Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:17]([O-])=O)=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][C:8](=[O:15])[N:7]=[C:6]2[CH3:16].[OH-].[NH4+]>O>[CH3:1][O:2][C:3]1[C:4]([NH2:17])=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][C:8](=[O:15])[N:7]=[C:6]2[CH3:16]
Reactant: COc1cc2[nH]c(=O)nc(C)c2c([N+](=O)[O-])c1OC
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COc1cc2[nH]c(=O)nc(C)c2c(N)c1OC
Reaction time: 0.5 h

Procedure:
A solution of 13 equivalents of FeSO4.7H2O in water (6 parts) is heated to 95° C. A slurry of 1 equivalent of 6,7-dimethoxy-5-nitro-4-methyl-2(1H)quinazolinone in water (800 ml) at 80° C. is added and the resulting yellow mixture is heated at 98°-100° C. for 15 minutes. Ammonium hydroxide (13 eq) is added to the mixture dropwise over a 15 minute period, maintaining the temperature at 98°-100° C. The resulting black reaction mixture is stirred at 98°-100° C. for 30 minutes, the hot mixture is filtered and the insoluble black residue is washed with hot water. The brownish filtrate is extracted with chloroform. The solvent is removed in vacuo to give a dark brown semisolid crude product, which is chromatographed on a silica gel column. Recrystallization of the crude product from ethyl alcohol affords purified product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[NH:9][C:10](=[O:12])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:13](Cl)(=[O:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[C:13]([C:6]1[C:7]2[S:11][C:10](=[O:12])[NH:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:15])[CH3:14]
Reactant: COc1cccc2sc(=O)[nH]c12
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(C)=O)c2sc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-methoxy-1,3-benzothiazol-2(3H)-one (DE 3017977 A1) (1.92 g) in dry dichloromethane (50 ml) was cooled to ˜5° C. under nitrogen. Acetyl chloride (1.43 ml) and aluminium chloride (3.43 g) were added in one portion, and stirred for 2 h at RT. The reaction was quenched carefully with water, followed by addition of 2N HCl and dichloromethane. The aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with brine and dried (Na2SO4) and evaporated in vacuo to give the title compound (1.92 g). LCMS RT=2.50 min
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]([O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=3)=[N:18][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)=[CH:20][CH:21]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:38]([C:35]1[CH:36]=[CH:37][C:32]([O:31][C:17]2[C:16]([C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[O:15])=[CH:21][CH:20]=[C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[N:18]=2)=[CH:33][CH:34]=1)#[N:39]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Oc3ccc(C#N)cc3)nc2Oc2ccc(C#N)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(Oc2ccc(C(=O)N3CCNCC3)c(Oc3ccc(C#N)cc3)n2)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
4-[2,6-Bis-(4-cyano-phenoxy)pyridine-3-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester 1.2 g (2.28 mmol) was dissolved in 5 ml of DCM at 5° C. under inert atmosphere. 0.7 ml of TFA was added over a 10 min period, while the temperature was maintained at 5° C. Stirring was continued for 1 h at RT and reaction progress was monitored by TLC. The reaction mixture was concentrated under reduced pressure and the residual crude product was purified by column chromatography using chloroform: ethylacetate (8:2) as eluant to afford 0.9 g of the required product. Percentage purity (LCMS): 88.2%, (M+1): 425.1. 1H NMR (DMSO-d6): δ 3.15 (2H, m), 3.22 (2H, m), 3.64 (2H, m), 3.85 (2H, m), 7.00 (1H, d), 7.34 (4H, t), 7.82 (4H, t), 8.08 (1H, d), 9.02 (1H, brs).
Reaction SMILES: C([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=4[CH:16]=3)[CH:13]=2)[CH:8]=[C:7]([C:29]([O:31]C)=[O:30])[CH:6]=1)(=O)C>O>[OH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:21]([CH3:25])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:27])([CH3:28])[C:17]=4[CH:16]=3)[CH:13]=2)[CH:8]=[C:7]([C:29]([OH:31])=[O:30])[CH:6]=1
Reactant: COC(=O)c1cc(OC(C)=O)c2cc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)ccc2c1
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(-c3ccc4cc(C(=O)O)cc(O)c4c3)ccc21
Yield: 87.9 %

Procedure:
1.7 g (3.95 mmoles) of ester obtained in Example 1 are added to a mixture of 100 ml of methanolic soda (2M) and 50 ml of water. The mixture is heated for 4 hours, evaporated dry, and, after 100 ml of water are added, extracted with ether (300 ml). The aqueous phase of the product is recuperated, brought to pH 1 with concentrated hydrochloric acid. After extraction of the precipitate with ether (300 ml), it is washed in water until neutral, then dried and evaporated. The solid obtained is recrystallized in acetonitrile. Thus is obtained 1.3 g (88%) of 4-hydroxy-6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-naphthoic acid which melts at 299° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:50][C@@H:51]1[CH2:56][NH:55][CH2:54][C@H:53]([CH3:57])[NH:52]1.C(O)(=O)C>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:55]6[CH2:54][C@H:53]([CH3:57])[NH:52][C@H:51]([CH3:50])[CH2:56]6)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[N:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(C=O)c3)c2)n1
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4C[C@@H](C)N[C@@H](C)C4)c3)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.5 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]-2,6-pyridinedicarboxamide (0.059 mmol) was diluted in DMSO (1.5 mL) and dispensed into a 1 dram vial containing (2R,6S)-2,6-dimethylpiperazine (0.177 mmol, 3.0 eq) and acetic acid (3.55 mg, 0.059 mmol) and fitted a magnetic stir bar. The resulting solution was stirred at room temperature for 4 h. MP-B(OAc)3H (0.591 mmol, 138 mg, 10.0 eq) was added and the solution was stirred for another 12 h. The polymer reagent was filtered. Purification was completed via a Gilson HPLC (acidic conditions). The product was dissolved in 3 mL of MeOH and passed through 0.5 g amine columns (washed with 8 mL of MeOH) to afford 29.9 mg of the title compound (66.5%). LC-MS m/z 763 (M+H)+, 1.31 min (ret time).
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][C:6]=1[CH2:7][Cl:8])[CH:2]([CH3:4])[CH3:3].[Br:16]Br>[Fe].C(Cl)(Cl)(Cl)Cl>[Br:16][C:11]1[C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][C:6]([CH2:7][Cl:8])=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH:12]=1
Reactant: BrBr
Reactant: CC(C)Cc1ccc(C(C)C)cc1CCl
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)Cc1cc(Br)c(C(C)C)cc1CCl

Procedure:
In a flask are placed 225 parts of 2-isobutyl-5-isopropylbenzyl chloride, 300 parts of carbon tetrachloride and 2.5 parts of iron powder. Bromine (160 parts) in 100 parts of carbon tetrachloride is added dropwise during 7 hr. The solution is washed twice with hydrochloric acid then with sodium bicarbonate solution, dilute sodium bisulfite solution, and water. The solution is dried, the carbon tetrachloride removed, and the 4-bromo-2-isobutyl-5-isopropylbenzyl chloride distilled under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1[C:6]([S:7]([N:10]2[CH2:20][CH2:19][C:13]3([C:17](=[O:18])[NH:16][CH2:15][CH2:14]3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])=[C:5]([CH3:21])[O:4][N:3]=1.I[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1>>[CH3:1][C:2]1[C:6]([S:7]([N:10]2[CH2:11][CH2:12][C:13]3([C:17](=[O:18])[N:16]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[CH2:15][CH2:14]3)[CH2:19][CH2:20]2)(=[O:9])=[O:8])=[C:5]([CH3:21])[O:4][N:3]=1
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: Cc1noc(C)c1S(=O)(=O)N1CCC2(CCNC2=O)CC1
Product: Cc1noc(C)c1S(=O)(=O)N1CCC2(CCN(c3ccc(C(F)(F)F)cc3)C2=O)CC1

Procedure:
This material was prepared according to example 162 step B) from 8-(3,5-dimethyl-isoxazole-4-sulfonyl)-2,8-diaza-spiro[4.5]decan-1-one and 1-iodo-4-trifluoromethyl-benzene. Off white solid. MS (ESI): 458.13 MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([NH:14][CH3:15])=[O:13])[CH:6]=[CH:5]2.O1CCCC1.C([Mg]Cl)(C)C.CCCCCC.C([Li])CCC.[C:37]1([S:43]([N:46]2[CH:50]=[C:49]([CH:51]=[O:52])[N:48]=[CH:47]2)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[OH:52][CH:51]([C:49]1[N:48]=[CH:47][N:46]([S:43]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)(=[O:45])=[O:44])[CH:50]=1)[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([NH:14][CH3:15])=[O:13])[CH:6]=[CH:5]2
Reactant: CNC(=O)c1ccc2cc(Br)ccc2c1
Reactant: O=Cc1cn(S(=O)(=O)c2ccccc2)cn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CNC(=O)c1ccc2cc(C(O)c3cn(S(=O)(=O)c4ccccc4)cn3)ccc2c1
Temperature: -30 °C
Yield: 57.5 %

Procedure:
Under a nitrogen atmosphere, 6-bromo-N-methyl-2-naphthamide (10.0 g, 37.9 mmol) was added to tetrahydrofuran (250 mL), and to the obtained solution was added dropwise 2.0 mol/L isopropylmagnesium chloride tetrahydrofuran solution (18.9 mL) at room temperature. The obtained reaction mixture was cooled to −30° C., 1.65 mol/L n-butyllithium hexane solution (37.9 mL) was added dropwise thereto, and the mixture was stirred at the same temperature for 1 hr or more. To the reaction mixture was added dropwise a solution of 1-(phenylsulfonyl)-4-formyl-1H-imidazole (13.4 g, 56.8 mmol) in tetrahydrofuran (100 mL) at −20° C., and the mixture was stirred at the same temperature for 2 hr. The reaction mixture was warmed over 2 hr to 0° C., and 20 w/v % aqueous ammonium chloride solution (150 mL) was added dropwise thereto. The separated organic layer was concentrated to the volume of about 130 mL under reduced pressure to give a residue. To the obtained residue was added tetrahydrofuran (200 mL), and the mixture was concentrated to the volume of about 130 mL under reduced pressure to give a residue. To the obtained residue was added ethyl acetate (200 mL), and the mixture was concentrated to the volume of about 200 mL under reduced pressure. These operations were repeated three times to give a residue. To the obtained residue was added ethyl acetate to adjust the volume to about 200 mL. The obtained reaction mixture was stirred at room temperature for 2 hr or more to give crystals. The crystals was collected by filtration, and washed with ethyl acetate (100 mL) to give wet crystals. The obtained wet crystals were dried under reduced pressure at an outside temperature of 50° C. to give 6-(hydroxy(1-(phenylsulfonyl)-1H-imidazol-4-yl)methyl)-N-methyl-2-naphthamide (9.2 g, 21.8 mmol). yield 58%.
Reaction SMILES: [NH2:1][C@@H:2]1[C:13]2[C:7](=[CH:8][CH:9]=[C:10]([S:15][CH3:16])[C:11](=[O:14])[CH:12]=2)[C:6]2[C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[C:19]([O:21][CH2:22][CH3:23])=[CH:20][C:5]=2[CH2:4][CH2:3]1.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[F:50][C:51]1[C:59]([CH2:60][OH:61])=[CH:58][CH:57]=[CH:56][C:52]=1[C:53](O)=[O:54]>ClCCl.C(OCC)(=O)C.C(#N)C>[CH2:22]([O:21][C:19]1[C:18]([O:24][CH3:25])=[C:17]([O:26][CH3:27])[C:6]2[C:7]3[C:13]([CH:2]([NH:1][C:53](=[O:54])[C:52]4[CH:56]=[CH:57][CH:58]=[C:59]([CH2:60][OH:61])[C:51]=4[F:50])[CH2:3][CH2:4][C:5]=2[CH:20]=1)=[CH:12][C:11](=[O:14])[C:10]([S:15][CH3:16])=[CH:9][CH:8]=3)[CH3:23]
Reactant: CCOc1cc2c(c(OC)c1OC)-c1ccc(SC)c(=O)cc1[C@@H](N)CC2
Reactant: O=C(O)c1cccc(CO)c1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCOc1cc2c(c(OC)c1OC)-c1ccc(SC)c(=O)cc1C(NC(=O)c1cccc(CO)c1F)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 5586 %

Procedure:
163 g (421 mmol, 1.0 eq) of (7S)-7-amino-3-ethoxy-1,2,-dimethoxy-10-methylsulfanyl-6,7-dihydro-5H-benzo[a]heptalene-9-one was dissolved in 1.4 l of dichloromethane, and then 105 g (547 mmol, 1.3 eq) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 5.7 g (42.1 mmol, 0.1 eq) of 1-hydroxybenzotriazol hydrate were added. 93.6 g (54 7 mmol, 1.3 eq) of 2-fluoro-3-(hydroxymethyl)benzoic acid was added and then stirred for 2 hours at a room temperature. After completing the reaction, the reaction mixture was washed with purified water; dehydrated with magnesium sulfate anhydrous; and then concentrated under reduced pressure to obtain a product in a yellow solid phase. The mixed solution of 300 ml of acetonitrile and 250 ml of ethyl acetate was added to the obtained product, and then stirred for 30 minutes at a room temperature and for 2 hours at 0° C. The resulting solid was filtered, washed with ethyl acetate, and then dried to obtain 211 g of N-(3-ethoxy-1,2-dimethoxy-10-methylsulfanyl-9-oxo-5,6,7,9-tetrahydro-benzo[a]heptalene-7-yl)-2-fluoro-3-hydroxymethylbenzamide in a yellow solid phase.
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.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH3:23])=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]([N:24]2[CH2:25][CH2:26][N:27]([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)[CH2:28][CH2:29]2)[CH3:23])=[CH:18][CH:17]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: C[C@H](c1ccc(Br)cc1)N1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](c1ccc(Br)cc1)N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 80 °C
Yield: 84.9 %

Procedure:
6-Chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (251 mg, 1.13 mmol), (R)-1-[1-(4-bromophenyl)ethyl]piperazine (obtained as described in Example 270, preparation of starting materials, 304 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 then quenched with water (10 mL) to give a pale brown precipitate. The precipitate was collected by filtration, washed sequentially with water, acetonitrile and ether and dried under vacuum to afford 6-[4-[(1R)-1-(4-bromophenyl)ethyl]piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (437 mg, 85%) as a pale brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12](=O)[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.[C:22]1([S:28]([NH:31][NH2:32])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C.Cl>[C:22]1([S:28]([NH:31][N:32]=[C:12]2[CH2:11][CH2:10][C@H:9]3[C@@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C:18]2[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH2:6][CH2:7]4)(=[O:29])=[O:30])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NNS(=O)(=O)c1ccccc1
Reactant: COc1ccc2c(c1)CC[C@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: Cl
Solvent: CCO
Product: COc1ccc2c(c1)CC[C@H]1[C@@H]2CC[C@]2(C)C(=NNS(=O)(=O)c3ccccc3)CC[C@@H]12
Yield: 92.3 %

Procedure:
A suspension of 5.68 g (20 mmol) of 3-methoxy-8α-estra-1,3,5(10)-trien-17-one and 4.30 g (25 mmol) of benzenesulfonic acid hydrazide in 70 ml of ethanol is mixed with 3 drops of concentrated hydrochloric acid and then allowed to react at a bath temperature of 80–90° C. for three hours while being stirred vigorously. After the reaction solution is cooled, the precipitated product is suctioned off, rewashed with a little cold ethanol, and the hydrazone is dried in a vacuum. 8.10 g (92%) of product, which melts at 183–185° C., is obtained.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([OH:15])[CH:7]=1.C[Si](Cl)(C)C.Br[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[SiH3]Cl>O1CCOCC1>[OH:15][C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH2:3][NH:2][C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: Brc1ncccn1
Reactant: NCCOc1ccc(C(=O)O)c(O)c1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [SiH3]Cl
Solvent: C1COCCO1
Product: O=C(O)c1ccc(OCCNc2ncccn2)cc1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.5 %

Procedure:
A mixture of compound (14) (20 g), dissopropylethylamine (74 mL), trimethylsilylchloride (21.6 mL) and 2-bromopyrimidine (Lancaster, 13.5 g) were combined in 350 mL 1,4-dioxane at room temperature, then brought to reflux under N2 atmosphere. After 2 days, an additional 12 mL silylchloride was added, and the mixture continued at reflux for an additional 2 days (until TLC showed no starting material remained). The reaction mixture was cooled to ambient temperature, concentrated to dryness in vacuo on a rotary evaporator and the residue suspended in water. The heterogeneous mixture was refluxed briefly, allowed to cool to room temperature, the product collected on a vacuum filter and air dried to give 15.3 g of (16), as a tan powder. NMR (400 MHz, DMSO-d6) d 12 (very broad, 2H) 8.3 (d, J=5 Hz, 2H) 7.7 (d, J=9 Hz, 1H), 7.28 (t, J=6 Hz, 1H), 6.57 (t, J=5 Hz, 1H), 6.49 (m, 2H), 4.13 (t, J=6 Hz, 2H), 3.62 (q, 2H); MS (+ESI) m/z 276 (M+H)+; IR (KBr) n (cm−1) 3275, 3000, 1660, 1625.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CN(C)C=O.C(Cl)(=O)C([Cl:22])=O>ClCCl>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([Cl:22])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc2ncccc2c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2ncccc2c1
Reaction time: 2 h

Procedure:
Quinoline-6-carboxylic acid (1.4 g) was dissolved in dichloromethane (50 ml). N,N-dimethylformamide (100 μL) and oxalyl chloride (1.6 g) were added to this solution at room temperature and stirred for two hours followed by reflux for 20 minutes. The solvent was removed by distillation under the reduced pressure to obtain crude quinoline-6-carbonyl chloride. It was dissolved in pyridine and added to 2-bromo-4-(1-bromo-1,1,2,3,3,3-hexafluoropropan-2-yl)-6-(difluoromethoxy)aniline (0.73 g) also dissolved in pyridine, and the resulting mixture was heated under reflux for 5 hours. After cooling to room temperature, the reaction solution was diluted with 1 N hydrochloric acid and extracted twice with ethyl acetate. The solvent was removed by distillation under the reduced pressure. The resulting residues were dissolved in tetrahydrofiaran (30 ml), added with 1 M aqueous solution of lithium hydroxide (50 ml), and stirred at room temperature for 2 hours. The reaction solution was extracted twice with ethyl acetate. The organic phases were combined, washed with water, and dried over anhydrous magnesium sulfate. The drying agent (anhydrous magnesium sulfate) was removed by filtration and the solvent was distilled off under the reduced pressure. The resulting residues were purified by column chromatography to obtain N-[2-bromo-4-(1-bromo-1,1,2,3,3,3-hexafluoropropan-2-yl)-6-(difluoromethoxy)phenyl]quinoline-6-carboxamide (0.84 g, 86%).
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([NH:20][NH:21]C(OC(C)(C)C)=O)[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].S(N1C2=NC=C(N(C(OC(C)(C)C)=O)N)N=C2C=C1)(C1C=CC(C)=CC=1)(=O)=O.Cl>O1CCOCC1>[NH:20]([C:18]1[N:19]=[C:14]2[CH:13]=[CH:12][N:11]([S:1]([C:4]3[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=3)(=[O:2])=[O:3])[C:15]2=[N:16][CH:17]=1)[NH2:21]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NNC(=O)OC(C)(C)C)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2ccc3nc(N(N)C(=O)OC(C)(C)C)cnc32)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a mixture of tert-butyl 2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate and tert-butyl 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate (18.8 g, 46.6 mmol) in 1,4-dioxane (239 mL) was added HCl (4 M in 1,4-dioxane, 86 mL, 345 mmol). The reaction was heated at about 60° C. for about 1 h and then cooled to about 15-20° C. The solid was collected by vacuum filtration, washed with cold 1,4-dioxane (2×20 mL), and then stirred with a solution of saturated NaHCO3 and water (1:1, 150 mL). After about 1 h, the effervescence had subsided and the solid was collected by vacuum filtration, washed with ice cold water (3×20 mL), and dried in a vacuum oven to a constant weight to afford 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine as a light yellowish brown solid (8.01 g, 50%): LC/MS (Table 2, Method d) Rt=1.28 min; MS m/z: 304 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][C:2]1=[O:8].[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1.CO>C(Cl)Cl.CCOCC>[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:8])[CH:3]=2)=[CH:12][CH:11]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C1CCNC(=O)C1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: O=C1C=C(Nc2ccc(F)cc2)CCN1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 38.4 %

Procedure:
Piperidine-2,4-dione (I-59d: 10 g, 88.40 mmol) and 4-fluoroaniline (9.82 g, 88.40 mmol) were heated at 120° C. for 5 hours under argon atmosphere. The reaction was monitored by TLC (10% methanol in DCM). The reaction mass was cooled to room temperature, diluted with ether and stirred for 20 minutes. The solid precipitated was collected by filtration to afford 7 g of the product (38.46% yield).