Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=[CH:6][N:5]=1)([O-:3])=[O:2].[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C(N(CC)CC)C>C(O)C>[N+:1]([C:4]1[C:9]([CH2:10][CH2:11][NH:12][CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)=[CH:8][CH:7]=[CH:6][N:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: C=Cc1cccnc1[N+](=O)[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(NCCc2cccnc2[N+](=O)[O-])CC1
Temperature: 90 °C
Yield: 48 %

Procedure:
2-Nitro-3-vinylpyridine (0.300 g, 2 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (0.601 g, 3.00 mmol), and ethanol (5 ml) were combined. Triethylamine (0.836 ml, 6.00 mmol) was added. The vial was capped and heated at 90° C. for 62 hours. More tert-butyl 4-aminopiperidine-1-carboxylate (0.601 g, 3.00 mmol), and triethylamine (0.836 ml, 6.00 mmol) were added and the mixture was heated at 90° C. for 20 hours. Mixture was concentrated by roto-vap. Silica gel chromatography eluting ethyl acetate-hexanes afforded the title compound as tan solid in 48% yield. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 8.38 (dd, J=4.58, 1.53 Hz, 1 H) 7.84 (dd, J=7.63, 1.53 Hz, 1 H) 7.49 (dd, J=7.63, 4.58 Hz, 1 H) 3.92 (s, 2 H) 2.85-2.98 (m, 3 H) 2.75 (t, J=11.75 Hz, 2 H) 2.50-2.62 (m, 1 H) 1.75 (d, J=12.51 Hz, 2 H) 1.40 (s, 9 H) 1.00-1.27 (m, 4 H).
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH3:14])[CH:4]=1)=O.[C:15](=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][C:5]1[CH:4]=[C:3]([CH:1]=[CH2:15])[CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1ccc(C=O)cc1C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Product: C=Cc1ccc(C(=O)OCC)c(C)c1
Temperature: 100 °C
Yield: 262.8 %

Procedure:
To a stirred solution of ethyl 4-formyl-2-methylbenzoate (2.8 g, 4 mmol) in 1,4-dioxane (20 mL) were added potassium carbonate (K2CO3; 3.01 g, 21.87 mmol) and methyltriphenyl phosphonium bromide (7.8 g, 21.87 mmol) at 25° C. Then the reaction mixture was heated at 100° C. for 18 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to 25° C. and filtered, and the filtrate was concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh; eluting with 25-30% EtOAc in n-Hexane) to afford the title compound as a solid (2.0 g, 72%): 1H NMR (400 MHz, CDCl3) δ 7.86 (m, 1H), 7.27 (m, 2H), 6.68 (dd, J=17.6, 10.8 Hz, 1H), 5.84 (d, J=17.6 Hz, 1H), 5.39 (d, J=10.8 Hz, 1H), 4.39 (m, 2H), 2.60 (s, 3H), 1.40 (m, 3H); ESIMS m/z 191.10 ([M−H]−); IR (thin film) 2980, 1716, 1257 cm−1.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[NH:10][CH:11]([C:16]1[CH:20]=[C:19]([CH:21]=O)[O:18][N:17]=1)[CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:30]([O:36][CH2:37][CH3:38])(=[O:35])[CH2:31]C(O)=O>O>[CH2:37]([O:36][C:30](=[O:35])[CH:31]=[CH:21][C:19]1[O:18][N:17]=[C:16]([CH:11]([NH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:23])[CH2:12][CH:13]([CH3:14])[CH3:15])[CH:20]=1)[CH3:38]
Reactant: CCOC(=O)CC(=O)O
Reactant: CC(C)CC(NC(=O)OCc1ccccc1)c1cc(C=O)on1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)C=Cc1cc(C(CC(C)C)NC(=O)OCc2ccccc2)no1
Temperature: 55 °C
Yield: 95.5 %

Procedure:
A stirred mixture of [1-(5-formyl-isoxazol-3-yl)-3-methyl-butyl]-carbamic acid benzyl ester (407 mg, 1.3 mmol), pyridine (10 ml) and ethyl hydrogen malonate (255 mg, 1.9 mmol) was warmed to 55° C. After 2 days the mixture was cooled to room temperature, poured into water and extracted into EtOAc (3×). The combined organics were washed with 1N HCl, water, and brine; dried over NaSO4, filtered and concentrated under reduced pressure to give 480 mg of a yellow oil. Purification by Flash 40(small) chromatography eluting with 1:3 EtOAc/hexane gave 220 mg of the title compound as a light yellow oil. MS [M+1]+ 387.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH3:28][C:29]([CH3:31])=[O:30].P([O-])(O)(O)=O.[K+]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([C:29]([OH:30])([CH3:31])[CH3:28])=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1cc(-c2ccccc2)on1
Reactant: CC(C)=O
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1noc(-c2ccccc2)c1C(C)(C)O
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 44 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-phenylisoxazole (0.8 g) was dissolved in tetrahydrofuran (16 ml), butyllithium (1.6M hexane solution, 3.7 ml) was added dropwise thereto at -70° C. under a nitrogen atmosphere, and the resulting mixture was stirred at the same temperature for 10 minutes. After acetone (0.3 ml) was added dropwise to the reaction mixture and the mixture was stirred for 10 minutes, the temperature of the mixture was raised to 0° C. The reaction mixture was poured into ice-cold water and the pH of the mixture was adjusted to a value of 6 with an aqueous potassium dihydrogenphosphate solution. The mixture was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous NaCl solution, followed by evaporation of the solvent under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=3/1) to obtain the title compound (0.42 g, 44%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:21]=[CH:20]3)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]C(C)(C)C.C[O:39][B:40](OC)[O:41]C>C1COCC1>[C:29]([O:28][C:26]([N:22]1[C:23]2[C:19](=[CH:18][C:17]([S:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)(=[O:16])=[O:15])=[CH:25][CH:24]=2)[CH:20]=[C:21]1[B:40]([OH:41])[OH:39])=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: COB(OC)OC
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3c(ccn3C(=O)OC(C)(C)C)c2)CC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3c(c2)cc(B(O)O)n3C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of the tert-butyl 5-{[4-(tert-butoxycarbonyl)piperazin-1-yl]sulfonyl}-1H-indole-1-carboxylate (2-4, 1.06 g) in THF (55 mL) was stirred at −78° C. and treated with t-BuLi (1.7M, 2.68 mL, 4.55 mmol). After stirring for 45 minutes, the solution was treated with trimethylborate (640 μL, 5.69 mmol). The solution was warmed to 0° C. and stirred for 10 min, then partitioned between ethyl acetate (2×100 mL) and saturated NH4Cl solution (100 mL). The combined organics were dried over Na2SO4, filtered and concentrated to provide 1-(tert-butoxycarbonyl)-5-{[4-(tert-butoxycarbonyl)piperazin-1-yl]sulfonyl}-1H-indol-2-ylboronic acid (2-5) as a yellow foam. LRMS m/z: Cal'd for C22H32BN3O8S (M+H) 509.39, found 510.1.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:6]#[N:7].Cl.[CH3:15][NH:16][CH3:17].C(N(CC)CC)C>C(Cl)Cl>[CH3:15][N:16]([CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:6]#[N:7])[CH3:17]
Reactant: CNC
Reactant: N#Cc1cc(CBr)cc([N+](=O)[O-])c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)Cc1cc(C#N)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
To a stirred mixture of 3-(bromomethyl)-5-nitrobenzonitrile (1.50 g, 6.22 mmol) (prepared according to the method described in J. Org. Chem. 55: 1040-1043 (1990)) and dimethylamine hydrochloride (1.01 g, 12.44 mmol) in CH2Cl2 (15 mL) was added triethylamine (1.88 g, 18.66 mmol) dropwise at 0° C. The resulting mixture was stirred at room temperature for 3 h and evaporated to dryness under reduced pressure. The residue was diluted with water (15 mL) and extracted with EtOAc (3×50 mL). The EtOAc solution was dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 3-((dimethylamino)methyl)-5-nitrobenzonitrile (1.10 g, 87%) as a viscous liquid. 1H NMR (400 MHz, CDCl3): δ 8.45 (s, 1 H), 8.40 (d, 1H, J=1.6 Hz), 8.01 (s, 1H), 3.59 (s, 2H), 2.30 (s, 6H).
Reaction SMILES: [Cl:1][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[C:17]3[N:16]=[CH:15][N:14]=[C:12]([NH2:13])[C:11]=3[N:10]=[C:9]2[CH3:18])[C@H:5]([OH:19])[C@@H:4]1[OH:20].N1C=CC=C[CH:22]=1.O=S(Cl)Cl>CC#N>[Cl:1][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[C:17]3[N:16]=[CH:15][N:14]=[C:12]([NH2:13])[C:11]=3[N:10]=[C:9]2[CH2:18][CH3:22])[C@H:5]([OH:19])[C@@H:4]1[OH:20]
Reactant: c1ccncc1
Reactant: Cc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1O
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: CCc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1O

Procedure:
The procedure was the same as reported above for 3a using 2b40 (1.28 g, 4.33 mmol), pyridine (685 mg, 0.70 mL, 8.65 mmol), CH3CN (10 mL), and SOCl2 (2.57 g, 1.58 mL, 21.60 mmol): yield 498 mg (37%); MS m/z 314 (M+H)+; 1HNMR (DMSO-d6) δ 8.09 (bs, 1H, H-2), 7.14 (bs, 2H, 6-NH2), 5.80 (d, 1H, H-1′, J1′,2′=5.7 Hz), 5.48 (d, 1H, 2′-OH, J2′-2′OH=6.1 Hz), 5.45 (d, 1H, 3′-OH, J3′-3′OH=5.4 Hz), 5.20 (ddd, 1H, H-2′, J1′,2′=5.7 Hz, J2′,3′=4.6 Hz, J2′-2′OH=6.1 Hz), 4.30-4.37 (bm, 1H, H-3′), 4.03-4.10 (bm, 1H, H-4′), 3.94-4.0 (m, 1H, 5′-CH2), 3.83-3.89 (m, 1H, 5′-CH2), 2.89 (q, 2H, 8-CH2CH3), 1.31 (t, 3H, 8-CH2CH3).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[N:24]([CH:31]2[CH2:34][CH2:33][CH2:32]2)[N:25]=[C:26]([CH:28]2[CH2:30][CH2:29]2)[CH:27]=1)=[O:4].[OH-].[Li+]>>[CH:31]1([N:24]2[C:23]([N:6]3[CH2:7][C@H:8]([S:10]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:19]([F:20])([F:21])[F:22])(=[O:12])=[O:11])[CH2:9][C@H:5]3[C:3]([OH:4])=[O:2])=[CH:27][C:26]([CH:28]3[CH2:29][CH2:30]3)=[N:25]2)[CH2:34][CH2:33][CH2:32]1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C2CC2)nn1C1CCC1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C2CC2)nn1C1CCC1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-1-(2-cyclobutyl-5-cyclopropyl-2H-pyrazol-3-yl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as yellow solid which was used in the next step without further purification.
Reaction SMILES: C(NCC)C.C(O)(C)(C)C.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][C:13]=1[N+:21]([O-:23])=[O:22].Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=1)=[O:27].S(=O)(=O)(O)O>[Cl-].[Zn+2].[Cl-].C1C=CC=CC=1>[Br:34][C:31]1[CH:32]=[CH:33][C:28]([C:26](=[O:27])[CH2:25][CH2:19][C:18]([C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[C:13]([N+:21]([O-:23])=[O:22])[CH:14]=2)=[O:20])=[CH:29][CH:30]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)(C)O
Solvent: c1ccccc1
Solvent: CCNCC
Product: O=C(CCC(=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
Zinc chloride (2.73 g, 20 mmole) was treated with anhydrous benzene (10 mL) followed by diethylamine (1.55 mL, 15 mmole) and tert-butanol (1.4 mL, 15 mmole) and the resulting slurry was stirred at room temperature for 1.75 hr until all solids had dissolved. To the cloudy suspension was added 4′-chloro-3′-nitroacetophenone followed by 2,4′-dibromoacetophenone and the resulting light yellow slurry was stirred at room temperature for 68 hours. The resulting thick white slurry was treated with 25 mL 5% aqueous sulfuric acid with stirring and the resulting slurry was filtered. The solid was washed with water (50 mL), MeOH (50 mL) and CH2Cl2 (50 mL), then dried in vacuo at room temperature for 1 hr and at 55° C. for 5 hr. giving the title compound as a white solid, 3.4 g, 86%.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19](O)=[O:20])=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)=[N:4][N:3]=1.[CH2:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:40]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][NH:37][C:38]=4[CH:39]=3)[O:31][CH2:30]2)[CH2:26][CH2:25]1)[CH3:23]>>[CH2:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:40]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][N:37]([C:19]([C:16]5[CH:15]=[CH:14][C:13]([C:10]6[CH:11]=[CH:12][C:7]([C:5]7[O:6][C:2]([CH3:1])=[N:3][N:4]=7)=[CH:8][CH:9]=6)=[CH:18][CH:17]=5)=[O:20])[C:38]=4[CH:39]=3)[O:31][CH2:30]2)[CH2:26][CH2:25]1)[CH3:23]
Reactant: Cc1nnc(-c2ccc(-c3ccc(C(=O)O)cc3)cc2)o1
Reactant: CCN1CCC2(CC1)COc1cc3c(cc12)NCC3
Product: CCN1CCC2(CC1)COc1cc3c(cc12)N(C(=O)c1ccc(-c2ccc(-c4nnc(C)o4)cc2)cc1)CC3
Yield: 31 %

Procedure:
The title compound was prepared from 4'-(5-methyl-1,3,4-oxadiazol-2-yl)biphenyl-4-carboxylic acid (D11) and 1'-ethyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D109) using a similar procedure as that outlined in Example 1, to afford the title compound as a yellow gum (31%). This was converted to its hydrochloride salt to yield an off white solid m.p. 245-249° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH2:16])=[CH:4][C:5]([CH3:13])=[C:6]2[C:10]=1[C:9](=[N:11]O)[CH2:8][CH2:7]2.[H][H].[ClH:25]>C(O)(=O)C.C(O)C.[Pt]=O>[ClH:25].[NH2:11][CH:9]1[C:10]2[C:6](=[C:5]([CH3:13])[CH:4]=[C:3]([CH:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:15][CH3:16])[C:2]=2[OH:1])[CH2:7][CH2:8]1
Reactant: C=CC(c1ccccc1)c1cc(C)c2c(c1O)C(=NO)CC2
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: CCC(c1ccccc1)c1cc(C)c2c(c1O)C(N)CC2

Procedure:
2.93 Grams of 2,3-dihydro-7-hydroxy-4-methyl-6-(1-phenyl-2-propenyl)-1H-inden-1-one oxime and 0.293 g of platinum oxide were suspended in 200 ml of acetic acid, then the suspension was reduced at room temperature under 3 atmospheric hydrogen pressure for 8 hours. After the completion of hydrogenation, the catalyst was removed by filtration, and the filtrate thus obtain was concentrated to dryness under a reduced pressure. The residue thus obtained was dissolved in 100 ml of ethanol and the pH of the solution was adjusted to about pH=1 by adding an ethanol solution saturated with hydrogen chloride gas, then this solution was again concentrated to dryness under a reduced pressure. The residue thus obtained was recrystallized from ethanoldiethyl ether to obtain 0.88 g of 1-amino-2,3-dihydro-7-hydroxy-4-methyl-6-(1-phenylpropyl)-1H-indene hydrochloride. Colorless powdery crystals. Melting point: 187.5°-189.5° C.
Reaction SMILES: [C:1]1(=[O:8])O[C:5](=[O:6])[CH:4]=[C:2]1[CH3:3].Cl.Cl.[CH2:11]([NH:18][NH2:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(=O)C.[K+]>C(O)(=O)C>[CH2:11]([N:18]1[C:5](=[O:6])[CH:4]=[C:2]([CH3:3])[C:1](=[O:8])[NH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1=CC(=O)OC1=O
Reactant: NNCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1cc(=O)n(Cc2ccccc2)[nH]c1=O

Procedure:
A slurry of citraconic anhydride (5.61 g, 50.0 mmol), benzylhydrazine dihydrochloride (9.80 g, 50.0 mmol) and potassium acetate (9.80 g, 100 mmol) in acetic acid (100 mL) was heated to reflux for 17 h. The reaction mixture was cooled and filtered. The filtrate was evaporated under reduced pressure and re-evaporated from toluene. The gummy yellow residue was partitioned between sodium carbonate solution (90 mL, 4 N) and EtOAc (50 mL). The aqueous extract was washed once with EtOAc and then slowly added to hydrochloric acid (3 M, 140 mL). The resulting white precipitate was collected, washed with water and dissolved in chloroform (1 L). The insoluble material was collected and boiled in EtOAc and filtered hot, to give 1,2-dihydro-1-benzyl-4-methyl-3,6-pyridazinedione as a white solid, mp >200° C. (1.85 g, 17%). Part IA compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-])=O)[C:5]([O:7][CH3:8])=[O:6].C(Cl)Cl.O>C(O)(=O)C.[Fe]>[NH2:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(N)c(F)c1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 96.9 %

Procedure:
A mixture of methyl 3-fluoro-4-nitrobenzoate(2.14 g, 10.8 mmol) and iron powder(2.63 g) in acetic acid(22 ml) was stirred at 50° C. for 2.5 h. After cooling down to room temperature, CH2Cl2(100 ml) and water(300 ml) was added to the mixture and filtered to remove iron powder. The organic layer was separated and the aqueous layer was extracted with CH2Cl2(70 mlx2). The CH2Cl2 solution was combined, washed with water, brine, dried(Na2SO4), and concentrated to give 1.77 g(97%) of pale brown solid.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=O.C1(C)C=CC=CC=1.[CH3:15][NH:16][NH2:17]>C1COCC1>[CH3:15][NH:16]/[N:17]=[CH:2]/[C:1]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CNN
Reactant: CCOC(=O)C=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)/C=N/NC
Temperature: 0 °C
Reaction time: 16 h
Yield: 78.8 %

Procedure:
47% ethyl glyoxylate in toluene (polymer type) (467.84 g, 2.15 mol) was dissolved in THF (620 ml), to the solution was slowly added methylhydrazine (103 g, 1.02 eq) under ice-cooled. After the addition was complete, the mixture was stirred at 0° C. for 30 minutes and at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in toluene (400 ml), and concentrated under reduced pressure. The resulting solid was washed with tert-butyl methyl ether (200 ml), and allowed to stand at 0° C. for 30 minutes. Then, the mixture was filtered, and washed with cooled tert-butyl methyl ether (100 ml) to give 223.91 g of Compound (XVI-1) (yield: 78.8%) as solid.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH3:19][C:20]1[CH:33]=[CH:32][C:23]([C:24]([NH:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)=[O:25])=[CH:22][C:21]=1B1OC(C)(C)C(C)(C)O1>>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:17]=[CH:18][C:2]([C:21]3[CH:22]=[C:23]([C:24](=[O:25])[NH:26][C:27]4[S:28][CH:29]=[CH:30][N:31]=4)[CH:32]=[CH:33][C:20]=3[CH3:19])=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(NC(=O)c2ccc(Cl)nc2)cc1
Product: COc1ccc(NC(=O)c2ccc(-c3cc(C(=O)Nc4nccs4)ccc3C)nc2)cc1

Procedure:
N-(4-Methoxyphenyl)-6-[2-methyl-5-(thiazol-2-ylcarbamoyl)-phenyl]-nicotinamide was prepared from 6-chloro-N-(4-methoxyphenyl)nicotinamide (Intermediate 2) and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide (Intermediate 11) using General Method B. LCMS: retention time 3.22 min, MH− 445. NMR: δH [2H6]-DMSO 12.72,(1H, s), 10.40,(1H, s), 9.22,(1H, d), 8.44,(1H, dd), 8.24,(1H, s), 8.09,(1H, d), 7.87,(1H, d), 7.71,(2H, d), 7.58,(1H, d), 7.53,(1H, d), 7.30,(1H, d), 6.97,(2H, d), 3.76,(3H, s), 2.48,(3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](Br)[C:5]([C@@H:8]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[N:6][CH:7]=1.[Cl:27][C:28]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[C:33]2[C:29]=1[C:30]([NH:47][S:48]([CH3:51])(=[O:50])=[O:49])=[N:31][N:32]2[CH3:46].C(=O)(O)[O-].[Na+]>C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.Cl[Pd]Cl.O1CCOCC1>[NH2:1][C:2]1[CH:3]=[C:4]([C:34]2[CH:35]=[CH:36][C:28]([Cl:27])=[C:29]3[C:33]=2[N:32]([CH3:46])[N:31]=[C:30]3[NH:47][S:48]([CH3:51])(=[O:49])=[O:50])[C:5]([C@@H:8]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1ncc(N)cc1Br
Reactant: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(B3OC(C)(C)C(C)(C)O3)c21
Agent: Cl[Pd]Cl
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3cc(N)cnc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)OC(C)(C)C)c21
Temperature: 150 °C

Procedure:
In a microwave tube were charged with of (S)-tert-butyl (1-(5-amino-3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (46A, 350 mg, 0.8 mmol), N-(4-chloro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)methanesulfonamide (410 mg, 1.06 mmol) and PdCl2[P(Cy)3]2 (18 mg, 0.025 mmol). To the mixture was added 16 mL of 1,4-dioxane and 4.9 mL of sodium bicarbonate aqueous solution (1M). The system was purged with argon and then the microwave tube was sealed and the reaction mixture was heated up in a heating bath at 150° C. for 1 hour. After cooling to room temperature, the reaction was partitioned between EtOAc and water. The organic layer was separated and washed with brine, then dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with EtOAc/hexanes to afford the title product. MS (m/z): 606.88 [M+H]+.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CCCCCC.C([Li])CCC.[Cl-:25].[Cl-].[CH3:27][C:28]1([Zr+2:33][C:34]2([CH3:39])[CH:38]=[CH:37][CH:36]=[CH:35]2)[CH:32]=[CH:31][CH:30]=[CH:29]1>C(OCC)C>[Cl-:25].[CH3:27][C:28]1([Zr+:33]([C:34]2([CH3:39])[CH:38]=[CH:37][CH:36]=[CH:35]2)[C:1]2[C:13]3[CH2:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[CH:4]=[CH:3][CH:2]=2)[CH:29]=[CH:30][CH:31]=[CH:32]1
Reactant: CC1([Zr+2]C2(C)C=CC=C2)C=CC=C1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1([Zr+](c2cccc3c2Cc2ccccc2-3)C2(C)C=CC=C2)C=CC=C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
About 2.4 mmol of fluorene was dissolved in 50 ml of diethylether and mixed with 1.5 ml of a 1.6M hexane solution of butyllithium and stirred for 2 hrs at room temperature. Then 0.77 g of bis(methylcyclopentadienyl) zirconium dichloride was added. The reaction mixture was then stirred for an addition 90 mins. Then the solvent was removed using a vacuum. The residue was extracted with toluene and a suspension filtered over sodium sulfate. The filtrate was freed from solvent and taken up in 50 ml of diethylether. Crystallization at -30° C. yields the product bis(methylcyclopentadienyl) (fluorenyl) zirconium chloride, referred to hereinafter as Catalyst No. 79. The x-ray analysis of the solid Catalyst No. 79 is believed to demonstrate that the fluorenyl is a σ-bound ligand rather than a π-bound ligand.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)[N:3]=1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C.O>CN(C)C=O>[S:9]1[CH:10]=[CH:11][C:7]([C:4]2[N:3]=[C:2]([N:15]3[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]3)[S:6][N:5]=2)=[CH:8]1
Reactant: Clc1nc(-c2ccsc2)ns1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccsc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To a solution of 5-chloro-3-(3-thienyl)-1,2,4-thiadiazole (2.47 g, 12.2 mmol) and tert-butyl piperazine-1-carboxylate (2.27 g, 12.2 mmol) in dimethylformamide (25 ml) was added triethylamine (6.8 ml, 48.8 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=9:1) to give 3.72 g (86.5%) of the desired product as a solid.