Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1.O[CH:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:13]=[CH:14][C:15]([O:18][CH:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)=[CH:16][CH:17]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1
Reactant: CN1CCC(O)CC1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OC3CCN(C)CC3)cc2)cc1
Yield: 57 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-(4-hydroxybenzoyl)benzo[b]thiophene (1.17 g, 3.00 mmol) and 4-hydroxy-1-methylpiperidine (691 mg, 6.00 mmol) were dissolved in 50 mL of anhydrous tetrahydrofuran. This solution was stirred and triphenylphosphine (1.57 g, 6.00 mmol) and diethylazodicarboxylate (DEAD) (6.00 mmol) were added. The resulting solution was allowed to stir at room temperature for 18 hours. The solvent was removed under reduced pressure and the resulting mixture is flash chromatographed (eluent: 7:3 ethyl acetate:methanol) to give 834 mg of the title compound. Yield: 57%. MS(FD) 488(M+). EA calculated for C29H29NO4S: C, 71.43; H, 5.99; N, 2.87. Found: C, 71.14; H, 5.93; N, 2.61.
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[CH:10]=[C:9]1B(O)O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].I[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:33][CH2:32][CH2:31][S:30]2(=[O:35])=[O:34])=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[CH:10]=[C:9]1[C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:33][CH2:32][CH2:31][S:30]2(=[O:35])=[O:34])=[CH:27][CH:28]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=S1(=O)CCCN1c1ccc(I)cc1
Reactant: COc1ccc2cc(B(O)O)n(C(=O)OC(C)(C)C)c2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc2cc(-c3ccc(N4CCCS4(=O)=O)cc3)n(C(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a mixture of 1-Boc-6-methoxyindole-2-boronic acid prepared in step B above (0.36 g, 1.25 mmol), 2-(4-iodophenyl)isothiazolidine-1,1-dioxide (0.32 g, 1.0 mmol) and PdCl2(dppf) (0.037 g, 0.05 mmol) in DMF (4.0 mL), is added aqueous K2CO3 solution (1.5 mL, 2.0 M, 3.0 mmol). The mixture is stirred at room temperature overnight and then poured into ice-water (100 mL). The precipitate is collected and washed with water and purified by flash column chromatography (silica gel, DCM/EtOAc, 9/1) to furnish 1-Boc-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxy-1H-indole (0.43 g, 98%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[C:25]3[S:29][C:28](=[O:30])[NH:27][C:26]3=[O:31])=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].Cl>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH:25]3[S:29][C:28](=[O:30])[NH:27][C:26]3=[O:31])=[CH:20][CH:19]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)C(=Cc2ccc(OC3CCN(C(=O)OCc4ccccc4)CC3)cc2)S1
Agent: Cl
Agent: [Mg]
Solvent: CO
Product: O=C1NC(=O)C(Cc2ccc(OC3CCN(C(=O)OCc4ccccc4)CC3)cc2)S1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
To a stirred suspension of the product (4 g) obtained in example 1 in methanol (40 ml) at room temperature, magnesium turnings (3.8 g) were added and the reaction mixture was stirred at the same temperature for 1 h. The reaction mixture was added to ice water (20 ml), the pH was adjusted to 6.5-7.0 using 10% aqueous hydrochloric acid and the solution was extracted with chloroform (3×100 ml). The combined organic extract was washed with H2O, dried (CaCl2) and the solvent was removed under reduced pressure. The residual mass was chromatographed on silica gel using 0.4% methanol in chloroform to give 2.4 g (68%) of the title compound. mp 72°-74° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[S:7][C:8]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-])=O>P(OCC)(OCC)OCC>[C:11]1([C:10]2[NH:1][C:4]3[CH:5]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[S:7][C:8]=3[CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(/C=C/c2ccccc2)s1
Agent: CCOP(OCC)OCC
Product: COC(=O)c1cc2[nH]c(-c3ccccc3)cc2s1
Yield: 32 %

Procedure:
A solution (1 M) of methyl 4-nitro-5-[(E)-2-phenylethenyl]thiophene-2-carboxylate in triethyl phosphite was heated to reflux for 28 h. After cooling down a part of the solvent was evaporated under high vacuum (2 mbar, water bath 60° C.) then the residue was purified by flash chromatography on silica gel (1:4 acetone/toluene) to afford the title compound (32%) as a solid.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][C:7]1[CH:8]=[C:9]([NH:14][C:15](=[O:19])[CH:16]=NO)[CH:10]=[CH:11][C:12]=1[CH3:13]>O>[CH3:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[C:8]=1[C:16](=[O:2])[C:15](=[O:19])[NH:14]2
Reactant: Cc1ccc(NC(=O)C=NO)cc1C
Reactant: O=S(=O)(O)O
Solvent: O
Product: Cc1ccc2c(c1C)C(=O)C(=O)N2
Temperature: 85 °C
Reaction time: 2 h

Procedure:
To a solution of concentrated sulfuric acid (85 ml) in water (17 ml) there was slowly added N-(3,4-dimethylphenyl)-2-hydroxyimino-acetamide (30 g, 0.156 mmol), and the mixture was stirred at 85° C. for 2 hours. The obtained solution was poured into ice water, and the precipitated orange solid was filtered out. The obtained solid was dissolved in 10% aqueous sodium hydroxide, active carbon was added, and the mixture was stirred. The obtained solution was filtered, and acetic acid was used for acidification to obtain 4,5-dimethyl-1H-indole-2,3-dione as crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[O:11]=[C:12]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[CH:18]2)=[N:13]1.[Cl-].[Cl-].[Cl-].[Al+3]>>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:11])[CH2:20]3)=[O:9])[CH:3]=1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: O=C1C=c2ccccc2=N1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1Cc2cc(C(=O)c3cc(Cl)ncn3)ccc2N1
Temperature: 0 °C

Procedure:
3.93 g (22.2 mmol) 6-chloropyrimidine-4-carboxylic acid chloride, 2.96 g (22.2 mmol) 2-oxoindole and 14.8 g (111 mmol) aluminium trichloride were combined and heated for 3 h to 130° C. Then the mixture was mixed with ice water and extracted twice with EtOAc. The organic phases were combined, dried and evaporated down. The residue was triturated in DIPE, suction filtered, washed and dried.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:13])=[CH:7][C:8]([C:11]#[N:12])=[N:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.Cl.[NH2:22][OH:23]>CO>[OH:23][NH:22][C:11]([C:8]1[CH:7]=[C:6]([CH3:13])[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:10][N:9]=1)=[NH:12]
Reactant: NO
Reactant: Cc1cc(C#N)ncc1CC(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1cc(C(=N)NO)ncc1CC(C)C
Temperature: 75 °C
Reaction time: 18 h
Yield: 123 %

Procedure:
To a solution of 5-isobutyl-4-methyl-pyridine-2-carbonitrile (106 mg, 608 μmol) in methanol (3 mL), triethylamine (123 mg, 1.22 mmol) and hydroxylamine hydrochloride (63 mg, 913 μmol) is added. The mixture is stirred at 75° C. for 18 h before it is concentrated. The residue is dissolved in aq. NaHCO3 (pH 7-8) and extracted with DCM (6×50 mL). The org. extracts are combined, dried over MgSO4, filtered, concentrated and dried to give the title compound (155 mg) as a white solid; LC-MS: tR=0.67 min, [M+1]+=208.01; 1H NMR (CD3OD): δ0.97 (d, J=6.8 Hz, 6H), 1.84-1.96 (m, 1H), 2.37 (s, 3H), 2.58 (d, J=7.3 Hz, 2H), 7.67 (s, 1H), 8.26 (s, 1H).
Reaction SMILES: [CH2:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Br:18]Br.[N+]([O-])(O)=O.C(O)(=O)C>O.C(O)C.[N+]([O-])([O-])=O.[Ag+]>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:16][C:17]=1[Br:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: BrBr
Reactant: CCCCCCCCc1ccc(C(=O)O)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: CCCCCCCCc1ccc(C(=O)O)cc1Br
Reaction time: 0.5 h
Yield: 54.3 %

Procedure:
7 g (0.03 mole) of p-octyl benzoic acid and 6.4 g (0.04 mole) of bromine are added to a mixture of 15 ml of deionized water, 20 ml of nitric acid and 90 ml of acetic acid, the temperature of which is 25° C. A solution of 5.1 g (0.03 mole) of silver nitrate in 15 ml of deionized water is then added over a period of half an hour. The solution is stirred for 3 hours 30 minutes, then the solid in suspension is filtered and washed with deionized water until the washing water shows a neutral reaction. The acid is dissolved in ethanol and the solution is bleached while hot with vegetable black. The crude product obtained after distillation of the ethanol is recrystallized in a 75% ethanol/25% water mixture. 5.1 g of pure product are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]([OH:30])=O)[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:34][CH:35]3[CH2:37][CH2:36]3)[C:17](=[O:33])[N:18]([CH3:32])[C:19]2=[O:31])=[N:14]1.N.[C:39](P(=O)(OCC)OCC)#[N:40]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]([NH:40][CH3:39])=[O:30])[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:34][CH:35]3[CH2:36][CH2:37]3)[C:17](=[O:33])[N:18]([CH3:32])[C:19]2=[O:31])=[N:14]1
Reactant: Cn1cc(C(=O)O)cc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12
Reactant: CCOP(=O)(C#N)OCC
Agent: N
Product: CNC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC4CC4)c3nn2Cc2ccnc3ccc(Cl)cc23)n(C)c1

Procedure:
This compound was synthesized by the reaction of 5-[2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carboxylic acid and ammonia using diethyl cyanophosphonate as a coupling reagent. Mass: 532.17 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].C([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:27]=[N:28][C:29]([N:32]([CH3:34])[CH3:33])=[N:30][CH:31]=2)[CH:21]=1)(=O)C>>[CH3:33][N:32]([CH3:34])[C:29]1[N:28]=[CH:27][C:26]([C:22]2[CH:21]=[C:20]([NH:19][C:5]3[CH:6]=[CH:7][C:8]([N:10]4[CH:14]=[CH:13][CH:12]=[CH:11]4)=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])[CH:25]=[CH:24][CH:23]=2)=[CH:31][N:30]=1
Reactant: O=[N+]([O-])c1cc(-n2cccc2)ccc1F
Reactant: CC(=O)Nc1cccc(-c2cnc(N(C)C)nc2)c1
Product: CN(C)c1ncc(-c2cccc(Nc3ccc(-n4cccc4)cc3[N+](=O)[O-])c2)cn1
Yield: 20 %

Procedure:
N-(3-(2-(Dimethylamino)pyrimid-5-yl)phenyl)-2-nitro-4-(1-pyrrolyl)aniline (3f) was prepared analogously from 1a and 2i. Yield: 20%. Mp 166-168° C.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH:11]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[C:2]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:12]
Reactant: C1CNCCN1
Reactant: N#Cc1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Product: N#Cc1ccc(-n2c(N3CCNCC3)c(C=O)c3ccccc32)cc1

Procedure:
4-(2-chloro-3-formylindol-1-yl)-benzonitrile is reacted with piperazine as described in Step 2 of Example 29 to afford 4-[3-formyl-2-(piperazin-1-yl)-indol-1-yl]-benzonitrile as a light tan solid. ESI/MS 331 (M+H); NMR (CDCl3) 10.35 (1H, s); 8.31 (1H, d, J=9 Hz); 7.92 (2H, d); 7.60 (2H, d); 7.31 (3H, m); 6.99 (1H, d, J=9 Hz); 3.28 (4H, m); 2.79 (4 H, m).
Reaction SMILES: [C:1]([C:5]1[CH:44]=[CH:43][C:8]([C:9]([NH:11][C@@H:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[O:28][N:27]=[C:26]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:31][CH:30]=4)[N:25]=3)=[CH:20][CH:19]=2)[C:13]([O:15]C)=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([C:5]1[CH:44]=[CH:43][C:8]([C:9]([NH:11][C@@H:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[O:28][N:27]=[C:26]([C:29]4[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:33][CH:34]=4)[N:25]=3)=[CH:20][CH:19]=2)[C:13]([OH:15])=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCCCCCOc1ccc(-c2noc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)OC)cc3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCOc1ccc(-c2noc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)O)cc3)n2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 7.7 %

Procedure:
Prepared using General Procedure 4: To a solution of (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(3-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-5-yl)phenyl)propanoate (4.52 mg, 0.008 mmol) in MeOH (2 mL) was added of 1 N NaOH (1 mL). The reaction mixture was stirred at 50° C. for 3 h. The resulting mixture was purified by preparative HPLC to afford 0.36 mg (8%) of (S)-2-(4-(tert-butyl)benzamido)-3-(4-(3-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-5-yl)phenyl) propanoic acid. LCMS-ESI (m/z) calculated for C35H41N3O5: 583.7; no m/z observed, tR=12.59 min (Method 2).
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)[CH3:2].C([Li])CCC.C(#N)C.[N+:16]([C:19]1[C:20]([NH:28][CH:29]2[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]2)=[C:21]2[S:27][CH:26]=[CH:25][C:22]2=[N:23][CH:24]=1)([O-:18])=[O:17]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[OH:35][C:32]1([CH2:2][C:1]#[N:4])[CH2:31][CH2:30][CH:29]([NH:28][C:20]2[C:19]([N+:16]([O-:18])=[O:17])=[CH:24][N:23]=[C:22]3[CH:25]=[CH:26][S:27][C:21]=23)[CH2:34][CH2:33]1
Reactant: O=C1CCC(Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CC#N
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: N#CCC1(O)CCC(Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 48 %

Procedure:
A solution of N,N-diisopropylamine (0.19 mL, 1.4 mmol) in tetrahydrofuran (3 mL) was cooled to 0° C. 1.6 M n-butyllithium in hexanes (0.86 mL, 1.4 mmol) was added dropwise, keeping the temperature below 5° C. After the addition was complete, the mixture was stirred for 20 min at 0° C. The mixture was then cooled to −78° C. and acetonitrile (0.072 mL, 1.4 mmol) was added, keeping the temperature below −70° C. After the addition was complete, the mixture was stirred for 20 min at −78° C. and a mixture of 4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexanone (0.20 g, 0.69 mmol) in tetrahydrofuran (3 mL)/hexamethylphosphoramide (3 mL) was added, keeping the temperature below −70° C. After the addition was complete, the mixture was stirred for 30 min at −78° C. and then stirred at room temperature for 5 h. The mixture was partitioned between methylene chloride and sat. aq. NH4Cl solution. The organic phase was washed with water, dried over sodium sulfate, concentrated and purified on silica gel column (eluting with 0-30% EtOAc in methylene chloride) to give the desired product (0.11 g, 48%). LCMS calculated for C15H17N4O3S (M+H)+: m/z=333.1. Found: 333.0.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:22]=[C:21](I)[CH:20]=[C:19]([C:24]([F:27])([F:26])[F:25])[N:18]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:16][C:17]1[CH:22]=[C:21]([N:12]2[CH2:13][CH2:14][N:10]([C:5]3[CH:6]=[N:7][CH:8]=[CH:9][C:4]=3[CH:1]3[CH2:3][CH2:2]3)[C:11]2=[O:15])[CH:20]=[C:19]([C:24]([F:25])([F:26])[F:27])[N:18]=1
Reactant: FC(F)(F)c1cc(I)cc(Cl)n1
Reactant: O=C1NCCN1c1cnccc1C1CC1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2cc(Cl)nc(C(F)(F)F)c2)CCN1c1cnccc1C1CC1
Yield: 10.6 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 110 mg, 0.5412 mmol) was reacted with 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (200 mg, 0.6494 mmol), 1,4-dioxane (5 mL), copper iodide (10 mg, 0.0541 mmol), trans-N1,N2-dimethylcyclohexane-1,2-diamine (23 mg, 0.1623 mmol) and potassium phosphate (345 mg, 1.6236 mmol) to afford the crude product. Purification by column chromatography on silica gel (1.5% methanol in CHCl3), followed by prep HPLC afforded 22 mg of the product (10% yield).
Reaction SMILES: [NH3:1].[Br:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11].BrCC1C=CC(S(Cl)(=O)=O)=CC=1>O1CCCC1>[Br:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH2:1])(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)c1ccccc1CBr
Reactant: N
Agent: O=S(=O)(Cl)c1ccc(CBr)cc1
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccccc1CBr

Procedure:
A solution of ammonia (1.0 ml) in tetrahydrofuran (50 ml) at -78° was contacted dropwise with a solution of a 60/40 mixture of 2-(bromomethyl)benzenesulfonyl chloride/4-(bromomethyl)benzenesulfonyl chloride (4.52 g) in tetrahydrofuran (20 ml). The stirred mixture was allowed to warm to 0° and volatiles were removed in vacuo. The residue was contacted with water (50 ml) and extracted three times with ethyl acetate. Combined organic portions were washed with brine, dried, and evaporated to give 4.00 g of white solid. 1H nmr δ(CD3)2COTMS 8.15-7.20 (m), 6.7-6.3 (m, NH), 4.95 (q, area 21), 4.55 (s, area 18), consistent with a ca. 60/40 mixture of 2-(bromomethyl)-/4-(bromomethyl)-benzenesulfonamides. The sample was fractionally recrystallized from chloroform, but without significant change in isomeric content.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C@@H:7]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:8]1)=[O:6])[C:2]#[CH:3]>C(#N)C.[Au](Cl)(Cl)Cl>[CH3:3][C:2]1[O:6][C:5]([C@@H:7]2[CH2:11][CH2:10][C@H:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[CH2:8]2)=[N:4][CH:1]=1
Reactant: C#CCNC(=O)[C@@H]1CC[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl[Au](Cl)Cl
Solvent: CC#N
Product: Cc1cnc([C@@H]2CC[C@H](NC(=O)OC(C)(C)C)C2)o1
Temperature: 50 °C
Reaction time: 16 h
Yield: 79.9 %

Procedure:
To a solution of Example 125A (500 mg, 1.88 mmol) in acetonitrile (8 mL) was added a solution of gold (III) chloride (56.9 mg, 0.188 mmol) in acetonitrile (2 mL). The reaction mixture was stirred at 50° C. for 16 hours and then concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% of MeOH/EtOAc (1:10) in hexanes) to obtain 400 mg (80%) the title compound. MS (ESI+) M/Z 267 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:8]([C:13]([F:16])([F:15])[F:14])[O:9]2)=[CH:4][CH:3]=1.[Cl:22]Cl>CC(O)=O>[Cl:22][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH3:12])[C:2]=1[CH3:1])[O:9][CH:8]([C:13]([F:16])([F:14])[F:15])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6]2
Reactant: ClCl
Reactant: CCOC(=O)C1=Cc2ccc(C)c(C)c2OC1C(F)(F)F
Solvent: CC(=O)O
Product: CCOC(=O)C1=Cc2cc(Cl)c(C)c(C)c2OC1C(F)(F)F
Reaction time: 2 h

Procedure:
To a solution of ethyl 7,8-dimethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylat (4.0 g, 13.3 mmol) in 75 mL HOAc was added Cl2 until the solvent was saturated as indicated by the greenish chlorine cloud above the solvent. After 2 h, the reaction was flushed with N2 and subsequently treated with excess Zn dust for 1.5 h. The reaction mixture was decanted from the Zn and concentrated under vacuum. The resulting residue was dissolved in 300 mL of EtOAc and washed with 100 mL 1 M KHSO4 and 100 mL brine. The organic layer was dried over MgSO4, filtered and concentrated under vacuum. The yield of ethyl 6-chloro-7,8-dimethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate was 5.2 g.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-:19])=O)=[C:10]([C:14]([O-])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][CH:25]=1.Cl>>[CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:6][C:7]2=[CH:8][C:9]3[C:17](=[O:19])[N:23]([C:24]4[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][CH:25]=4)[C:14](=[O:15])[C:10]=3[CH:11]=[C:12]2[CH2:13]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Reactant: NC(=O)c1ccc(N)cc1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(c1ccc(C(N)=O)cc1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.3 g, 1.0 mmol) was treated with 4-aminobenzamide (1.4 g, 10.0 mmol). Purification on silica gel, eluting with 9:1 CH2Cl2 /MeOH sat'd w/ NH3, afforded a solid that was converted to an HCl salt and recrystallized from EtOAc/MeOH to give 122 as a white solid (m.p. 275-276° C.).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]#[CH:21])[CH:15]=[CH:14][C:13]=2[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH2:32][S:33]([CH3:35])=[O:34])[CH:25]=2)=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[O-:36][C:37]#[N:38].[Na+]>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:12]3[C:13](=[CH:14][CH:15]=[C:16]([O:18][CH2:19][C:20]#[CH:21])[CH:17]=3)[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH2:32][S:33]([CH3:35])=[O:34])[CH:25]=3)[C:37](=[O:36])[N:38]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: C#CCOc1ccc(NCc2cccc(OCCS(C)=O)c2)c(C(=O)c2ccc(C(C)C)cc2)c1
Reactant: N#C[O-]
Agent: [Na+]
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc(OCCS(C)=O)c1

Procedure:
The title compound (yellow oil) is prepared from (4-isopropyl-phenyl)-{2-[3-(2-methanesulphinyl-ethoxy)-benzylamino]-5-prop-2-ynyloxy-phenyl}-methanone and sodium cyanate as described for the preparation of example 3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].Cl.[CH3:12][NH:13][O:14][CH3:15].Cl.CN(C)CCCN=C=NCC>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:13]([O:14][CH3:15])[CH3:12])=[O:6]
Reactant: CNOC
Reactant: O=C(O)c1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 75 h

Procedure:
To a suspension of 3-fluorobenzoic acid (140 mg, 1 mmol) and N,O-dimethylhydroxylamine hydrochloride (107 mg, 1.1 mmol) in dichloromethane (2.5 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC) (211 mg, 1.1 mmol) and the mixture stirred at room temperature for 75 h. The solvents were removed under reduced pressure and the residue chromatographed using ethyl acetate-hexane (4:6) to separate the pure product (130 mg, 71%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH3:10])=[CH:4][C:3]=1[CH:11]=[CH:12][C:13]([CH3:16])(O)[CH3:14].C[N+](C)=CCl.[Cl-].P(Cl)(Cl)(Cl)=O.[C:28]([O-])(=[O:30])C.[Na+]>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH3:10])=[CH:4][C:3]=1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:28]=[O:30]
Reactant: COc1cc(C)c(C=CC(C)(C)O)cc1C
Reactant: CC(=O)[O-]
Agent: C[N+](C)=CCl
Agent: [Cl-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc(C)c(C=CC(C)=CC=O)cc1C
Temperature: 80 °C
Reaction time: 4 h
Yield: 63.8 %

Procedure:
4-(2,5-dimethyl-4-methoxyphenyl)-2-methyl-3-buten-2-ol (18 g, 0.08M) in 25 ml of N,N-dimethylformamide (DMF) was added dropwise at 0° C. (ice bath) to the Vilsmeier reagent prepared from 15.4 g of phosphorus oxychloride and 15 ml of DMF. The resulting mixture was heated slowly to 80° C. and was stirred at this temperature for 4 hrs. The content of reaction flask was poured into 250 ml of ice-water mixture and sodium acetate (80 g) was added slowly in portions. The product was then extracted into ether. After work-up, the residue was purified by a silica gel dry column (15% ethyl acetate in hexane) to give 12 g of pure material as yellow powder, m.p. 90°-92° C. MS(CI): 231(m+ +1).