Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6](=[O:14])[CH:5]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([CH:18]2[CH2:19][CH2:20][N:15]([CH2:2][CH2:3][C:4]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[NH:7][C:6](=[O:14])[CH:5]=3)[CH2:16][CH2:17]2)=[CH:22]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: O=c1cc(CCBr)c2ccccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(CCN2CCC(c3c[nH]c4ccccc34)CC2)c2ccccc2[nH]1
Temperature: 0 °C
Yield: 45.7 %

Procedure:
A suspension of 4-(2-bromethyl)-2-(1H)-quinolinone (II-2) (500 mg, 1.98 mmol), 3-(4-piperidinyl)-1H-indole (396.5 mg, 1.98 mmol) and sodium hydrogencarbonate (249.5 mg, 2.97 mmol) in dry dimethylformamide (5 ml) was react at 80 ° C. for 5 hours. The reaction mixture was poured into ice-water and the separated solid was filtered by aspiration. The residue was washed with water and recrystallized from methanol/tetrahydrofuran/water to give the desired product (336 mg) (III-2) as pale yellow crystals (mp 259°-260 ° C. (methanol/tetrahydrofuran/water)). Yield 45.7%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:2]1([NH:1][C:20]2[C:15]([C:12]3[CH:11]=[CH:10][CH:9]=[CH:14][CH:13]=3)=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: Nc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: c1ccc(Nc2ccccc2-c2ccccc2)cc1
Temperature: 105 °C

Procedure:
Into a 250 mL round bottom flask was placed palladium acetate (120 mg) and Cytop-216 (120 mg) and was stirred in toluene (10 mL) for 1 hour at room temperature under argon. To this was added, in order, aniline (15 mL), 4-bromobiphenyl (12.5 g), sodium t-pentoxide (7 g), and a further 10 mL of toluene. The resulting mixture was heated at 100-110° C. for between 4 and 6 hours. The mixture was cooled to room temperature and diluted with 20 mL of toluene, filtered to remove insolubles, and 10-20 g of Al2O3 was added. The resulting slurry was heated to ˜80° C. and filtered while hot. The toluene was removed by rotary evaporation and the residue was recrystallized from 150 mL of isopropyl alcohol. The solid produced on cooling was filtered by suction, washed with a further 100 mL of isopropyl alcohol, and dried overnight. Yield was 8.9 g with a purity >99% which was determined by HPLC and NMR.
Reaction SMILES: CC1(C)[N:6](C(OC(C)(C)C)=O)[C@:5]([CH3:20])([C:14]2[S:15][C:16]([CH3:19])=[N:17][N:18]=2)[CH2:4][O:3]1.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>ClCCl>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[NH2:6][C@@:5]([C:14]1[S:15][C:16]([CH3:19])=[N:17][N:18]=1)([CH3:20])[CH2:4][OH:3]
Reactant: Cc1nnc([C@]2(C)COC(C)(C)N2C(=O)OC(C)(C)C)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nnc([C@@](C)(N)CO)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1.2 g of tert-butyl (4S)-2,2,4-trimethyl-4-(5-methyl-1,3,4-thiadiazol-2-yl)-1,3-oxazolidine-3-carboxylate in 12 ml of dichloromethane was added 4 ml of trifluoroacetic acid, followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was azeotropic distilled with methanol to obtain 1.59 g of (2S)-2-amino-2-(5-methyl-1,3,4-thiadiazol-2-yl)propan-1-ol trifluoroacetate as a crude product.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[O:14]1[CH:18]=[CH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Pd].O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[O:14]1[CH2:18][CH:17]=[CH:16][CH:15]1[C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: COc1cc(OC)c(C=O)cc1Br
Reactant: C1=COCC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(OC)c(C2C=CCO2)cc1C=O
Temperature: 45 °C
Yield: 34.2 %

Procedure:
Ex-121A: 5-Bromo-2,4-dimethoxybenzaldehyde (1.0 g, 4.0 mmol) and 2,3-dihydrofuran (0.85 g, 12.2 mmol) were dissolved in dioxane (10.0 mL). Nitrogen was bubbled into the solution for 15 min followed by the sequential addition of cesium carbonate (1.4 g, 4.5 mmol) and bis(tri-t-butylphosphine)palladium (0) (0.021 g, 0.041 mmol). The solution was immediately heated to 45° C. and aged for 72 h. Additional equivalents of cesium carbonate (0.70 g, 2.1 mmol), 2,3-dihydrofuran (0.85 g, 12.2 mmol), and Pd catalyst (0.0021 g, 0.0041 mmol) were added after 24 h and 48 h to drive the reaction to completion. Upon completion, as determined by HPLC, the reaction was diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried over sodium sulfate and concentrated to an orange oil. Silica gel chromatography (ethyl acetate/hexanes, 1:2) afforded 0.32 g (50%) of 5-(2,5-dihydro-furan-2-yl)-2,4-dimethoxy-benzaldehyde as a pale yellow solid, mp 84–85° C. 1H-NMR (300 MHz, CDCl3) δ 10.29 (s, 1H), 7.79 (s, 1H), 6.42 (s, 1H), 5.99–6.06 (m, 2H), 5.89–5.92 (m, 1H), 4.80–4.87 (m, 1H), 4.71–4.77 (m, 1H), 3.95 (s, 3H), 3.92 (s, 3H). MS (EI) m/z=234 ([M]+, 100%). Anal. Calcd. C13H14O4: C, 66.66; H, 6.02. Found: C, 66.49; H, 6.08.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH:3]([OH:12])[CH2:2]1.[CH3:13][O:14][C:15]([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22](O)[CH:23]=2)[CH:18]=1)=[O:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH2:5]1[C:6]2([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:1][CH2:2][CH:3]([O:12][C:22]2[CH:23]=[C:24]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C:15]([O:14][CH3:13])=[O:16])[CH:26]=[CH:25]3)[CH2:4]1
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Reactant: OC1CCC2(CCCCC2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(OC3CCC4(CCCCC4)CC3)ccc2c1

Procedure:
A mixture of spiro[5.5]undecan-3-ol (0.999 g, 0.00593 mol), 6-hydroxy-naphthalene-2-carboxylic acid methyl ester (1.00 g, 0.00494 mol) and triphenylphosphine (1.56 g, 0.00593 mol) in toluene (10 mL, 0.1 mol) was heated to reflux. Diisopropyl azodicarboxylate (1.17 mL, 0.00593 mol) was then added dropwise and the resulting mixture was refluxed for 6 hours. The mixture was then diluted with dichloromethane and subjected to chromatographic purification with ethyl acetate:hexane (0:100 to 40:60) to give methyl 6-(spiro[5.5]undecan-3-yloxy)-2-naphthoate as a white solid. (1.09 g, 62%). 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 8.01 (dd, J=8.7, 1.7 Hz, 1H), 7.84 (d, J=9.6 Hz, 1H), 7.72 (d, J=8.7 Hz, 1H), 7.17 (m, 2H), 4.45 (m, 1H), 3.97 (s, 3H), 1.93-1.28 (m, 18H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)Cc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)Cc1cccc(N)c1
Reaction time: 14 h
Yield: 93 %

Procedure:
Thus obtained ethyl 3-nitrophenylacetate (5.0 g, 24 mmol) was then dissolved in methanol (80 mL) together with 10 wt % of palladium/carbon (150 mg), and stirred under a hydrogen atmosphere (1 kg/cm2) for 14 hours. The reaction solution was filtered through Celite so as to remove the palladium/carbon catalyst, evaporated under reduced pressure so as to remove the solvent, and the residue was purified through silica gel column chromatography (hexane:ethyl acetate (v/v)=7:3) to thereby obtain a purified ethyl 3-aminophenylacetate (yield: 4.0 g, yield ratio: 100%) as a syrup.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[CH3:10][S:11](Cl)(=[O:13])=[O:12].CCOC(C)=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][S:11]([CH3:10])(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(N)cc1Br
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(NS(C)(=O)=O)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A cooled (0° C.) solution of 3-bromo-4-methylaniline (ABCR; 1.00 g; 5.37 mmol) in pyridine (20 ml) was treated with methanesulfonyl chloride (500 μl; 6.45 mmol). The reaction mixture was allowed to warm to RT and stirred for 1 hour, then EtOAc was added and the organic layer was washed with a 1N aqueous solution of HCl. The organic layer was dried over MgSO4, filtered and concentrated to dryness to give the title compound as a brown solid (1.42 g, quantitative).
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]([CH2:35][OH:36])[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26](=[O:34])[NH:27][C@@H:28]([CH2:32][OH:33])[C:29]([NH2:31])=[O:30])=[O:20])=[O:13])C1C=CC=CC=1>CO.[Pd]>[NH2:31][C:29](=[O:30])[C@@H:28]([NH:27][C:26]([C@@H:22]1[CH2:23][CH2:24][CH2:25][N:21]1[C:19]([C@@H:15]1[CH2:16][CH2:17][CH2:18][N:14]1[C:12](=[O:13])[C@@H:11]([NH2:10])[CH2:35][OH:36])=[O:20])=[O:34])[CH2:32][OH:33]
Reactant: NC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@H](CO)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CO
Reaction time: 2 h
Yield: 68.3 %

Procedure:
Benzyl-(S)-1-((S)-2-((S)-2-((S)-1-amino-3-hydroxy-1-oxopropan-2-ylcarbamoyl)pyrrolidine-1-carbonyl)pyrrolidin-1-yl)-3-hydroxy-1-oxopropan-2-ylcarbamate 7 (300 mg, 0.57 mmol) was dissolved in methanol (8 mL), 10% Pd/C (50 mg) was added and reaction mixture was stirred under hydrogen atmosphere for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to yield compound C (150 mg, 68%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].C(C(C)=O)=C.OCCC(C)=O.COCCC(C)=O.O(CCC(C)=O)C1C=CC=CC=1.C(OCCC(C)=O)(=O)C.C(OCCC(C)=O)(=O)C1C=CC=CC=1.C1(S(OCCC(C)=O)(=O)=O)C=CC=CC=1.CN(C)CCC(C)=O.ClCCC(C)=O.[Br-].C[S+](C)CCC(=O)C.[I-].C[N+](C)(C)CCC(=O)C.[OH-].[H-]>C(C(CC)=O)C>[CH3:1][C:2]1[C:3](=[O:10])[CH:4]([CH3:9])[CH2:5][CH2:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(C)c(O)c1C
Agent: C=CC(C)=O
Agent: CC(=O)CCCl
Agent: CC(=O)CCN(C)C
Solvent: CCC(=O)CC
Product: CC1=C(C)C(=O)C(C)CC1

Procedure:
A process for the production of 2,3,6-trimethylphenol which comprises reacting a carbonyl compound selected from the group consisting of methyl vinyl ketone, methyl β-hydroxyethyl ketone, methyl β-methoxyethyl ketone, methyl β-phenoxyethyl ketone, methyl β-acetyloxyethyl ketone, methyl β-benzoyloxyethyl ketone, methyl β-methyl-sulfonyloxyethyl ketone, methyl β-phenylsulfonyloxyethyl ketone, methyl β-dimethylaminoethyl ketone, methyl β-chloroethyl ketone, dimethyl-(β-acetylethyl)-sulfonium bromide or trimethyl-(β-acetylethyl)-ammonium iodide to a mixture of diethyl ketone and a basic reagent selected from the group consisting of an alkali metal, an alkaline earth metal, a hydroxide, oxide, alcoholate, amide, hydride or organo metallic compound of an alkali metal or alkaline earth metal, and a quaternary ammonium hydroxide, the amount of said diethyl ketone being in the molar ratio of 1:1 to 50:1 with respect to the total amount of carbonyl compound added, at a reaction temperature of 20° to 150° C. to produce 2,3,6-trimethyl-2-cyclohexen-1-one, and dehydrogenating the latter to produce 2,3,6-trimethylphenol.
Reaction SMILES: ClCCCl.[Br:5]CC1C=C2C(=CC=1)N=CC=N2.[CH3:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[N:20]=[CH:21][CH:22]=[N:23]2.BrN1C(=O)CCC1=O>C(O)(=O)C.C(Cl)Cl>[Br:5][CH2:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[N:20]=[CH:21][CH:22]=[N:23]2
Reactant: BrCc1ccc2nccnc2c1
Reactant: Cc1cccc2nccnc12
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: BrCc1cccc2nccnc12

Procedure:
In polar solvents, such as 1,2-dichloroethane, a good yield of 6-(bromomethyl)-quinoxaline was observed and consequently other hydrochlorocarbons (for example, methylene chloride) would be expected to be good as well. However, these solvents are less preferred due to their high toxicity and volatility. In other polar solvents, such as acetic acid, 5-(methyl)-quinoxaline reacted with N-bromosuccinimide almost quantitatively to give 5-(bromomethyl)-quinoxaline. However, the 6-isomer reacted to give 6-(bromomethyl)-quinoxaline that quickly decomposed to give a black tar. Therefore, benzylic bromination with N-bromosuccinimide in acetic acid can only apply to one isomer (the 5-isomer) but not to the mixtures of 5- and 6-methylquinoxalines obtained from ortho-toluene diamine. In acetonitrile, the 5-isomer reacted with N-bromosuccinimide to give 5-(bromomethyl)-quinoxaline in a good yield (>90%) but the 6-isomer did not react. Therefore, benzylic bromination with N-bromosuccinimide in acetonitrile can only apply to one isomer (the 5-isomer) but not to the methylquinoxalines mixtures obtained from ortho-toluene diamine. An acceptable yield was obtained for the benzylic chlorination of 6-methyl-quinoxaline using N-chlorosuccinimide in acetonitrile (conversion=60% and selectivity=80%) but the reaction was very slow requiring 8 to 12 hours reflux (Example 15).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1I>>[NH2:9][C:3]1[CH:4]=[C:5]([Br:8])[CH:6]=[CH:7][C:2]=1[C:16]1[CH:15]=[CH:14][C:13]([F:12])=[CH:18][C:17]=1[F:19]
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Reactant: Fc1ccc(I)c(F)c1
Product: Nc1cc(Br)ccc1-c1ccc(F)cc1F

Procedure:
2,5-Dibromo-1-nitrobenzene and 2,4-difluoro-1-iodobenzene were reacted under Ullmann conditions to give 4-bromo-2',4'-difluoro-2-nitrobiphenyl, b.p. 126°-136°C./0.2mm (m.p. 52°-53°C. after recrystallisation from methanol). This was reduced to give 2-amino-4-bromo-2',4'-difluorobiphenyl, b.p. 120°-124°C./0.5mm, which was subjected to a Schiemann reaction, using hydrofluoroboric acid to give the product, m.p. 67°-69°C., after distillation.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]([C:19]([CH:21]3[CH2:23][CH2:22]3)=[O:20])[C@@H:7]([CH3:18])[CH2:8][N:9]2[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1.O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:44]2[CH:45]=[N:46][N:47](C(OC(C)(C)C)=O)[CH:48]=2)O1>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH:21]1([C:19]([N:6]2[C:5]3[C:10](=[CH:11][C:2]([C:44]4[CH:45]=[N:46][NH:47][CH:48]=4)=[CH:3][CH:4]=3)[N:9]([C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[CH2:8][C@@H:7]2[CH3:18])=[O:20])[CH2:23][CH2:22]1
Reactant: CC(C)OC(=O)N1C[C@H](C)N(C(=O)C2CC2)c2ccc(Br)cc21
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)OC(=O)N1C[C@H](C)N(C(=O)C2CC2)c2ccc(-c3cn[nH]c3)cc21
Temperature: 90 °C
Reaction time: 5 h
Yield: 71.1 %

Procedure:
A 50-mL round bottomed flask fitted with a nitrogen inlet and magnetic stir bar was charged with (S)-isopropyl 7-bromo-4-(cyclopropanecarbonyl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.801 g, 2.1 mmol), dioxane (11 mL), and water (4.6 mL). Cesium carbonate (2.053 g, 6.30 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-carboxylate (0.927 g, 3.15 mmol) were then added. The reaction was purged with nitrogen and bis(triphenylphosphine)palladium (II) dichloride (0.177 g, 0.252 mmol) was added. The mixture was heated at 90° C. with vigorous stirring for 5 h and then cooled to ambient temperature. Water (25 mL) was added, and the mixture was extracted with ethyl acetate (3×25 mL). The combined organic extracts were concentrated to afford a viscous oil and purified via column chromatography (gradient elution with 75-100% ethyl acetate-hexanes). The resulting material was triturated with diethyl ether (2×10 mL) to afford (S)-isopropyl 4-(cyclopropanecarbonyl)-3-methyl-7-(1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.55 g, 71% yield) as a solid. MS (ESI, pos. ion) m/z 369 [M+1]+.
Reaction SMILES: [F:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:13]([OH:15])=[O:14].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH2:36][CH2:37][CH2:38][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1.Cl>CS(C)=O>[F:1][C:2]1[C:11]([O:12][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:35][CH2:36][CH2:37][CH2:38][N:39]4[CH2:40][CH2:41][O:42][CH2:43][CH2:44]4)=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][CH:24]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:13]([OH:15])=[O:14]
Reactant: COc1cc2c(Cl)ccnc2cc1OCCCN1CCOCC1
Reactant: O=C(O)c1cccc2c(F)c(O)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COc1cc2c(Oc3ccc4c(C(=O)O)cccc4c3F)ccnc2cc1OCCCN1CCOCC1
Reaction time: 0.25 h

Procedure:
In a microwave tube, 5-fluoro-6-hydroxy-1-naphthoic acid (300 mg, 1.48 mmol) and Cs2CO3 (1.45 g, 4.44 mmol) in DMSO (1.5 mL) were stirred for 3 min at RT. 4-Chloro-6-methoxy-7-(3-morpholinopropoxy)quinoline (500 mg, 1.48 mmol) was added and the vessel sealed. The mixture was subjected to the microwave (Personal Chemistry) at 160° C. for 15 min, then 30 min. The vessel was opened and the mixture stirred with a spatula, resealed and heated another 5 minutes. The reaction mixture made pH 7 with 1N HCl and evaporated. The residual solid was taken up into MeOH and filtered and evaporated. The solid was then taken up into and CH2Cl2/MeOH mixture and filtered. The filtrate was evaporated to dryness and triturated with ethyl acetate/hexanes and the title compound collected as a yellow solid.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:20]1[CH2:22][CH:21]1[CH2:23][O:24][C:25]1[C:37]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]=2[CH:28]=[CH:27][CH:26]=1>C(O)C>[CH2:1]([N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[CH2:22][CH:21]([OH:20])[CH2:23][O:24][C:25]1[C:37]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]=2[CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc2c(c1)[nH]c1cccc(OCC3CO3)c12
Reactant: COc1ccccc1OCCNCc1ccccc1
Solvent: CCO
Product: COc1ccccc1OCCN(Cc1ccccc1)CC(O)COc1cccc2[nH]c3ccccc3c12
Temperature: 0 °C
Reaction time: 5 h

Procedure:
35.0 g of benzyl-[2-(2-methoxy-phenoxy)-ethyl]-amine (136 mmol) were dissolved in 225 ml ethanol. To the stirred solution 30.1 g of 4-oxiranylmethoxy-9H-carbazole (126 mmol) were added and the mixture was heated under reflux for 15 h. The boiling solution was treated with 3 g of activated carbon for 30 min. The activated carbon was filtered off in the heat, and washed with 20 ml ethanol. The solution was stirred for 3 h at room temperature and next 5 h at 0° C. The product was filtered under suction and washed twice with 10 ml cold ethanol. The substance was dried at 50° C. for 12 h
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:37]=[CH:38][N:39]=3)[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([NH:24][C:25]([C:27]4[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][CH:28]=4)=[O:26])[CH2:19]3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].[OH-].[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:37]=[CH:38][N:39]=3)[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([NH:24][C:25]([C:27]4[CH:36]=[CH:35][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=4)=[O:26])[CH2:19]3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(C(=O)NC2CCCN(c3cc(Nc4ccc(OC)c(OC)n4)c4nccn4n3)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Nc2cc(N3CCCC(NC(=O)c4ccc(C(=O)O)cc4)C3)nn3ccnc23)nc1OC
Temperature: 40 °C
Reaction time: 3 h
Yield: 32.2 %

Procedure:
A mixture of methyl 4-(1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)piperidin-3-ylcarbamoyl)benzoate (50 mg, 0.09 mmol) and sodium hydroxide (50 mg, 1.25 mmol) in 1,4-dioxane (5 mL) and water (5 mL) was stirred at 40° C. for 3 h. The residue was concentrated in vacuo to ˜5 mL then adjusted pH to 2 with 1M HCl. The residue was concentrated and triturated with MeOH to give the product 4-(1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)piperidin-3-ylcarbamoyl)benzoic acid (15 mg, 31%) as yellow solid. 1H NMR (300 MHz, DMSO): δ 10.36 (s, 1H), 8.60 (d, 1H, J=7.2 Hz), 8.19 (s, 2H), 8.06-7.92 (m, 4 h), 7.45 (d, 1H, J=8.4 Hz), 6.95 (d, 1H, J=8.4 Hz), 4.18-4.07 (m, 3H), 3.99 (s, 3H), 3.91 (s, 3H), 3.07-2.99 (m, 2H), 1.98-1.88 (m, 2H), 1.70-1.64 (m, 2H). LC-MS: [M+H]+, 518, tR=1.295 min, HPLC: 95.24% at 214 nm, 95.25% at 254 nm, tR=4.981 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][NH:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[C:15]#[N:16].[C:18](Cl)(=[O:20])[CH3:19]>CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:17])[CH2:4][N:5]([C:18](=[O:20])[CH3:19])[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[C:15]#[N:16]
Reactant: COC(=O)CNc1cc([N+](=O)[O-])ccc1C#N
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Product: COC(=O)CN(C(C)=O)c1cc([N+](=O)[O-])ccc1C#N
Yield: 86 %

Procedure:
At 50° C., (2-cyano-5-nitro-phenylamino)-acetic acid methyl ester (0.5 g, 2.1 mmol) was heated in acetyl chloride (100 mL) for 3 hours in the presence of catalytic DMAP. The mixture was poured over ice and then partitioned between ethyl acetate (100 ml) and water (50 ml). The organic layer was washed once with 1 M NaOH (100 mL) and dried over sodium sulfate. Concentration and silica gel purification (EtOAc/hexanes 9:1) gave [acetyl-(2-cyano-5-nitro-phenyl)-amino]-acetic acid methyl ester (0.5 g, 1.8 mmol, 86%): 1H NMR (300 MHz, CDCl3) δ 8.59 (d, 1H), 8.36 (dd, 1H), 7.99 (d, 1H), 3.9 (b, 2H), 3.78 (s, 3H), 2.00 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:73]=[CH:72][C:67]([C:68]([O:70][CH3:71])=[O:69])=[C:66]([Cl:74])[CH:65]=1>>[CH3:71][O:70][C:68](=[O:69])[C:67]1[CH:72]=[CH:73][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][C:66]=1[Cl:74]
Reactant: COC(=O)c1ccc(N)cc1Cl
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1Cl
Yield: 32.3 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.25 g, 0.44 mmol), was reacted with diisopropylethylamine (0.23 g, 1.8 mmol), diphenylphosphinic chloride (0.32 g, 1.3 mmol), then reacted with methyl 4-amino-2-chlorobenzoate (0.099 g, 0.53 mmol) to give rac-2-chloro-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-benzoic acid methyl ester as a white solid (Yield 0.09 g, 32%).