Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])(=[NH:4])=[O:3].[I:13][C:14]1[C:15]([NH2:23])=[N:16][CH:17]=[C:18]([CH:22]=1)[C:19](O)=[O:20].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH2:23][C:15]1[N:16]=[CH:17][C:18]([C:19]([N:4]=[S:2]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])([CH3:1])=[O:3])=[O:20])=[CH:22][C:14]=1[I:13]
Reactant: COC(=O)CCCCS(C)(=N)=O
Reactant: Nc1ncc(C(=O)O)cc1I
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(I)c1
Temperature: 70 °C
Yield: 50.3 %

Procedure:
A solution of methyl 5-(S-methylsulfonimidoyl)pentanoate (2.32 g) was dissolved in anhydrous DMF (30 mL) and to this solution was added 5-iodo-6-amino-nicotinic acid (3.17 g, ˜1 eq), diisopropylethylamine (4.2 mL, 2 eq), and BOP (5.85 g, 1.1 eq). The reaction mixture was heated at 70° C. for 1 hour and then partitioned between EtOAc and aq NH4Cl. The organic layer was separated, washed sequentially with aq NH4Cl (1×), saturated aq NaHCO3 (1×), brine (1×), and dried with anhydrous Na2SO4 overnight. The upper solution layer was decanted, concentrated, and the brown oily reside was subject to column chromatography (acetone-CHCl3 1:100 to MeOH-acetone-CHCl3 1:2:50). Concentration of the product eluting fractions provided the title compound as a slight yellow colored foam (2.65 g).
Reaction SMILES: [F:1][CH:2]([C:4]1[N:9]=[C:8]([CH2:10][CH2:11][CH3:12])[NH:7][C:6](=[O:13])[CH:5]=1)[CH3:3].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[F:1][CH:2]([C:4]1[N:9]=[C:8]([CH2:10][CH2:11][CH3:12])[N:7]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[C:6](=[O:13])[CH:5]=1)[CH3:3]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCc1nc(C(C)F)cc(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCc1nc(C(C)F)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
A mixture of 6-(1-fluoroethyl)-2-propylpyrimidin-4(3H)-one (5.7 g), 4′-(bromomethyl)biphenyl-2-carbonitrile (9.3 g) and potassium carbonate (8.5 g) in acetonitrile (50 mL) was stirred overnight at 50° C. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale yellow solid (5 g, 43%).
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:8]([F:15])=[C:9]([OH:14])[C:10](=[O:13])[NH:11][CH:12]=2)[CH:2]=1.[OH-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[CH2:24]([O:14][C:9]1[C:10](=[O:13])[NH:11][CH:12]=[C:7]([C:3]2[CH:2]=[C:1]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:6]=[CH:5][CH:4]=2)[C:8]=1[F:15])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]cc(-c2cccc(-c3ccccc3)c2)c(F)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=c1[nH]cc(-c2cccc(-c3ccccc3)c2)c(F)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
To a suspension of 5-biphenyl-3-yl-4-fluoro-3-hydroxypyridin-2(1H)-one (60 mg, 0.213 mmol) was added 1 N aqueous NaOH solution (0.235 mL, 0.235 mmol) and the resulting mixture was sonicated to make a clear solution. To this mixture was added a solution of benzyl bromide (37 mg, 0.213 mmol) in MeOH (0.3 mL) dropwise, stirred overnight at room temperature and then concentrated. Purification by preparative HPLC (10-70% CH3CN/H2O over 20 min, 0.05% added TFA) afforded 25 mg (32%) of 3-(benzyloxy)-5-(biphenyl-3-yl)-4-fluoropyridin-2(1H)-one as a white solid. LC/MS (M+H)+ 372.2.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[NH:28][C:29](=[O:39])[CH2:30][N:31]1[CH2:36][CH2:35][NH:34][CH:33]([CH2:37][OH:38])[CH2:32]1.C(N(CC)CC)C>CN(C)C=O>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:4][CH2:3][CH2:2][N:34]2[CH2:35][CH2:36][N:31]([CH2:30][C:29]([NH:28][C:22]3[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:21]=3[Cl:20])=[O:39])[CH2:32][CH:33]2[CH2:37][OH:38])=[CH:7][CH:8]=1
Reactant: Cc1cccc(Cl)c1NC(=O)CN1CCNC(CO)C1
Reactant: Fc1ccc(C(CCCI)c2ccc(F)cc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc(Cl)c1NC(=O)CN1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)C(CO)C1
Temperature: 70 °C
Reaction time: 4 h
Yield: 33.1 %

Procedure:
A mixture of 7.4 parts of 1,1'-(4-iodobutylidene)bis[4-fluorobenzene], 5.5 parts of N-(2-chloro-6-methylphenyl)-3-(hydroxymethyl)-1-piperazineacetamide, 4.0 parts of N,N-diethylethanamine and 68 parts of N,N-dimethylformamide was stirred for 4 hours at about 70° C. The reaction mixture was cooled overnight to room temperature and the solvent was evaporated. The residue was taken up in trichloromethane. The organic phase was washed with water, dried, filtered and evaporated. The oily residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The oily residue solidified on triturating in 2,2'-oxybispropane. The product was filtered off and dried, yielding 3.21 parts (33.1%) of 4-[4,4-bis(4-fluorophenyl)butyl]-N-(2-chloro-6-methylphenyl)-3-(hydroxymethyl)-1-piperazineacetamide; mp. 149.8° C. (compound 51).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=[O:5].[CH3:17][O:18][C:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)=[O:20].OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[CH2:8][CH2:7][NH:6][C:4](=[O:5])[CH2:3][CH2:2][NH:1][C:25]([C:24]1[CH:28]=[CH:29][C:21]([C:19]([O:18][CH3:17])=[O:20])=[CH:22][CH:23]=1)=[O:26]
Reactant: COc1cccc(CCNC(=O)CCN)c1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)NCCC(=O)NCCc2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-amino-N-(3-methoxyphenethyl)propanamide (60 mg, 0.27 mmol) was added 4-(methoxycarbonyl)benzoic acid (49 mg, 0.27 mmol), hydroxybenzotriazole (3.7 mg, 0.027 mmol), triethylamine (42 μL, 0.30 mmol) and dimethyformamide (2.7 mL). Lastly, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (57 mg, 0.30 mmol) was added and the solution was allowed to stir overnight at room temperature in a capped vial. Upon completion of the reaction an aqueous workup is performed to give the crude product which was purified using flash chromatography.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][N:5]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]2[CH:13]=[CH:14][CH:15]=[C:16]([N+:17]([O-])=O)[C:6]1=2>C(O)C.C1COCC1.[Pd]>[NH2:17][C:16]1[C:6]2[N:5]([CH2:4][CH2:3][N:2]([CH3:20])[CH3:1])[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:13]=[CH:14][CH:15]=1
Reactant: CN(C)CCN1C(=O)CCCc2cccc([N+](=O)[O-])c21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(C)CCN1C(=O)CCCc2cccc(N)c21
Reaction time: 3 h

Procedure:
1-(2-(dimethylamino)ethyl)-9-nitro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (100 mg, 0.361 mmol) was stirred to dissolve in a mixture of ethanol (4 mL) and THF (3 mL). To this solution was added palladium on carbon, 10 wt %, (40 mg) as a solid. The black suspension was stirred under hydrogen gas for 3 h. When TLC analysis showed that the starting material was consumed the reaction mixture was filtered through a pad of celite and washed with methanol. The filtrate was concentrated and then chromatographed on silica gel in 10% 2 N NH3/MeOH in dichloromethane. Yield 90 mg (quantitative). 1H NMR (DMSO-d6) δ 6.86 (d, 1H, J=8.1 Hz), 6.53 (d, 1H, J=3.0 Hz), 6.38 (dd, 1H, J=8.1, 3.0 Hz), 5.02 (brs, 2H), 2.50 (m, 2H), 2.25 (m, 2H), 1.8-2.2 (m, 10H); ESI-MS (m/z, %): 248 (MH+, 58), 203 (100).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH2:32][C:33](=[O:39])[NH:34]2>>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[C:32](=[CH:20][C:3]1[NH:4][C:5]3[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]4[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]4)[C:7](=[O:19])[C:6]=3[C:2]=1[CH3:1])[C:33](=[O:39])[NH:34]2
Reactant: O=C1Cc2c(cccc2-c2c(F)cccc2F)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3cccc(-c4c(F)cccc4F)c32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Yield: 70.7 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(2,6-difluoro-phenyl)-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 2-[4-(2,6-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (70 mg, 70.7%) as an orange solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[CH:22]=1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH2:28][CH3:29]>>[CH2:28]([N:27]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[CH:22]=1)[CH2:26][CH2:25][O:24][CH3:23])[CH3:29]
Reactant: CCNCCOC
Reactant: Fc1ccc(-c2csc3cc(OCCCCBr)ccc23)cc1
Product: CCN(CCCCOc1ccc2c(-c3ccc(F)cc3)csc2c1)CCOC

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and N-(2-methoxyethyl)ethylamine were converted to yield Ethyl-{4-[3-(4-fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-(2-methoxy-ethyl)-amine as colorless oil, MS: 402 (MH+).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH2:13][N:14]3C(OC(C)(C)C)=O)[CH2:11]2)=[N:7][CH:8]=1.Cl>CCOC(C)=O.O1CCOCC1>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH2:13][NH:14]3)[CH2:11]2)=[N:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C[C@@H](Oc3ccc(C(F)(F)F)cn3)[C@@H]1C2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(O[C@@H]2C[C@@H]3CN[C@H]2C3)nc1
Reaction time: 2 h
Yield: 112.8 %

Procedure:
xHCl. To the title compound of step A (622 mg, 1.74 mmol) in EtOAc (1 mL) was added 4M HCl in dioxane (10 mL). After 2 h, the reaction was concentrated to give the title compound of step B (507 mg) which was used without further purification. MS (ESI) mass calcd. for C12H13F3N2O, 258.1. m/z found 259.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[CH:31]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH:31]1([NH:37][C:12]2[N:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[CH3:30])[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: NC1CCCCC1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1C
Product: Cc1cc(F)ccc1-c1nc(NC2CCCCC2)nc2c1ccc(=O)n2-c1ccccc1C
Yield: 48.1 %

Procedure:
Following the general procedure outlined in Example 126, the product of Example 121 (200 mg, 0.47 mmol), and cyclohexylamine (0.27 mL, 2.36 mmol) were reacted to give the crude material, which was purified as described in Example 198 to give the desired product 100 mg (48%). LC-MS: 443.4 (MH+, m/z), 2.79 (Rt, min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].CC(O)=O.[Br:24]Br.OS([O-])=O.[Na+]>O>[Br:24][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:11]([C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)=[O:10])[CH2:12][CH2:13]2
Reactant: O=C(c1ccc(Cl)c(Cl)c1)N1CCc2ccccc21
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(c1ccc(Cl)c(Cl)c1)N1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of (3,4-dichlorophenyl)(indolin-1-yl)methanone (2.6 g, 8.90 mmol) in AcOH (8.2 mL, 142 mmol) was added bromine (504 μL, 9.79 mmol) dropwise via syringe at 0° C. Additional AcOH (6.0 mL) was added, and the reaction mixture was stirred at room temperature for 1 h. Cold water was added to the reaction mixture followed by sat. aq. NaHSO3 solution. The resulting mixture was stirred for 10 min, and the precipitate was collected via filtration to give the title compound (3.30 g, 100%) as a light brown solid. 1H NMR (DMSO-d6) δ 7.90 (d, J=1.5 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.49 (s, 1H), 7.38 (br s, 1H), 4.02 (t, J=8.3 Hz, 2H), 3.10 (t, J=8.3 Hz, 2H); MS(ESI+) m/z 371.9 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:30][O:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6]([C:5]3[CH:28]=[CH:29][C:2]([N:35]4[CH2:36][CH2:37][CH:32]([O:31][CH3:30])[CH2:33][CH2:34]4)=[N:3][CH:4]=3)=[O:7])=[CH:11][N:12]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:16]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Reactant: COC1CCNCC1
Product: COC1CCN(c2ccc(C(=O)NCc3cn(-c4ccccc4)c4cc(Cl)ccc4c3=O)cn2)CC1

Procedure:
4-Methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate E and 4-methoxypiperidine. MS calcd. for C28H27ClN4O3 [(M+H)+] 503.2, obsd. 503.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-])=O.[C:14]1([NH:20][C:21](=O)[CH3:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:22][C:21]1[N:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=2[N:11]=1
Reactant: CC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Reactant: CC(=O)Nc1ccccc1
Product: CC(=O)c1ccc2c(c1)nc(C)n2-c1ccccc1
Yield: 62.3 %

Procedure:
The title compound was prepared with the analogous procedure described in example 1 using 1-(4-Bromo-3-nitrophenyl)-ethanone (122 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) as starting materials to yield the title compound as a yellow solid (78 mg, 62%). 1H NMR (DMSO) δ 2.54 (s, 3 H), 2.68 (s, 3 H), 7.27 (d, J=8.6 Hz, 1 H), 7.58-7.71 (m, 5 H), 7.92 (d, J=8.86 Hz, 1 H), 8.35 (br s, 1 H); 13C NMR δ 13.8, 27.0, 110.4, 117.9, 123.5, 126.7, 129.7, 130.0, 132.4, 133.9, 137.9, 153.8, 157.2, 197.0.
Reaction SMILES: [CH3:1][S:2]([CH:4]=[C:5]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH2:7][C:6]1([CH3:13])[CH3:12])=O.C([Cl:17])(=O)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:17][CH2:1][S:2][CH:4]=[C:5]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH2:7][C:6]1([CH3:13])[CH3:12]
Reactant: CS(=O)C=C1C(C)(C)CCC1(C)C
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)C1=CSCCl
Yield: 87.9 %

Procedure:
1.0 g of 2,2,5,5-tetramethylcyclopentylidenemethyl methyl sulfoxide was dissolved in 10 ml of methylene chloride, and 470 mg of acetyl chloride was added dropwise. The mixture was subjected to reaction at room temperature for 12 hours, and then 50 ml of 5% sodium hydrogen carbonate was added thereto. The mixture was extracted twice with 50 ml of chloroform, and the organic layers were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, whereby 960 mg of 2,2,5,5-tetramethylcyclopentylidenemethyl chloromethyl sulfide was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)=[CH:9]/[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:39][S:40][CH2:41][C:42]#[CH:43]>O1CCCC1.[Cu]I.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>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28]([C:43]#[C:42][CH2:41][S:40][CH3:39])=[CH:27][CH:26]=2)=[CH:9]/[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: C#CCSC
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(F)cc2)c2ccc(I)cc2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(F)cc2)c2ccc(C#CCSC)cc2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl (Z)-[4-[3-(4-Fluorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (400 mg, 0.75 mmol; example 10) was dissolved in anhydrous tetrahydrofuran (10 mL); anhydrous triethylamine (20 mL) and a solution of 3-(methylsulfanyl)propyne (130 mg, 1.51 mmol) in anhydrous tetrahydrofuran (2 mL) were added. Resulting solution was degassed and copper(I) iodide (23 mg, 0.12 mmol) and tetrakis(triphenylphosphine)palladium (70 mg, 0.06 mmol) were added under nitrogen atmosphere. Reaction mixture was stirred at ambient temperature overnight, the resulting suspension was filtered through a paddle of silica gel and silica gel was thoroughly washed with ethyl acetate. The filtrate was evaporated in vacuo; the obtained residue was dissolved in dichloromethane and the solution was washed with water (2×30 mL) and brine (2×30 mL), dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 90:10) yielding methyl (E)-[4-[3-(4-fluorophenyl)-3-[4-[3-(methyl-sulfanyl)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetate as yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].C(=O)([O-])[O-].[Na+:12].[Na+].O.[Br:15][CH2:16][C:17](Br)=[O:18]>C(Cl)Cl>[Na+:12].[Br:15][CH2:16][C:17]([NH:1][CH2:2][CH2:3][S:4]([O-:7])(=[O:6])=[O:5])=[O:18]
Reactant: NCCS(=O)(=O)O
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(CBr)NCCS(=O)(=O)[O-]
Temperature: 10 °C
Yield: 43.8 %

Procedure:
Taurine (50 g, 0.40 mol) and sodium carbonate (48 g, 0.45 mol) were combined with 250 mL of water in a 1-L flask and chilled in an ice bath (10° C.). Bromoacetyl bromide (100 g, 0.50 mol) in 250 mL of methylene chloride was added dropwise over a 1 hr period with rapid stirring while maintaining the temperature at 10°-15° C. After addition, the ice bath was removed and the mixture was stirred for 3 hr. The aqueous layer was separated and washed with two portions of methylene chloride, and most of the water was evaporated affording a moist white solid. The solid was washed thoroughly with acetone and dried (90 g, 85% yield). The product was purified by dissolving it in 1200 mL of hot methanol, filtering, and evaporating the methanol until the product crystallized out (volume ca 650 mL). This afforded 47 g (44% yield) of product; mp>250° C. Anal. Calcd. for C4H7BrNO4SNa: C, 17.9; H, 2.6; N, 5.4. Found: C, 17.6; H, 2.4; N, 4.5.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[N:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH2:31])[CH:22]=[CH:23][C:24]=1[N:25]1[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]1.C(N(CC)CC)C>CO>[Cl:8][C:6]1[N:5]=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[N:3]=[C:2]([NH:31][C:21]2[CH:22]=[CH:23][C:24]([N:25]3[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]3)=[C:19]([O:18][CH3:17])[CH:20]=2)[N:7]=1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: Clc1ccc(Cc2nc(Cl)nc(Cl)n2)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1cc(Nc2nc(Cl)nc(Cc3ccc(Cl)cc3)n2)ccc1-n1cnc(C)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
2,4-Dichloro-6-(4-chloro-benzyl)-[1,3,5]triazine (0.78 g, 2.8 mmol) was added at 5° C. to a solution of 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (0.61 g, 3.0 mmol) and triethylamine (0.36 ml, 0.26 mmol) in 15 ml of methanol. The mixture was stirred at 5° C. for 1 h and thereafter evaporated under reduced pressure. The residual material was purified by chromatography on silica gel using heptane/0-100% ethyl acetate as eluent to give the title compound (0.53 g, 40%) as a yellow viscous oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15](O)=[O:16])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH:26]1([NH2:29])[CH2:28][CH2:27]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:18])([CH3:19])[C:15]([NH:29][CH:26]2[CH2:28][CH2:27]2)=[O:16])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Reactant: NC1CC1
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NC3CC3)c2c1N

Procedure:
Prepared as in Example Da from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example 47b) and cyclopropanamine as a pale yellow solid (64%). 1H NMR (400 MHz, DMSO-d6) δ 0.14-0.45 (m, 2H), 0.57-0.62 (m, 2H), 1.25 (s, 6H), 1.35 (t, J=8.0 Hz, 3H), 2.58 (s, 3H), 2.62-2.65 (m, 1H), 4.13 (s, 2H), 4.35 (q, J=8.0 Hz, 2H), 6.90 (d, 1H), 7.27 (d, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.79 (d, J=4.0 Hz, 1H), 8.09 (s, 2H). MS 386 (MH+).
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:9]2[O:10][C:11]3[C:12](=[O:17])[NH:13][N:14]=[CH:15][C:16]=3[C:8]=2[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6][CH:5]=1.Cl.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](NN)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:13]2[C:12](=[O:17])[C:11]3[O:10][C:9]4[C:4]([O:3][CH:2]([F:1])[F:23])=[CH:5][CH:6]=[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8]=4[C:16]=3[CH:15]=[N:14]2)=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1ccc(OC(F)F)c2oc3c(=O)[nH]ncc3c12
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(OC(F)F)c2oc3c(=O)n(-c4ccc(Cl)cc4)ncc3c12
Reaction time: 4 h
Yield: 92 %

Procedure:
To a solution of ethyl 6-difluoromethoxy-4-oxo-3,4-dihydrobenzo[4,5]furo[2,3-d]pyridazine-9-carboxylate (from step 6 of example 4) (168 mg, 0.4 mmol) in ethanol (20 ml), p-chloro phenylhydrazine hydrochloride (72 mg, 0.4 mol) and sodium carbonate (43 mg, 0.4 mmol) was added at room temp. The reaction mixture was stirred at room temp. for 4 hrs. Ethanol was distilled out under vacuum. The concentrated mass was heated to reflux temperature in acetic acid. Progress of reaction was monitored by TLC. At the end, water was added, the solid obtained was filtered and suck dried. The solid was dried in oven. White colored solid (160 mg) was obtained.