The mixture was stirred for 30 minutes, and then Pd(PPh3)4 (46 mg, 0.04 mmol) was added and the reaction mixture was then refluxed for 16 h, diluted with water and extracted with EtOAc (2×40 mL). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo to afford 7-(pyridin-4-yl)-6-(4-(quinolin-2-ylmethoxy)phenyl)-4-oxaspiro[2.4]hept-6-en-5-one (30 mg, 18%) as white solid. 1H NMR (500 MHz, d6-DMSO): δ 8.64-8.61 (m, 2 H), 8.40 (d, J=7.2 Hz, 1 H), 8.02-7.99 (m, 2 H), 7.81-7.77 (m, 1 H), 7.67- 7.51 (m, 3 H), 7.38-7.24 (m, 5 H), 5.36 (s, 2 H), 1.88-1.85 (m, 2 H), 1.24-1.21 (m, 2 H). MS: M+H: m/z=421.2; M+Na: m/z=443.2. HPLC: 92%, (Condition-I).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](N2C(C)=CC=C2C)=[C:7]([N+:18]([O-])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCO[C:24]([CH3:26])=O>[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:5]2[CH:6]=[C:7]([CH3:8])[NH:18][C:24]=2[CH3:26])=[C:7]([CH:6]=1)[NH2:18])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(C)n1-c1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Reactant: CCOC(C)=O
Agent: [Pd]
Product: Cc1cc(-c2ccc(C(C)(C)C)cc2N)c(C)[nH]1
Yield: 99 %

Procedure:
A slurry of 1-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole (0.341 g, 1.25 mmol), 10% Pd/C (0.056 g) and EtOAc (50 mL) under an H2 atmosphere (balloon) was stirred for 72 h, then filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to give 5-tert--butyl-2-(2,5-dimethylpyrrolyl)aniline as yellowish solids (0.30 g, 99%): TLC (10% EtOAc/90% hexane) Rf 0.43; 1H NMR (CDCl3) δ1.28 (s, 9H), 1.87-1.91 (m, 8H), 5.85 (br s, 2H), 6.73-6.96 (m, 3H), 7.28 (br s, 1H).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]([F:23])([F:22])[CH:19]([F:21])[F:20])=[CH:12][CH:11]=1)=[O:8])C.Cl>CO.O>[F:23][C:18]([F:22])([CH:19]([F:20])[F:21])[CH2:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([N:9]2[CH:4]=[CH:5][NH:6][C:7]2=[O:8])=[CH:15][CH:14]=1
Reactant: CCOC(CNC(=O)Nc1ccc(OCC(F)(F)C(F)F)cc1)OCC
Agent: Cl
Solvent: CO
Solvent: O
Product: O=c1[nH]ccn1-c1ccc(OCC(F)(F)C(F)F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.1 %

Procedure:
N-(2,2-Diethoxyethyl)-N'-[4-(2,2,3,3-tetrafluoropropoxy)phenyl] urea (37.5 g) was dissolved in a mixture of 560 ml of methanol and 280 ml of water. To the solution was added 300 ml of an aqueous solution containing 0.48M of hydrochloric acid and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure and the precipitated crystals were washed with a mixture of water-methanol (5:1) to give 22.8 g of 1-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-(1H,3H)-imidazolone as colorless powder.
Reaction SMILES: [CH3:1][N:2]([N:4]=[N:5][C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([O:13]C)=[O:12])[CH3:3].[OH-].[Na+].Cl>CO.O>[CH3:3][N:2]([N:4]=[N:5][C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]([OH:13])=[O:12])[CH3:1]
Reactant: COC(=O)c1sccc1N=NN(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)N=Nc1ccsc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.8 %

Procedure:
To a solution of methyl 3-[(dimethylamino)diazenyl]thiophene-2-carboxylate (200 mg, 0.93 mmol) in methanol (10 mL) was added a solution of sodium hydroxide (93 mg, 2.3 mmol) in water (2 mL) and stirred at rt for 2 h. The mixture was diluted with ice cold water and acidified with dil. HCl and extracted with chloroform. The combined chloroform layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-ethyl acetate (80:20) as eluents to give the product as an off-white solid (70 mg, 38%), mp 108-110° C. IR (neat) νmax 3402, 3082, 2923, 1708, 1218, 1116, 1066, 1016, 880, 773 cm−1; 1H NMR (400 MHz, CDCl3): δ 12.21 (1H, s), 7.47 (1H, d, J=5.2 Hz), 7.30 (1H, d, J=5.2 Hz), 3.65 (3H, s), 3.28 (3H, s); LC-MS (positive ion mode): m/z 200 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([OH:8])=O.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[C:10]1([NH:9][C:6]([C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)=[O:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)c1ncc[nH]1
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccccc1)c1ncc[nH]1
Temperature: 25 °C
Reaction time: 21 h
Yield: 95.2 %

Procedure:
To a solution of 1H-imidazole-2-carboxylic acid (0.975 g, 8.7 mmol) in DMF (30 mL) were added aniline (0.67 mL, 8.7 mmol), EDC.HCl (2.54 g, 13.05 mmol) and HOBt (1.76 g, 13.05 mmol). The reaction mixture was stirred at room temperature for 21 hours. Then, it was poured into water and extracted with ethyl acetate. The combined organic layer was dried over sodium sulphate, filtered and concentrated. The crude residue was purified by flash chromatography (2% to 3% methanol in dichloromethane) to yield 1.55 g (96% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[C:5]([F:11])[C:3]=1[NH2:4].Br[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1>[F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[C:5]([F:11])[C:3]=1[NH:4][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1
Reactant: Cc1ccc(Br)cc1
Reactant: Nc1c(F)cc(F)c(F)c1F
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(Nc2c(F)cc(F)c(F)c2F)cc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
A mixture of 2,3,4,6-tetrafluoroaniline (0.72 g, 4.4 mmol), 4-bromotoluene (0.8 g, 4.7 mmol), toluene (55 ml), sodium tert-butoxide (0.8 g, 8.3 mmol), tri-tert-butylphosphine (130 mg, 0.64 mmol) and bis-dibenzylideneacetone-palladium(0) (125 mg, 0.2 mmol) is heated under nitrogen to 85° C. for 3 h. After cooling, water (50 ml), concentrated aqu. HCl (10 ml) and hyflo (1 g) is added and stirring is continued for about one hour followed by filtration. The organic phase is washed with water twice, evaporated and the residue is subjected to flash chromatography on silica (45 g) using heptane/toluene (2:1) as the eluent to afford N-(2′,3′,4′,6′-Tetrafluorophenyl)-4-methylaniline (0.92 g, 3.6 mmol) as an oil which crystallises (mp. 64-65° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][NH:10][S:9]1(=[O:19])=[O:18].[Br:20][CH2:21][CH2:22][CH2:23][CH2:24]O>>[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][N:10]1[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[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: OCCCCBr
Reactant: O=S1(=O)NCc2ccccc2N1c1ccccc1F
Product: O=S1(=O)N(CCCCBr)Cc2ccccc2N1c1ccccc1F
Yield: 66.3 %

Procedure:
In an analogous manner to Example 11 step 4, a solution of 1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.75 g, 2.7 mmol) was reacted with 4-bromobutanol (0.83 mL, 5.2 mmol) to afford 3-(4-bromobutyl)-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.74 g, 66%) as a white solid:
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH:24]=[CH:23][CH:22]([C:26]([OH:28])=[O:27])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH:24]=[CH:23][CH:22]([C:26]([O:28][CH3:1])=[O:27])[CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CC=CC(C(=O)O)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1C=CCN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h

Procedure:
1,1'-Carbonyldiimidazole (4 g, 24.7 mmol) in methylene chloride (100 ml) was added dropwise to a solution of 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine-3-carboxylic acid (5 g, 22 mmol) in methylene chloride (200 ml) under a nitrogen atmosphere. Stirring was continued for 1 h followed by addition of methanol (300 ml), and reflux for 26 h. 10% aqueous citric acid (100 ml) was added and the mixture extracted with methylene chloride. The organic layer was dried over magnesium sulphate, evaporated to dryness in vacuo and purified on a silica gel column (Eluent: methylene chloride/methanol (90/1)) to give methyl 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine-3-carboxylate as yellow oil. (Yield: 3.9 g, 73%)