Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=CC(CN2C3C(=CC(S(C)(=O)=O)=CC=3)C=C2C2SC=CN=2)=CC=1.FC1C=CC(CN2C3=NC=C(S(C)(=O)=O)C=C3C=[C:34]2[C:46]2[O:47]C=C[N:50]=2)=CC=1.[F:53][C:54]1[CH:78]=[CH:77][C:57]([CH2:58][N:59]2[C:67]3[C:62](=[CH:63][C:64]([S:68]([CH3:71])(=[O:70])=[O:69])=[CH:65][CH:66]=3)[CH:61]=[C:60]2[C:72]2OC=N[N:76]=2)=[CH:56][CH:55]=1>>[F:53][C:54]1[CH:78]=[CH:77][C:57]([CH2:58][N:59]2[C:67]3[C:62](=[CH:63][C:64]([S:68]([CH3:71])(=[O:70])=[O:69])=[CH:65][CH:66]=3)[CH:61]=[C:60]2[C:72]2[N:50]=[C:46]([CH3:34])[O:47][N:76]=2)=[CH:56][CH:55]=1
Reactant: CS(=O)(=O)c1cnc2c(c1)cc(-c1ncco1)n2Cc1ccc(F)cc1
Reactant: CS(=O)(=O)c1ccc2c(c1)cc(-c1nnco1)n2Cc1ccc(F)cc1
Agent: CS(=O)(=O)c1ccc2c(c1)cc(-c1nccs1)n2Cc1ccc(F)cc1
Product: Cc1nc(-c2cc3cc(S(C)(=O)=O)ccc3n2Cc2ccc(F)cc2)no1

Procedure:
Among the above compounds, 1-(4-fluorobenzyl)-5-methanesulfonyl-2-(thiazol-2-yl)indole; 1-(4-fluorobenzyl)-2-(oxazol-2-yl)-5-methanesulfonyl-1H-pyrrolo [2,3-b]pyridine; and 1-(4-fluorobenzyl)-5-methanesulfonyl-2-([1,3,4]oxadiazol-2-yl)indole and addition salts thereof with a pharmaceutically acceptable acid or base, and hydrates thereof are particularly preferred.
Reaction SMILES: [NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[C:15]([Br:17])=[CH:16][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1.[CH2:22]([O:24][C:25](=[O:44])[C@H:26]([CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[NH:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1)[CH3:23]>C(Cl)Cl>[NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:18]([NH:35][C:32]4[CH:31]=[CH:30][C:29]([C:28]([NH:27][C@H:26]([C:25]([O:24][CH2:22][CH3:23])=[O:44])[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:36])=[CH:34][CH:33]=4)(=[O:20])=[O:19])[C:15]([Br:17])=[CH:16][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(N)cc1)C(=O)OCC
Reactant: Nc1nc2c(c(=O)[nH]1)-c1cc(S(=O)(=O)Cl)c(Br)cc1CC2
Solvent: ClCCl
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(NS(=O)(=O)c2cc3c(cc2Br)CCc2nc(N)[nH]c(=O)c2-3)cc1)C(=O)OCC
Temperature: 25 °C
Yield: 26.1 %

Procedure:
3-Amino-8-bromo-5,6-dihydrobenzo[f]quinazolin-1(2H)-one-9-sulfonyl chloride (2.00 g, 4.50 mmole) and N-(4-aminobenzoyl)-L-glutamic acid diethyl ester (7.26 g, 22.5 mmole) (Aldrich) were placed together in a test tube and melted at 175° C. The mixture was heated for 1 hour, 20 minutes, the cooled residue suspended in methylene chloride and filtered to remove undissolved solid. The filtrate was evaporated to dryness and the residue subjected to chromatography on a Waters Prep 500 instrument (silica column, elution with methanol/methylene chloride (1:24)). The combined fractions containing product were evaporated and the residue dried under high vacuum. The solid was suspended in boiling ethanol (900 ml), the suspension cooled to room temperature and filtered to give diethyl N-(4-(((3-amino-8-bromo-1,2,5,6-tetrahydro-1-oxobenzo[f]quinazolin-9-yl)sulfonyl)amino)benzoyl)-L-glutamate (0.794 g, 260). Mp>250° C. 1H NMR (DMSO-d6, 200 MHz) δ: 1.12 (t, J=7 Hz, 3H, ester-CH3), 1.14 (t, J=7 Hz, 3H, ester-CH3), 1.89-2.09 (m, 2H, glu-CH2), 2.37 (t, J=7 Hz, 2H, glu-CH2), 2.48-2.59 (m, 2H, ArCH2), 2.77-2.85 (m, 2H, ArCH2), 3.99 (q, J=7 Hz, 2H, esterCH2), 4.05 (q, J=7 Hz, 2H, esterCH2), 4.29-4.40 (m, 1H, glu-CH), 6.84 (br s, 2H, NH2), 7.14 (d, J=9 Hz, 2H, Ar), 7.54 (s, 1H, Ar), 7.69 (d, J=9 Hz, 2H, Ar), 8.48 (d, J=8 Hz, 1H, NH), 9.37 (s, 1H, Ar), 10.87 (br s, 1H, NH), 11.04 (br s, 1H, NH). Anal. Calculated for C28H30BrN5O8S:1/4H2O C, 49.38; H, 4.51; Br, 11.73; N, 10.20; S, 4.71. Found: C, 49.33; H, 4.40; Br, 11.79; N, 10.20; S, 4.74.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([OH:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([OH:28])[CH2:23][CH2:24][N:25]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=4)[N:7]=3)[CH2:26][CH2:27]2)=[CH:18][CH:17]=1
Reactant: OC1(c2ccc(F)cc2)CCNCC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: OC1(c2ccc(F)cc2)CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 80 °C
Yield: 74.3 %

Procedure:
6-Chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Monatsh. Chem. 1972, 103, 1591) (251 mg, 1.13 mmol), 4-(4-fluorophenyl)piperidin-4-ol (215 mg, 1.13 mmol) and DIPEA (0.20 mL, 1.13 mmol) in DMF (3 mL) were stirred and heated at 80° C. for 1 hour. The resulting solution was cooled to ambient temperature, and quenched with water (10 mL). The precipitated solid was collected by filtration, washed sequentially with water, acetonitrile and ether and dried under vacuum to give 4-(4-fluorophenyl)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (320 mg, 74%).
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:15]1[CH:39]=[CH:38][C:18]([O:19][CH2:20][CH:21]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:16]=1.[F:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1>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.C(O)C>[F:40][C:41]1[CH:46]=[C:45]([C:15]2[CH:39]=[CH:38][C:18]([O:19][CH2:20][CH:21]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:17][CH:16]=2)[CH:44]=[CH:43][CH:42]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)(C)[Si](C)(C)OC(CCc1cccnc1)COc1ccc(Br)cc1
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: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC(CCc1cccnc1)COc1ccc(-c2cccc(F)c2)cc1
Temperature: 120 °C
Yield: 60.7 %

Procedure:
Prepared according to the method described in Example 33a) from toluene (5 ml), aqueous sodium carbonate (2 M, 2.2 ml), (±)-3-(4(4-bromophenoxy)-3-(tert-butyldimethylsilyloxy)butyl)pyridine (0.79 g), ethanol (1.3 ml), 3-fluorobenzeneboronic acid (0.25 g) and tetrakis(triphenylphosphine)palladium(0) (72 mg) with heating at 120° C. for 6 hours. The residue obtained after work up was purified by column chromatography over silica to give the sub-title compound as an oil (0.49 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8](=[S:12])[NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].Br[CH:14]([CH3:18])[C:15](=O)[CH3:16].O=P(Cl)(Cl)Cl>CCO>[CH2:1]([O:3][C:4]([C:6]1[N:7]2[C:8]([S:12][C:14]([CH3:18])=[C:15]2[CH3:16])=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CC(=O)C(C)Br
Reactant: CCOC(=O)c1[nH]c(=S)[nH]c1C
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2sc(C)c(C)n12

Procedure:
A mixture of 5-methyl-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylic acid ethyl ester (10.7 mmol) and 3-bromo-2-butanone (10.7 mmol) in EtOH (16 mL) is heated at reflux for 3 h. The solvents are removed in vacuo and POCl3 (161 mmol) is added. The mixture is stirred at reflux for 3 h, concentrated in vacuo and diluted with chloroform. Ice water is added and the mixture is neutralized by addition of Na2CO3. The layers are separated and the aq. layer is extracted with chloroform. The combined organic layers are dried over Na2SO4 and concentrated in vacuo to give a mixture of two regioisomers which are separated by FC (heptane/EtOAc 9/1 to EtOAc). 2,3,6-trimethyl-imidazo[2,1-b]thiazole-5-carboxylic acid ethyl ester is obtained as minor isomer. LC-MS: tR=0.84 min; [M+H]+=239.0.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][CH:7]([NH2:8])[CH:3]([CH2:4]2)[CH2:2]1.[OH-].[Na+].Cl[CH2:12][CH:13]([OH:19])[CH2:14][S:15]([OH:18])(=[O:17])=[O:16].[Na]>O1CCOCC1.O>[CH:3]12[CH2:4][CH:5]([CH2:1][CH2:2]1)[CH2:6][CH:7]2[NH:8][CH2:12][CH:13]([OH:19])[CH2:14][S:15]([OH:18])(=[O:17])=[O:16]
Reactant: NC1CC2CCC1C2
Reactant: O=S(=O)(O)CC(O)CCl
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)(O)CC(O)CNC1CC2CCC1C2
Temperature: 80 °C
Reaction time: 5 h
Yield: 17 %

Procedure:
To an 80° C. solution of exo-2-aminonorbornane (910 mg, 8.2 mmol) and sodium hydroxide (242 mg, 6.1 mmol) in 1,4-dioxane (4 mL) and water (4 mL) was added via syringe pump (1 hour addition) a solution of 3-chloro-2-hydroxy-propane sulfonic acid, sodium salt (1.09 g, 5.5 mmol) in 1,4-dioxane (0.5 mL) and water (5.5 mL). The solution was stirred at 80° C. for an additional 5 hours. The reaction was cooled to room temperature. The solvent was evaporated under reduced pressure. The solid was suspended in EtOH (25 mL). The mixture was heated to reflux for 1 minute. The solid was recovered by filtration and it was passed through an ion exchange column (Dowex 50×8, 100 g, solvent: water). The product was recrystallized in EtOH/water (99/1). Yield: 17%. 1H NMR (D2O, 500 MHz) δ ppm 4.25 (m, 1H), 3.25 (m, 2H), 3.01 (m, 4H), 2.39 (m, 1H), 2.27 (m, 1H), 1.69 (m, 1H), 1.51 (m, 1H), 1.38 (m, 3H), 1.19 (m, 1H), 1.07 (m, 2H). 13C (D2O, 125 MHz) δ ppm 63.66, 63.50, 62.21, 61.98, 54.94, 50.11, 50.04, 39.26, 39.21, 36.02, 35.97, 35.91, 35.80, 34.70, 34.61, 27.11, 27.08, 26.50, 26.45. ES-MS 250 (M−1).
Reaction SMILES: [C:1]1([P:7]([O:15][C:16]2[C@H:17]([CH3:40])[C@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si:41](Cl)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42].N1C=CN=C1.CO>CN(C)C=O>[Si:41]([O:38][C@@H:36]([C@H:35]1[C:34](=[O:39])[N:19]2[C:20]([C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=3)=[O:22])=[C:16]([O:15][P:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:8])[C@H:17]([CH3:40])[C@@H:18]12)[CH3:37])([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CO
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
To a solution of p-nitrobenzyl(1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (5.00 g, 8.41 mmol) in dimethylformamide (250 ml) were added t-butyldimethylsilyl chloride (2.54 g, 16.8 mmol) and imidazole (1.14 g, 16.8 mmol) in an ice bath, and the reaction mixture was stirred in the ice bath for 7 hours. After checking the completion of the reaction, methanol was added thereto and the resulting mixture was stirred for 30 minutes. The reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (3:1) as the eluant to afford p-nitrobenzyl (1R,5S,6S)-6-[(R)-1-t-butyldimethylsilyloxyethyl]-2-(diphenylphosphoryloxy)-1-methylcarbapen-2-em-3-carboxylate (5.27 g, yield 88%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:12][CH:13]=1)=[O:6].[Cl:25][C:26]1[N:31]=[C:30](Cl)[C:29]([Cl:33])=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:25][C:26]1[N:31]=[C:30]([NH:1][C:2]2[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=2)[C:5]([NH:7][C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:18])[CH3:19])[CH:11]=[CH:12][CH:13]=2)=[O:6])[C:29]([Cl:33])=[CH:28][N:27]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)(C)OC(=O)Nc1cccc(NC(=O)c2cccc(N)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(NC(=O)c2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.9 %

Procedure:
To a solution of tert-butyl {3-[(3-aminobenzoyl)amino]phenyl}carbamate (0.500 g, 1.53 mol) and 2,4,5-trichloropyrimidine (0.25 g, 1.4 mmol) in DMF (3.7 mL) was added potassium carbonate (0.29 g, 2.1 mmol). The resulting mixture was stirred overnight at room temperature. The reaction was quenched with saturated (sat'd) NH4Cl and water. EtOAc was added and the layers separated. The aqueous layer was extracted with EtOAc twice and the combined organics were washed with water, dried, filtered and concentrated to give 800 mg of crude product, which was purified by Combi-Flash column chromatography (12 g column, 0 to 30% EtOAc in hexane) to give the desired product (66 mg, 10%). LCMS for C22H21Cl2N5O3 (M-tBu+H)+: m/z=420.0, 418.1. 1H NMR (400 MHz, CD3OD): δ 8.26 (s, 1H), 8.11 (t, J=2.0 Hz, 1H), 7.89 (ddd, J=8.0, 2.0, 1.2 Hz, 1H), 7.85 (t, J=2.0 Hz, 1H), 7.74 (ddd, J=7.6, 2.0, 0.8 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.32 (dd, J=8.0, 1.2 Hz, 1H), 7.24 (t, J=8.0 Hz, 1H), 7.19 (m, 1H), 1.52 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=O.C(Cl)Cl>CO>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[C:7]1[C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: COc1ccccc1C=O
Reactant: O=[N+]([O-])c1ccc2c(c1)Cc1ccccc1-2
Solvent: CO
Solvent: ClCCl
Product: COc1ccccc1C=C1c2ccccc2-c2ccc([N+](=O)[O-])cc21
Temperature: 72 °C
Reaction time: 6 h

Procedure:
To a solution of 2-nitrofluorene (1.05 g, 5 mmol) and 2-methoxybenzaldehyde (0.816 g, 6 mmol) in 20 mL of methanol was added KF—Al2O3 (0.75 g, 4.5 mmol). The resulting mixture was stirred at 72° C. After 6 hrs, TLC indicated that the starting material was gone. 40 mL of CH2Cl2 was added into the reaction mixture. The insoluble solid was filtrated, and the filtrate was concentrated under vacuum to give a yellow solid, which was recrystallized from alcohol and CH2Cl2 to give 1.2 g of CYD-1-70 as a yellow solid. 1H-NMR (600 MHz, CDCl3) δ 8.84 (s, 0.36H), 8.26 (m, 1.65H), 8.10 (m, 3.05H), 8.02 (s, 0.57H), 7.55 (m, 4H), 7.24 (m, 1.24H), 7.10 (m, 0.91H), 3.84 (s, 3H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH:17]([CH3:19])[CH3:18])=[C:12]([N+:20]([O-])=O)[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[H][H]>[Ni].C(O)C>[NH2:20][C:12]1[CH:11]=[C:10]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:9])[CH:15]=[CH:14][C:13]=1[NH:16][CH:17]([CH3:18])[CH3:19]
Reactant: CC(C)Nc1ccc(C(=O)c2ccc(F)cc2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CC(C)Nc1ccc(C(=O)c2ccc(F)cc2)cc1N
Yield: 92.1 %

Procedure:
A solution of 14.7 parts of (4-fluorophenyl) [4-[(1-methylethyl)-amino]-3-nitrophenyl]methanone in 120 parts of ethanol was hydrogenated at 2.105Pa with 3 parts of Raney nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off over diatomaceous earth and the filtrate was evaporated, yielding 12.3 parts (92.1%) of [3-amino-4-[(1-methylethyl)amino]phenyl] (4-fluorophenyl)-methanone as a residue (int. 2).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8])=[CH:2]1.C(=O)([O-])[O-].[Na+].[Na+].C([N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33])(OCC)=O.Cl>O.O1CCOCC1>[C:27]1(=[O:28])[N:23]([NH:8][C@H:7]([C:9]([OH:11])=[O:10])[CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[C:24](=[O:33])[C:25]2=[CH:32][CH:31]=[CH:30][CH:29]=[C:26]12
Reactant: N[C@@H](Cc1ccsc1)C(=O)O
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)[C@H](Cc1ccsc1)NN1C(=O)c2ccccc2C1=O
Temperature: 0 °C

Procedure:
3-(3-Thienyl)-L-alanine (2.45 g., 14.3 mmol.) was suspended in water/p-dioxane (22 ml/11 ml.) at room temperature under argon. Sodium carbonate (1.52 g.) was added and the mixture was stirred until homogeneous. N-Carbethoxyphthalimide (3.14 g.) was added, and the resulting mixture was stirred for 3.0 hours and then cooled to 0° C. The pH was adjusted to 1.5 with 6N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 10% potassium bisulfate and brine, dried (sodium sulfate), filtered, and concentrated. The crude product was flash chromatographed (Merck silica gel) eluting with 1:1 ethyl acetate/hexane/1% acetic acid. The fractions containing clean desired product were combined, concentrated, azeotroped with ethyl acetate, and washed with water to remove the acetic acid. The organic layer was dried (sodium sulfate), filtered, and concentrated to give 3.22 g. of title compound as a white crystalline product; m.p. 166°-168° C.; [α]D =-146.8° (c=0.46, methylene chloride). TLC (1% acetic acid in 1:1 ethyl acetate/hexane) Rf =0.31.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][C:13](=O)[C:14]([F:17])([F:16])[F:15])=[CH:7][C:6]=1[C:20]([F:23])([F:22])[F:21].[NH2:26][C:27]1[C:31]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=2)=[CH:30][NH:29][N:28]=1>>[F:1][C:2]([F:25])([F:24])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([C:14]([F:17])([F:16])[F:15])[N:28]3[N:29]=[CH:30][C:31]([C:32]4[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=4)=[C:27]3[N:26]=2)=[CH:7][C:6]=1[C:20]([F:23])([F:22])[F:21]
Reactant: Cc1cc(-c2c[nH]nc2N)ccn1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(OCC(F)(F)F)c(C(F)(F)F)c1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(OCC(F)(F)F)c(C(F)(F)F)c4)nc23)ccn1
Yield: 67.6 %

Procedure:
Reaction of 1-[4-(2,2,2-trifluoroethoxy)-3-trifluoromethyl-phenyl]-4,4,4-trifluoro-butane-1,3-dione (191 mg, 0.5 mmol), prepared from 4-(2,2,2-trifluoroethoxy)-3-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [see part synthesis of amino-pyrazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (176 mg, 68%). MS (ISP) 521.5 [(M+H)+]; mp 210° C.
Reaction SMILES: O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N:40]([CH:43]1[CH2:49][CH2:48][CH2:47][CH2:46][C:45]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[CH3:56])=[CH:44]1)=[N+]=[N-]>C1COCC1>[CH3:56][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=1[C:45]1[CH2:46][CH2:47][CH2:48][CH2:49][CH:43]([NH2:40])[CH:44]=1
Reactant: Cc1ccccc1C1=CC(N=[N+]=[N-])CCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1C1=CC(N)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.5 ml of H2O and then 4.23 g (16.1 mmol) of triphenylphosphine PPh3 are added to a solution of the compound obtained in Step D (2.4 g/10.73 mmol) in 60 ml of THF, and then the reaction mixture is stirred at room temperature overnight. The whole is then concentrated to dryness and subsequently chromatographed over silica gel (CH2Cl2, 20% MeOH, 2% NH4OH) to yield the title product in the form of a yellowish oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH2:12](I)[CH3:13].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:12]([O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[I:1])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(O)c(I)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc([N+](=O)[O-])cc1I
Temperature: 25 °C
Yield: 22.4 %

Procedure:
A suspension of 2-iodo-4-nitrophenol (21 g, 79.2 mmol) [ref: Kometani, T.; Watt, D. S.; Ji, T., Tetrahedron Lett. (1985), 26(17), 2043], ethyl iodide (9 mL, 0.48 mol) and potassium carbonate (40.7 g, 0.3 mol) in 100 mL of N,N-dimethylformamide was heated at 70° C. for 3 hours. The reaction was cooled to room temperature and ethyl acetate was added. The inorganic salts were filtered and washed with ethyl acetate. The organic material was washed with water (3×) and brine, dried over magnesium sulfate and filtered. Upon concentration of the filtrate a solid appeared. This solid was filtered and washed with hexanes to give 5.2 g of 1-ethoxy-2-iodo-4-nitrobenzene as white crystals. Concentration of the filtrate provided an additional 11.3 g of the desired product, mp 81-83° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.42 (t, 3H), 4.26 (q, 2H), 7.18 (d, 1H), 8.26 (dd, 1H), 8.55 (d, 1H)
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:6]=2[N:7]=1.[C:31]1(/[CH:37]=[CH:38]/B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:11][C:10]1[C:5]2[C:4]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:3][C:2](/[CH:38]=[CH:37]/[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:7][C:6]=2[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[N:9]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: CCOC(=O)c1cc(Cl)nc2c1c(C)nn2Cc1ccc(Oc2ccccc2)cc1
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: CCOC(=O)c1cc(/C=C/c2ccccc2)nc2c1c(C)nn2Cc1ccc(Oc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
(see, e.g., Greig, I. R., et al., J Med Chem 2006, 49, 7487-92; Li, X., et al., J Med Chem 2003, 46, 5663-73). To a mixture of 50 (205 mg, 0.49 mmol), Pd(PPh3)4 (27 mg, 0.02 mmol) and (E)-2-phenylvinylboronic acid (112 mg, 0.74 mmol) in 1,4-dioxane: H2O (3 mL/2 mL) was added Na2CO3 (153 mg, 1.45 mmol), followed by stirring at 90° C. overnight. To the reaction mixture was added H2O (10 mL) and the aqueous layer was extracted with EtOAc (10 mL×2). The combined organic layer was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. Crude was subjected to flash column chromatography on silica gel to provide the title compound (216 mg, 90%) as a light yellow oil which solidified upon standing. 1H NMR (500 MHz, CDCl3) δ 7.80 (d, J=16.1 Hz, 1H), 7.74 (s, 1H), 7.63 (d, J=7.6 Hz, 2H), 7.41 (t, J=7.6 Hz, 2H), 7.39-7.33 (m, 3H), 7.30 (t, J=7.7 Hz, 3H), 7.07 (t, J=7.4 Hz, 1H), 6.98 (d, J=8.6 Hz, 2H), 6.95 (d, J=8.3 Hz, 2H), 5.69 (s, 2H), 4.51 (q, J=7.1 Hz, 2H), 2.71 (s, 3H), 1.49 (t, J=7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 165.76, 157.04, 156.79, 154.93, 152.39, 141.19, 136.28, 134.74, 133.60, 132.13, 129.69, 129.50, 128.81, 127.69, 127.33, 123.28, 118.94, 118.82, 116.48, 110.28, 61.93, 49.80, 16.30, 14.30.