Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][CH3:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:12][O:13][C:14](=[O:27])[C:15]1[C:16](=[C:21]([CH2:25]Br)[CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH3:20])=[O:18]>CN(C=O)C>[CH3:12][O:13][C:14](=[O:27])[C:15]1[C:16](=[C:21]([CH2:25][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9])[CH3:8])[CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1cccc(CBr)c1C(=O)OC
Reactant: CNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN(C)C(=O)OC(C)(C)C)c1C(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
A solution of methyl-carbamic acid t-butyl ester (5.0 g, 38.0 mmol) in DMF (50 mL) was chilled in an ice bath, and NaH (60%, 1.7 g, 41.8 mmol) was added in portions at 10C. The mixture was stirred for an additional 30 minutes. A solution of 3-bromomethyl-phthalic acid dimethyl ester (10.9 g, 38.0 mmol) in DMF (20 mL) was slowly added, keeping the temperature at 10-15° C. The resulting mixture was stirred at room temperature overnight. The mixture was poured into ice water (400 mL) and extracted with EtOAc (4×70 mL). The combined EtOAc extracts were washed with water (3×50 mL) and brine (50 mL), and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography (SiO2, Hexane:EtOAc 8:2) to give 3-[(t-butoxycarbonyl-methyl-amino)-methyl]-phthalic dimethyl ester (7.7 g, 60%) as an oil: 1H NMR (CDCl3) δ 7.93-7.89 (m, 1H), 7.49-7.46 (m, 2H), 4.46 (s, 2H), 3.94 (s, 3H), 3.89 (s, 3H), 2.87-2.76 (b, 3H), 1.49-1.42 (b, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[CH2:7][CH2:6]1)=[O:4].Cl[C:13]1[N:18]=[C:17]([N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[N:20]2)[C:16]([Cl:28])=[CH:15][N:14]=1>C1COCC1>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[N:20]3)[C:16]([Cl:28])=[CH:15][N:14]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Reactant: Clc1ncc(Cl)c(-n2nnc3ccccc32)n1
Solvent: C1CCOC1
Product: COC(=O)C1CCC(Nc2ncc(Cl)c(-n3nnc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
trans-4-Amino-cyclohexanecarboxylic acid methyl ester (727 mg, 3.76 mmol) was added in portions, at RT under nitrogen atmosphere, to a solution of 1-(2,5-dichloro-pyrimidin-4-yl)-1H-benzotriazole (500 mg, 1.88 mmol) in THF (50 mL) followed by TEA (0.79 mL, 5.64 mmol). The resultant white suspension was stirred at RT overnight, and then at 60° C. for 2.5 days. The mixture was partitioned between water (100 mL) and EtOAc (100 mL). The organic layer was separated, washed twice with water (100 mL) and once with brine (100 mL), then dried over Na2SO4, filtered and the solvent evaporated under reduced pressure to give an off-white solid. This crude material was purified via flash chromatography (toluene/EtOAc, 90/10) to afford 538 mg (74% yield) of 4-(4-benzotriazol-1-yl-5-chloro-pyrimidin-2-ylamino)-cyclohexanecarboxylic acid methyl ester as an off-white solid. MS: 387.10 (M+1)+, 359.13 ((M+1)+−28).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([NH2:28])=[CH:23][C:22]=3[F:29])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[O-:30][C:31]#[N:32].[K+].C(O)(=O)C>C1COCC1.O>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([NH:28][C:31]([NH2:32])=[O:30])=[CH:23][C:22]=3[F:29])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: N#C[O-]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(N)cc3F)CC2)CC1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(NC(N)=O)cc3F)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 34-1 (72.5 mg, 0.18 mmol) in THF (1 mL) and water (1 mL), was added potassium cyanate (30 mg, 0.37 mmol), acetic acid (0.2 mL) and water (1.8 mL). The biphasic solution was stirred at room temperature for 2 h then concentrated, dissolved in DCM and purified on preparative HPLC to give 37-1: LC-MS 454.1 (MH), tR=6.42 (Method 2). EC50: 71 nM.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C:8]1[S:9][S:10][C:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2CF)=[CH:12][CH:13]=1)(C)(C)C.[F-:26].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(O)(=O)C>[OH:6][CH2:7][C:8]1[S:9][S:10][C:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:26])=[CH:12][CH:13]=1
Reactant: [F-]
Reactant: CC(C)(C)[Si](C)(C)OCC1=CC=C(COc2ccccc2CF)SS1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: OCC1=CC=C(COc2ccccc2F)SS1
Reaction time: 5 h
Yield: 68 %

Procedure:
To a stirred solution of the 3-[(tert-butyldimethyl-silyloxy)methyl]-6-[(2fluoromethylphenyloxy)methyl]-1,2-dithiin obtained above (250 mg, 0.65 mmol) in 5 mL THF was added a mixture of 3.0 mL of 1M tetrabutylammonium fluoride in THF and 2.0 mL of acetic acid. The reation mixture was stirred for 5 h until TLC analysis showed the reaction to be complete, then concentrated in vacuo. The residue was partitioned between 20 mL of water and 20 mL ethyl acetate. The organic phase was washed with 3% solution of aqueous sodium bicarbonate (50 mL), water, dried over sodium sulfate, and then concentrated to a small volume. The residue was purified by silica gel chromatography (ethyl acetate-hexane, 1:3) to yield 120 mg (68%) of the title compound; 1H NMR (CDCl3):δ7.12-6.9 (m, 4 H), 6.47 (d, J=6.0, 1 H), 6.39 (d, J=6.0, 1 H), 4.74 (s, 2 H), 4.28 (s, 2 H); MS (EI) 270.1 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](S(C)(=O)=O)[C:5]2[N:6]([C:8]([C:11]3[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH:18]4[CH2:20][CH2:19]4)=[O:16])=[C:13]([CH3:23])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.[CH3:28][S:29]([CH2:32][CH2:33][NH2:34])(=[O:31])=[O:30].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:34][CH2:33][CH2:32][S:29]([CH3:28])(=[O:31])=[O:30])[C:5]2[N:6]([C:8]([C:11]3[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH:18]4[CH2:20][CH2:19]4)=[O:16])=[C:13]([CH3:23])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1
Reactant: CS(=O)(=O)CCN
Reactant: Cc1cc(-c2cnc3c(S(C)(=O)=O)cc(Br)nn23)ccc1C(=O)NC1CC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2cnc3c(NCCS(C)(=O)=O)cc(Br)nn23)ccc1C(=O)NC1CC1
Temperature: 160 °C

Procedure:
To a stirred solution of 1.12 g (2.5 mmol) 4-[6-bromo-8-(methylsulfonyl)imidazo[1,2-b]pyridazin-3-yl]-N-cyclopropyl-2-methyl benzamide which was prepared according to intermediate example 516b in 15 mL NMP is added 924 mg (7.5 mmol) 2-(methylsulfonyl)ethanamine and 1.94 g (15 mmol) DIPEA and the mixture is heated at 160° C. for 4 h in a heating block. After working up and without further purification 1.18 g (96%) of the title compound are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[N:10]=[C:11]3[C:16](=[O:17])[N:15]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:14]([CH3:23])=[N:13][C:12]=23)=[CH:4][CH:3]=1.[CH2:31](B(O)O)[CH2:32][CH2:33][CH3:34].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>C1COCC1.O>[CH2:31]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[N:10]=[C:11]3[C:16](=[O:17])[N:15]([CH2:18][C:19]([F:20])([F:22])[F:21])[C:14]([CH3:23])=[N:13][C:12]=23)=[CH:4][CH:3]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCB(O)O
Reactant: Cc1nc2c(-c3ccc(Br)cc3)n(-c3ccccc3Cl)nc2c(=O)n1CC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CCCCc1ccc(-c2c3nc(C)n(CC(F)(F)F)c(=O)c3nn2-c2ccccc2Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of 3-(4-bromophenyl)-2-(2-chlorophenyl)-5-methyl-6-(2,2,2-trifluoroethyl)-2,6-dihydropyrazolo[4,3-d]pyrimidin-7-one (4A-9, 48.4 mg, 0.1 mmol), 1-butane boronic acid (12 mg, 0.12 mmol), K2CO3 (41 mg, 0.3 mmol), PdCl2dppf.CH2Cl2 (8 mg, 0.01 mmol) in THF (2 ml) was heated at 65° C. for 18 h. The reaction mixture was cooled to room temperature, diluted with H2O, and extracted with EtOAc (2×). The combined extracts were washed with 0.5 M citric acid, saturated aqueous NaCl, dried, and concentrated under vacuum. The crude residue was purified on a Chromatotron using 1 mm plates and 25% EtOAc/hexanes as a solvent to give 8A-1 (16 mg): MS (m/z) 475.5 (M+H)+; 1H NMR (400 MHz, CDCl3): δ 7.53-7.49 (m, 1H), 7.47-7.36 (m, 3H), 7.31 (d, J=8.3 Hz, 2H), 7.12 (d, J=8.3 Hz, 2H), 4.98-4.78 (br m, 2H), 2.60 (s, 3H), 2.56 (t, J=7.5 Hz, 2H), 1.6-1.5 (m, 2H), 1.36-1.27 (m, 2H), 0.89 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:11](=[O:12])[C:10]2[NH:9][C:8]([C:13]3[CH:18]=[CH:17][C:16]([S:19](O)(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[N:7][C:6]=2[N:5]([CH2:23][CH3:24])[C:4]1=[O:25])[CH3:2].CN(C)C=O.S(Cl)(Cl)=O.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>O>[CH2:1]([N:3]1[C:11](=[O:12])[C:10]2[NH:9][C:8]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)(=[O:20])=[O:21])=[CH:17][CH:18]=3)=[N:7][C:6]=2[N:5]([CH2:23][CH3:24])[C:4]1=[O:25])[CH3:2]
Reactant: C1COCCN1
Reactant: CCn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)O)cc3)nc2n(CC)c1=O
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)N4CCOCC4)cc3)nc2n(CC)c1=O
Temperature: 25 °C
Yield: 54.2 %

Procedure:
A mixture of 4-(1,3-diethyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)benzenesulfonic acid (5.0 g, 0.014 moles) and N,N-dimethylformamide (150 ml) is cooled to 0° and treated with thionyl chloride (3.3 g, 0.027 moles). When the addition is complete, the reaction mixture is permitted to warm to ambient temperature and stirred vigorously until a thick slurry results. To this slurry is added morpholine (20 g, 0.23 moles) in one portion. The resulting slurry is stirred one hour and poured into two liters of water. The resulting suspension is filtered, triturated with ethanol, and dried at 68° to yield 3.29 grams of 4-[[4-(1,3-diethyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)phenyl]sulfonyl]morpholine, mp 354°-355° C.(d).
Reaction SMILES: O1CCC[CH2:2]1.[OH:6][C:7]1[C:8]([CH:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:26])=[CH:9][C:10]2[O:15][CH2:14][CH2:13][O:12][C:11]=2[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCI>CN(C)C=O>[NH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]2([C:8]3[C:7](=[CH:16][C:11]4[O:12][CH2:13][CH2:14][O:15][C:10]=4[CH:9]=3)[O:6][CH2:2]2)[C:18]1=[O:26]
Reactant: O=C1Nc2ccccc2C1c1cc2c(cc1O)OCCO2
Reactant: C1CCOC1
Agent: ClCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
A 2000 L stainless steel crystallizer was charged with N,N-dimethylformamide (113.7 kg) and tetrahydrofuran (1070.9 kg). The contents were cooled to 0-5° C. and 3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one (12.0 kg, 42.4 mol) was added, followed by cesium carbonate (30.4 kg, 93.3 mol). A solution of chloroiodomethane (9.4 kg, 53.7 mol) in N,N-dimethylformamide (16.9 kg) was added at a rate of 39.5 kg/h such that the temperature of the reaction mixture was maintained between 0 and 5° C. The reaction mixture was stirred at 0-5° C. for 2 h and heated at 20-25° C. for 18.5 h. The mixture was filtered and the filter cake was suspended in tetrahydrofuran (26.4 kg) and filtered again. The combined filtrates were combined and concentrated to a volume of 110 L under reduced pressure at a temperature<60° C. The mixture was cooled to 20-25° C. and purified water (1200.8 kg) was added at a rate of 343.1 kg/h. The mixture was cooled to 0-5° C. and filtered. The filter cake was suspended in water (310.5 kg), filtered and dried at a temperature<60° C. until the water content was 10.6% by weight by Karl-Fisher titration. A 200 L reactor was charged with tetrahydrofuran (98.0 kg). The partially-dried filter cake (−11.0 kg) was added to the 200 L reactor by means of a solid addition funnel. The mixture was heated at reflux for 4.5 h, cooled to 10-15° C. and stirred for 3.5 h at 10-15° C. The mixture was filtered and the filter cake was washed with cold (0-5° C.) tetrahydrofuran (2×10.7 kg) and dried in a tray dryer at a temperature<55° C. to afford 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (6.88 kg, 63%) as a pale yellow solid: purity (HPLC-UV at 210 nm) 98.3%; mp>250° C.; 1H NMR (300 MHz, DMSO-d6) δ10.58 (br s, 1H), 7.26-7.19 (m, 1H), 7.09 (d, J=7.2 Hz, 1H), 6.99-6.90 (m, 2H), 6.47 (s, 1H), 6.16 (s, 1H), 4.74, 4.60 (ABq, JAB=9.2 Hz, 2H), 4.20-4.07 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ178.4, 154.7, 144.0, 141.8, 137.8, 132.6, 128.7, 123.8, 122.3, 121.5, 111.1, 109.8, 98.7, 79.5, 64.2, 63.6, 57.7; MS (ES+) m/z 295.9 (M+1).
Reaction SMILES: [C:1]([O:14]C)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH3:12].O.[OH-].[K+].II>CCOC(C)=O.C(O)(C)C>[C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH3:12]
Reactant: CCC=CCCCCCCCC(=O)OC
Agent: II
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCC=CCCCCCCCC(=O)O
Yield: 88.3 %

Procedure:
Methyl 9-dodecenoate (1273 g, 6.00 mol), water (540 mL), and isopropanol (300 mL) were added to a 5 L, 4-neck round-bottom flask at room-temperature. The flask was fitted with an over-head stirrer, condenser, a thermocouple, and an addition flask. Nitrogen was passed through the headspace for thirty-minutes while stirring. Potassium hydroxide (10 M, 660 mL, 6.60 mol) was added drop-wise over thirty-minutes. After stirring for about 45 minutes, an exotherm was observed and the mixture became homogenous. Within the next hour, stirring became impeded by formation of a gel. To re-enable stirring, an additional 300 mL of isopropanol was kneaded into the mixture with a metal spatula. The reaction was monitored by thin layer chromatography (10% EtOAc in hexanes eluent, iodine stain); reaction aliquots were quenched with aqueous hydrochloric acid, washed with water, then taken up in iPrOH. When all starting material had been consumed, the reaction was placed in an ice bath and acidified with 37% aqueous HCl (600 mL) while maintaining a temperature below 40° C. The reaction mixture was transferred into a large separatory funnel and washed with brine (3×250 mL), dried with magnesium sulfate, filtered, and dried in vacuo. The reaction was purified by vacuum distillation to give 9-dodecenoic acid (1054 g, 5.3 mol, 89% yield).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:23])[C:15]3[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[N:17][CH:16]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:26][CH:27]=[C:28]1[C:32](=O)[O:31][C:30]([CH3:34])=[N:29]1)C>C(O)C>[C:30]([NH:29][C:28]1[C:27](=[O:26])[N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:14]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:12][CH:11]=3)=[O:23])=[CH:16][N:17]=2)[NH:22][CH:32]=1)(=[O:31])[CH3:34]
Reactant: NNc1ccc(C(=O)Nc2ccc(C3CCCCC3)cc2)cn1
Reactant: CCOC=C1N=C(C)OC1=O
Solvent: CCO
Product: CC(=O)Nc1c[nH]n(-c2ccc(C(=O)Nc3ccc(C4CCCCC4)cc3)cn2)c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 5.5 %

Procedure:
N-(4-Cyclohexylphenyl)-6-hydrazinonicotinamide (0.20 g) and 4-(ethoxymethylene)-2-methyl-1,3-oxazol-5(4H)-one (0.12 g) were dissolved in ethanol (30 mL), and the solution was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure, and diisopropyl ether was added to the residue. The deposited solid was collected by filtration and washed with diisopropyl ether. The solid was dried under reduced pressure to obtain the title compound (0.015 g) as a white solid (yield: 5.5%).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:4].C([Li])CCC.CCCCCC.CN(C)[CH:27]=[O:28].Cl>O1CCCC1>[CH:27]([C:11]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[NH:5][C:3](=[O:4])[C:2]([CH3:13])([CH3:12])[CH3:1])=[O:28]
Reactant: CC(C)(C)C(=O)Nc1cccnc1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)C(=O)Nc1cnccc1C=O
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
A solution of 2,2-dimethyl-N-(3-pyridinyl)propanamide (3.56 gm, 20 mmol) (prepared as described in J. Org. Chem. 48, 3401 (1983)) in anhydrous tetrahydrofuran (40 mL) was cooled to −70° C. and a solution of 2.5 M n-butyl lithium/hexane (20 mL, 50 mmol) was added dropwise maintaining the temperature at −70° C. This reaction was slowly warmed to −5° C. giving a copious precipitate. This mixture was cooled to −70° C. and dry dimethyl formamide (4.64 mL, 60 mmol) was added. The reaction was allowed to warm to room temperature giving a clear yellow solution. This reaction was poured into 8 N aqueous HCl (16 mL) and ice. After stirring for 10 minutes the pH of the solution was adjusted to 7 and extracted with diethyl ether. The organic layer was dried (Na2SO4), filtered and the solvent evaporated. The residue was purified by column chromatography eluting with 30-100% ethyl acetate/hexane. The appropriate fractions were combined and the solvent removed in vacuo to give the title compound as a solid. 1H-NMR (500 MHz, CDCl3): δ 10.92 (1H, br s), 10.15 (1H, s), 10.05 (1H, s), 8.62 (2H, d, J=4.9 Hz), 7.56 (1H, d, J=4.9 Hz),), 1.39 (9H, s). m/e (m+1): 235.3.
Reaction SMILES: C(O)(=O)C.N=C1CC(C)CCN1.[NH2:13][C:14]1[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=1>>[ClH:20].[NH:13]=[C:14]1[CH2:19][CH2:18][CH:17]([C:21]([F:23])([F:22])[F:24])[CH2:16][NH:15]1
Reactant: Nc1ncc(C(F)(F)F)cc1Cl
Agent: CC1CCNC(=N)C1
Solvent: CC(=O)O
Product: Cl
Product: N=C1CCC(C(F)(F)F)CN1

Procedure:
The method of preparation of 2-imino-4-methylpiperidine acetate was used to convert 2-amino-3-chloro-5-(trifluoromethyl)pyridine to the title compound except platinum oxide was used as the catalyst. Product was triterated with ether to give a white solid. The analysis of the product was found to be consistent with the proposed structure. MH+=167; 1H NMR (D2O): δ3.65-3.50 (m, 1H); 3.40-3.20 (m, 1H); 2.85-2.45 (m, 3H); 2.15-2.00 (m, 1H); 1.80-1.60 (m, 1H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>[Cu].CN(C=O)C>[C:8]1([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([N:7]([C:8]4[C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[CH:11]=[CH:10][CH:9]=4)[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Reactant: c1ccc(Nc2cccc3ccccc23)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(N(c2ccc(-c3ccc(N(c4ccccc4)c4cccc5ccccc45)cc3)cc2)c2cccc3ccccc23)cc1
Temperature: 200 °C
Yield: 55.8 %

Procedure:
To 32.4 g (148 mmol) of N-phenyl-1-naphthylamine were added 25.1 g (61.5 mmol) of 4,4′-diiodobiphenyl, 2.14 g of polyethylene glycol (PEG-6000 (a trade name) manufactured by Wako Junyaku K.K.), 17.1 g (0.124 mol) of potassium carbonate and 15.7 g (247 mmol) of copper (powder) were added, and heated to 200° C. The reaction was traced by high-performance liquid chromatography. Heating was continued under stirring until the peaks of raw materials and intermediates were disappeared (for 12 hours). After the completion of the reaction, water and DMF are added, and the resulting mixture is dispersed, filtrated, and washed with water. The resulting crystal is purified by silica gel chromatography to afford 20.2 g (yield: 55.9%) of N,N′-di(l-naphthyl)-N,N′-diphenyl-4,4′-diaminobiphenyl represented by the formula:
Reaction SMILES: [CH2:1]([C@H:3]1[C:20](=O)[CH2:19][CH2:18][C@@:17]2([CH3:22])[CH:4]1[C:5](=[O:24])[CH2:6][C@@H:7]1[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]1[CH2:9][CH2:10][C:11]2=[O:23])[CH3:2].[ClH:25].Cl.[NH2:27][CH2:28][CH2:29][O:30][NH2:31]>C1COCC1.O>[ClH:25].[NH2:27][CH2:28][CH2:29][O:30]/[N:31]=[C:20]1/[C@H:3]([CH2:1][CH3:2])[CH:4]2[C@:17]([CH3:22])([CH2:18][CH2:19]/1)[C@@H:16]1[C@H:7]([C@H:8]3[C@@:12]([CH2:14][CH2:15]1)([CH3:13])[C:11](=[O:23])[CH2:10][CH2:9]3)[CH2:6][C:5]2=[O:24]
Reactant: CC[C@H]1C(=O)CC[C@@]2(C)C1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: NCCON
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC[C@H]1/C(=N/OCCN)CC[C@@]2(C)C1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 3.5 h

Procedure:
To a stirred solution of 4β-ethylandrostan-3,6,17-trione (Preparation 11, 67 mg) in THF (1.1 ml), a solution of 2-aminoethoxyamine dihydrochloride (31 mg) and Na2HPO4.12H2O (15 mg) in H2O (0.55 ml) was added in portions over 45 minutes. After 3.5 h, the solution was evaporated, water was added and the aqueous phase was extracted with THF. The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated to dryness. The crude product was triturated with Et2O and the precipitate was filtered to give the title compound I-bd (34 mg, 42%).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[N:13]1([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[C:21]3=[O:28])[CH:17]=[N:16][CH:15]=[N:14]1.[NH:29]([C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:40][CH3:41])(=[O:39])=[O:38])=[CH:33][CH:32]=1)[NH2:30]>>[N:13]1([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[C:21]3=[O:28])[CH:17]=[N:16][CH:15]=[N:14]1.[CH3:41][NH:40][S:37]([C:34]1[CH:35]=[CH:36][C:31]([NH:29][N:30]=[C:21]2[C:8]3[C:9](=[CH:10][CH:11]=[C:6]([N:1]4[CH:5]=[N:4][CH:3]=[N:2]4)[CH:7]=3)[NH:12][C:22]2=[O:27])=[CH:32][CH:33]=1)(=[O:39])=[O:38]
Reactant: CNS(=O)(=O)c1ccc(NN)cc1
Reactant: Nc1ccc(-n2cncn2)cc1
Agent: O=C1Nc2ccc(-n3cncn3)cc2C1=O
Product: CNS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(-n4cncn4)cc32)cc1

Procedure:
5-[1,2,4]Triazol-1-yl-1H-indole-2,3dione was prepared from 4-[1,2,4]-triazol-1-yl-phenylamine according to Procedure A in 6% yield: 1H NMR (DMSO-d6): δ 7.04 (d, J=8.4 Hz, 1H), 7.97 (d, J=2.2 Hz, 1H), 8.01 (dd, J=2.2, 8.4 Hz, 1H), 8.20 (s, 1H), 9.26 (s, 1H), 11.19 (bs, 1H); APCI−MS m/z 215 (M+1)+. Condensation of 5-[1,2,4]triazol-1-yl-1H-indole-2,3-dione with 4-hydrazino-N-methyl-phenylsulfonamide according to Procedure G gave the title compound in 86% yield: 1H NMR (DMSO-d6): δ 2.38 (d, J=5.0 Hz, 3H), 7.05 (d, J=8.4 Hz, 1H), 7.30 (q, J=5.0 Hz, 1H), 7.65 (d, J=8.7 Hz, 2H), 7.72 (d, J=8.7 Hz, 3H), 8.01 (s, 1H), 8.20 (s, 1H), 9.23 (s, 1H), 11.27 (s, 1H), 12.80 (s, 1H); Anal. Calcd for C16H15N7O3S.1.3 H2O: C, 48.52, H, 4.22; N, 23.30; S, 7.62. Found C, 48.53, H, 4.25; N, 23.17; S, 7.55.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[F:12][C:13]([F:18])([F:17])[C@H:14]([OH:16])[CH3:15]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([NH2:9])=[C:2]([O:16][C@H:14]([CH3:15])[C:13]([F:18])([F:17])[F:12])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: C[C@@H](O)C(F)(F)F
Product: C[C@@H](Oc1cc(F)ccc1N)C(F)(F)F

Procedure:
Is prepared in a similar manner as intermediate III.1 from 2,4-difluoro-1-nitro-benzene and (2R)-1,1,1-trifluoropropan-2-ol.