Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1)#[CH:2].I[C:18]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]>>[C:12]([O:11][C:10]([NH:9][C:5]1[CH:4]=[C:3]([C:1]#[C:2][C:18]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:19]=2[C:20]([O:22][CH3:23])=[O:21])[CH:8]=[CH:7][CH:6]=1)=[O:16])([CH3:13])([CH3:15])[CH3:14]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1I
Reactant: C#Cc1cccc(NC(=O)OC(C)(C)C)c1
Product: COC(=O)c1ccc([N+](=O)[O-])cc1C#Cc1cccc(NC(=O)OC(C)(C)C)c1
Yield: 87 %

Procedure:
This compound was prepared according to the procedure of Example B19 step C, using tert-butyl (3-ethynylphenyl)carbamate and methyl 2-iodo-4-nitrobenzoate as the starting materials in 87% yield. LCMS calculated for C21H21N2O6(M+H)+: m/z=397.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12][C:13]([OH:15])=O.C(Cl)CCl.C[CH2:21][N:22](CC)[CH2:23]C.Cl.CNC>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12][C:13]([N:22]([CH3:23])[CH3:21])=[O:15]
Reactant: CCN(CC)CC
Reactant: COc1ccc([N+](=O)[O-])cc1CC(=O)O
Agent: CNC
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])cc1CC(=O)N(C)C

Procedure:
2-(2-Methoxy-5-nitrophenyl)acetic acid (17.1 g, 1 eq, Step B), EDC (18.6 g, 1.2 eq.), Et3N (9.8 g, 13.6 mL, 1.2 eq) and dimethylamine hydrochloride (7.9 g, 1.2 eq.) in 150 mL of CH2Cl2 were stirred together with exclusion of air overnight. CH2Cl2 (150 mL) was added and the mixture was washed twice with 1M HCl, twice with 1M NaOH, H2O and brine. Removal of the solvent under reduced pressure followed by silica gel chromatography (90:10 CH2Cl2:EtOAc) afforded pure 2-(2-methoxy-5-nitrophenyl)-N,N-dimethyl-acetamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:26]([F:29])([F:28])[F:27])[O:14][N:13]=[C:12]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[C:17]([CH3:25])[CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].[OH-].[Na+].Cl>C1COCC1.O.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:26]([F:28])([F:29])[F:27])[O:14][N:13]=[C:12]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[C:17]([CH3:25])[CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.4 %

Procedure:
A mixture of methyl 4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoate (4.1 g, 8.8 mmol) and NaOH (3.5 g, 88 mmol) in THF—H2O-MeOH (1:1:1, 90 mL) was stirred at rt for 18 h. The mixture was acidified with 2 N HCl and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (3.8 g; yield 95%) as a white solid. MS: m/z=451.7 (M+1, ESI+).
Reaction SMILES: FC1N(C)CCN(C2C=CC(N[C:16]3[N:21]=[C:20]([C:22]4[CH:23]=[C:24]([NH:28][C:29](=[O:32])[CH:30]=[CH2:31])[CH:25]=[CH:26][CH:27]=4)[C:19]([NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=4)=[CH:18][N:17]=3)=CC=2)C1.[Cl:41]C1N=C(Cl)C(NC2C=CC=C(F)C=2)=CN=1.C(NC1C=C(B(O)O)C=CC=1)(=O)C=C>[Pd]>[Cl:41][C:16]1[N:21]=[C:20]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:32])[CH:30]=[CH2:31])[CH:25]=[CH:26][CH:27]=2)[C:19]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=2)=[CH:18][N:17]=1
Reactant: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCN(C)C(F)C4)cc3)ncc2Nc2cccc(F)c2)c1
Reactant: Fc1cccc(Nc2cnc(Cl)nc2Cl)c1
Agent: [Pd]
Agent: C=CC(=O)Nc1cccc(B(O)O)c1
Product: C=CC(=O)Nc1cccc(-c2nc(Cl)ncc2Nc2cccc(F)c2)c1

Procedure:
As an example, N-(3-(2-((4-(3-fluoro-4-methylpiperazin-1-yl)phenyl)amino)-5-((3-fluorophenyl)amino)pyrimidin-4-yl)phenyl)acrylamide can be prepared according to Route I. Beginning with 2,4-dichloro-N-(3-fluorophenyl)pyrimidin-5-amine, a palladium catalyzed coupling reaction with (3-acrylamidophenyl)boronic acid provides N-(3-(2-chloro-5-((3-fluorophenyl)amino)pyrimidin-4-yl)phenyl)acrylamide under mild conditions. Reaction of this product with 4-(3-fluoro-4-methylpiperazin-1-yl)aniline under palladium catalyzed aminolysis conditions yields N-(3-(2-((4-(3-fluoro-4-methylpiperazin-1-yl)phenyl)amino)-5-((3-fluorophenyl)amino)pyrimidin-4-yl)phenyl)acrylamide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]1.[CH2:27]([O:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][C:31]=1[OH:45])[CH3:28]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[N:17]2[CH2:18][CH2:19][CH:20]([CH2:23][N:24]([CH3:25])[CH3:26])[CH2:21][CH2:22]2)=[CH:3][C:2]([C:34]2[CH:33]=[CH:32][C:31]([OH:45])=[C:30]([O:29][CH2:27][CH3:28])[CH:35]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CN(C)CC1CCN(c2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: CCOc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Product: CCOc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N4CCC(CN(C)C)CC4)c3c2)ccc1O
Yield: 41.9 %

Procedure:
Following general procedure D, (6-bromo-4-{4-[(dimethylamino)methyl]piperidin-1-yl}quinolin-3-yl)(cyclopropyl)methanone (30 mg, 0.072 mmol) was reacted with 2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (40 mg, 0.150 mmol) to afford the desired product (14.3 mg, 42%) as a yellow solid: NMR (500 MHz, CD3OD) δ 8.73 (s, 1H), 8.31 (d, J=1.7 Hz, 1H), 8.03 (m, 2H), 7.30 (d, J=2.1 Hz, 1H), 7.22 (dd, J=8.2, 2.1 Hz, 1H), 6.95 (d, J=8.2 Hz, 1H), 4.22 (q, J=7.0 Hz, 2H), 3.54 (d, J=12.6 Hz, 2H), 3.26-3.12 (m, 2H), 2.59-2.50 (m, 1H), 2.44 (s, 2H), 2.37 (s, 6H), 2.02-1.83 (m, 3H), 1.68-1.53 (m, 2H), 1.49 (t, J=7.0 Hz, 3H), 1.35-1.26 (m, 2H), 1.26-1.15 (m, 2H); ESI MS m/z 474 [C29H35N3O3+H]+; HPLC 96.9% (AUC), tR=10.59 min.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([OH:27])=O)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.Cl.[N:29]([C@@H:32]1[CH2:36][C@@H:35]([NH2:37])[C@H:34]([F:38])[CH2:33]1)=[N+:30]=[N-:31]>>[N:29]([C@@H:32]1[CH2:36][C@@H:35]([NH:37][C:25]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[CH:8]=[C:9]([CH:12]([F:14])[F:13])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:16]=3[NH:23][C:22]=2[CH3:24])=[O:27])[C@H:34]([F:38])[CH2:33]1)=[N+:30]=[N-:31]
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)O
Reactant: [N-]=[N+]=N[C@@H]1C[C@@H](N)[C@H](F)C1
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1C[C@@H](N=[N+]=[N-])C[C@H]1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.g1) and (1R*,2R*,4R*)-4-azido-2-fluorocyclopentanamine hydrochloride (example C45) the title compound is obtained as pale yellow foam.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]1[O:17][C:16]2[CH:15]=[CH:14][C:13]([CH2:18][CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[CH:12][C:11]=2[O:10]1.[CH2:25]([C:27]1[O:31][C:30]([CH:32]=O)=[CH:29][CH:28]=1)[CH3:26].Cl[Sn](Cl)(Cl)Cl>C1COCC1.C(Cl)Cl>[CH2:25]([C:27]1[O:31][C:30]([C@@H:32]2[C:14]3[C:13](=[CH:12][C:11]4[O:10][CH2:9][O:17][C:16]=4[CH:15]=3)[CH2:18][CH2:19][C@H:20]2[C:21]([OH:23])=[O:22])=[CH:29][CH:28]=1)[CH3:26]
Reactant: CCc1ccc(C=O)o1
Reactant: COC(=O)CCCc1ccc2c(c1)OCO2
Agent: CC(C)[N-]C(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1ccc([C@@H]2c3cc4c(cc3CC[C@H]2C(=O)O)OCO4)o1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a freshly prepared solution of LDA (15 mmol) in 30 mL of THF cooled to -78° C. was added a solution of 3,4-methylenedioxybenzenebutanoic acid, methyl ester (14 mmol), from step 558 above, in 10 mL of THF. The solution was stirred for 5 minutes, and a solution of 5-ethylfuran-2-carboxaldehyde (13.8 mmol), from step 55b above, in 30 mL of THF was added. The reaction mixture was warmed to 0° C., and the reaction was quenched with 10 mL of satd NH4Cl. The organic layer was separated, and the aqueous layer was extracted with ether. The organic layers were combined, dried and concentrated. The residue was dissolved in 50 mL of methylene chloride, and the solution was cooled to 0° C. To this solution was added a solution of SnCl4 (1M, 13 mmol) in methylene chloride, and the reaction mixtrue was stirred for 5 minutes. The reaction was quenched with 1 N HCl (10 mL). The organic layer was separated, and the aqueous layer was extracted with methylene chloride. The organic layers were combined, dried, filtered and concentrated. The crude methyl ester intermediate was hydrolyzed with KOH in methanol by standard procedures, and the title product was isolated (3.04 g). NMR (CDCl3) δ:6.56 (s, 1H), 6.54 (s, 1H), 5.91-5.81 (m, 4H), 4.39 (d, J=7 Hz, 1H), 3.13 (m, 1H), 2.80 (t, J=7 Hz, 2H), 2.59 (q, J=8 Hz, 2H), 2.18-1.96 (m, 2H), 1.20 (t, J=8 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][CH:44]=1)[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([N:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[CH:32]=1>CN(C)C=O.CN(C)C(=O)C>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:24]=[C:23]([NH:22][C:8]([C:4]5[S:3][C:2]([CH3:1])=[N:6][C:5]=5[CH3:7])=[O:10])[CH:44]=[CH:43][CH:42]=4)=[CH:32][N:31]3[N:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: Cc1nc(C)c(C(=O)O)s1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1nc(C)c(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)s1
Yield: 26.6 %

Procedure:
In the same manner as in Example 18-4 and using 2,4-dimethyl-1,3-thiazole-5-carboxylic acid (107 mg, 0.678 mmol), tetrahydrofuran (8 mL), oxalyl chloride (118 μL, 1.36 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (70.0 mg, 0.226 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (27.0 mg, 27%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([C:4]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)[CH:2]=[CH2:3].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH2:1]([C:4]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)ccc2[nH]ccc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCc1c(OCc2ccccc2)ccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.4 %

Procedure:
4-Allyl-1H-indol-5-ol (Example 54, 2.67 g, 15.4 mmol), benzyl bromide (2.90 g, 17.0 mmol), and Cs2CO3 (6.03 g, 18.5 mmol) were combined in DMF (50 mL), and water (15 drops) was added. After stirring for 12 h at rt, the reaction mixture was concentrated under reduced pressure. The residue was taken up in water, and the aqueous phase was extracted with EtOAc (2×). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc/hexane (v/v)=1:7) gave 3.3 g (82%) of the title compound as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 3.74 (d, 2H), 5.00 (d, 1H), 5.09 (d, 1H), 5.10 (s, 2H), 6.07 (m, 1H), 6.55 (s, 1H), 6.98 (d, 1H), 7.20 (m, 2H), 7.31 (m, 1H), 7.38 (m, 2H), 7.48 (m, 2H), 8.03 (br, 1H).
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([N:27]1[CH:31]=[C-]O[C:28]1=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[CH2:20]([N:27]1[CH2:31][CH:11]2[CH:12]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9][C:10]2=[O:13])[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1C=CC(c2ccccc2)(c2ccccc2)CC1
Reactant: O=c1o[c-]cn1Cc1ccccc1
Solvent: Cc1ccccc1
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC12
Yield: 16.4 %

Procedure:
A solution of 4,4-diphenyl-2-cyclohexen-1-one (25 g) and 3-benzyl-5-oxazolidone (2.5 g) in dry toluene (100 cc) is heated to reflux for 2 hours 30 minutes. The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.2-0.063 mm, diameter 4.5 cm, height 23 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (80:20 by volume) and collecting 50-cc fractions. Fractions 13 to 17 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aRS,7aRS)-2-benzyl-7,7-diphenylperhydro-4-isoindolone (0.9 g) in the form of white crystals, m.p. 132° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[I:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[N:12]=[C:11]2[C:23](N(OC)C)=[O:24]>C1COCC1>[I:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[N:12]=[C:11]2[CH:23]=[O:24]
Reactant: CON(C)C(=O)c1nn(C2CCCCO2)c2ccc(I)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1nn(C2CCCCO2)c2ccc(I)cc12
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Lithium aluminum hydride (160 mg, 4.21 mmol) was added in portions to a cooled (0° C.) solution of 5-iodo-N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide (CXIII) (1.46 g, 3.5 mmol) in THF. Stirring was continued at 0° C. until the reaction was completed, approximately 30 min. The reaction was quenched by the slow addition of EtOAc at 0° C., and the whole mixture was poured into 0.4 N aqueous NaHSO4. The organic layer was washed with brine, dried over MgSO4, concentrated, and purified on a silica gel column (100% EtOAc→3:97 MeOH:DCM) to give 5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (CXIV) as a white solid (0.90 g, 3.15 mmol, 72% yield). 1H NMR (DMSO-d6) δ ppm 1.50-1.71 (m, 2H), 1.71-1.87 (m, 1H), 1.97-2.15 (m, 2H), 2.31-2.42 (m, 1H), 3.66-3.99 (m, 2H), 5.96-6.17 (m, 1H), 7.78 (d, J=6 Hz, 1H), 7.84 (d, J=6 Hz, 1H), 8.50 (s, 1H), 10.13 (s, 1H); ESIMS found for C13H13IN2O2 m/z 357 (M+H).
Reaction SMILES: CC(C)([O-])C.[K+].O[C@@:8]([CH3:37])([CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[C:33]3[S:34][CH:35]=[CH:36][C:32]=3[O:31][N:30]=2)[CH:24]=1)[CH2:9][O:10]S(C1C=CC(C)=CC=1)(=O)=O.C>O1CCCC1>[CH3:37][C@:8]1([CH2:21][O:22][C:23]2[CH:24]=[C:25]([C:29]3[C:33]4[S:34][CH:35]=[CH:36][C:32]=4[O:31][N:30]=3)[CH:26]=[CH:27][CH:28]=2)[CH2:9][O:10]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@](C)(O)COc2cccc(-c3noc4ccsc34)c2)cc1
Agent: C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@]1(COc2cccc(-c3noc4ccsc34)c2)CO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
Add potassium t-butoxide (0.67 g, 0.006 mol) in small portions to a chilled (0° C.) stirred solution of toluene-4-sulfonic acid (S)-2-hydroxy-2-methyl-3-(3-thieno[2,3-d]isoxazol-3-yl-phenoxy)-propyl ester (2.45 g, 0.00533 mol) and tetrahydrofuran (40 mL). Stir one hour at 0° C. and partition between ethyl acetate and water. Separate the organic phase, dry (MgSO4), filter, and concentrate in vacuo. Recrystallize the residue from ether-hexane to give the title compound (1.33 g, 87% yield), m.p. 84-85° C., MS (chemical ionization, CH4) MH+ 288.
Reaction SMILES: I[C:2]1[C:10]2[O:9][N:8]=[C:7]([NH:11][CH3:12])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:13].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2C)CCCCC1.CC1(C)C(C)(C)OBO1.CCN(CC)CC.Br[C:57]1[C:58](=[O:75])[N:59]([CH3:74])[C:60]2[N:65]([C:66]3[CH:71]=[CH:70][C:69]([F:72])=[CH:68][C:67]=3[F:73])[N:64]=[CH:63][C:61]=2[N:62]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:73][C:67]1[CH:68]=[C:69]([F:72])[CH:70]=[CH:71][C:66]=1[N:65]1[C:60]2[N:59]([CH3:74])[C:58](=[O:75])[C:57]([C:2]3[C:10]4[O:9][N:8]=[C:7]([NH:11][CH3:12])[C:6]=4[CH:5]=[CH:4][C:3]=3[CH3:13])=[N:62][C:61]=2[CH:63]=[N:64]1
Reactant: CNc1noc2c(I)c(C)ccc12
Reactant: Cn1c(=O)c(Br)nc2cnn(-c3ccc(F)cc3F)c21
Agent: [Pd+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: CNc1noc2c(-c3nc4cnn(-c5ccc(F)cc5F)c4n(C)c3=O)c(C)ccc12
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
The preparation of 7-iodo-N,6-dimethylbenzo[d]isoxazol-3-amine was disclosed in PCT Int. Appl. WO 2006094187 A2. A mixture of 7-iodo-N,6-dimethylbenzo[d]isoxazol-3-amine (250 mg, 0.87 mmol) followed by 2-(dicyclohexylphosphino)-2′-methylbiphenyl (63 mg, 0.17 mmol), Pd(OAc)2 (10 mg, 0.043 mmol) in 2.0 mL dioxane in a glass tube was treated with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.6 mL of 1.0 M in THF solution, 2.6 mmol) and Et3N (0.48 mL, 3.47 mmol) under argon. The glass tube was sealed and the reaction mixture was then heated in a microwave at 100° C. for 20 min. The reaction mixture was cooled to RT and transferred to a 20 mL of RBF, rinsing with 2 mL of THF. To the reaction mixture was added tetrakis(triphenylphosphine)palladium(0) (11.2 mg, 9.67 μmol), 5-bromo-1-(2,4-difluorophenyl)-7-methyl-1H-pyrazolo[4,3-b]pyrazin-6(7H)-one (110 mg, 0.32 mmol; made in a manner similar to the method described in Example 1, Steps 1-3). It was cooled to 0° C. with an ice bath, and sodium carbonate (1.1 mL of 1.0 N solution) was added drop wise. The reaction mixture was stirred at RT for 5 min, and heated in an oil bath at 70° C. for 5 h. The reaction mixture was treated with water and extracted with EtOAc (2×20 mL). The combine EtOAc layers were washed with brine and dried over MgSO4, filtered and concentrated. Purification on the ISCO (12 g column, 25-90% EtOAc in hexanes) afforded 1-(2,4-difluorophenyl)-7-methyl-5-(6-methyl-3-(methylamino)benzo[d]isoxazol-7-yl)-1H-pyrazolo[4,3-b]pyrazin-6(7H)-one as a light yellow amorphous solid. MS (ES+): 423.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([O:17][CH3:18])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[Cl:30].C(=O)([O-])[O-].[Na+].[Na+].[N+](C1C=CC=CC=1)([O-])=O>[Cu]Cl>[Cl:30][C:22]1[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=[CH:26][C:21]=1[NH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([O:17][CH3:18])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)c(Cl)c1
Reactant: COc1cccc2c1C(=O)c1cccc(N)c1C2=O
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1cccc2c1C(=O)c1cccc(Nc3ccc([N+](=O)[O-])cc3Cl)c1C2=O

Procedure:
12.65 parts of 1-amino-5-methoxyanthraquinone, 15.3 parts of 1-bromo-2-chloro-4-nitrobenzene, 5 parts of sodium carbonate and 1 part of copper-(I) chloride in 120 parts of nitrobenzene are stirred for 3 hours at 170°. To remove the water formed during the reaction, a stream of nitrogen is passed through the apparatus during the reaction. After cooling the reaction mixture to 25°, the 1-(2'-chloro-4'-nitroanilino)-5-methoxyanthraquinone formed is filtered off, washed with nitrobenzene, ethanol and hot water and extracted by boiling with 5% strength hydrochloric acid. The colorant is obtained in a yield of 19.5 parts, that is to say 95% of theory. It bulk-dyes polyester in an orange-coloured shade having excellent fastness properties.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH2:14][OH:15])[NH:8][C:7]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:6][CH2:5]1.[CH2:16](Br)[C:17]#[CH:18].C(O)C>C1COCC1.C(OCC)C>[CH3:3][C:4]1([CH2:14][O:15][CH2:18][C:17]#[CH:16])[NH:8][C:7]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:6][CH2:5]1
Reactant: C#CCBr
Reactant: CC1(CO)COC2(CCCCC2)N1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#CCOCC1(C)COC2(CCCCC2)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (55% in dispersion in oil) (0.636 g) was added portion wise to a solution of (3-methyl-1-oxa-4-aza-spiro[4.5]dec-3-yl)-methanol (2.0 g) in dry THF (30 ml) at 0° C. The reaction mixture was stirred at room temperature for 1 h. Propargyl bromide (0.972 ml) was added dropwise at 0° C. and the resulting mixture was stirred at room temperature for 2.5 h. The reaction mixture was treated with ethanol (4 ml) and diluted with diethyl ether and the mixture was filtered. The filtrate was concentrated in vacuo to providing a crude residue which was purified by column chromatography (hexane/ethyl acetate 1:1) to give 2.33 g of 3-methyl-3-prop-2-ynyloxymethyl-1-oxa-4-aza-spiro[4.5]decane as an orange liquid. 1H NMR (CDCl3) δ ppm: 4.18 (2H, d); 3.82 (1H, d); 3.53 (1H, d); 3.43 (1H, d); 3.38 (1H, d); 2.42 (1H, t); 1.7-1.2 (10H, m); 1.25 (1H, s).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[Cu][C:12]#[N:13].CN1CCCC1=O.Cl>[Fe](Cl)(Cl)Cl.O>[C:12]([C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1)#[N:13]
Reactant: N#C[Cu]
Reactant: Nc1c(F)cc(Br)cc1F
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1cc(F)c(N)c(F)c1
Yield: 57.3 %

Procedure:
132 g of 4-bromo-2,6-difluoroaniline, 70 g of copper (I) cyanide and 444 ml of N-methylpyrrolidone were mixed in a flask and refluxed for 3 hours. The reaction solution was poured into a solution including 266 g of iron (III) chloride, 85 ml of concentrated hydrochloric acid and 315 ml of water. The solution was extracted with chloroform and washed with water and an aqueous 10% solution of potassium hydroxide. The chloroform was distilled off. The residue was distillated under a reduced pressure (bp: 90°-110° C./4 mmHg) and recrystallized from a solvent mixture of hexane and chloroform, to yield 56 g of 4-cyano-2,6-difluoroaniline.
Reaction SMILES: C(NCC(N)=O)CS(O)(=O)=O.[OH-].[Na+].[CH:14]1[CH:19]=[N+:18]([C@@H:20]2[O:24][C@H:23]([CH2:25][O:26][P:27]([O:30][P:31]([O:34][CH2:35][C@H:36]3[O:40][C@@H:39]([N:41]4[C:45]5[N:46]=[CH:47][N:48]=[C:49]([NH2:50])[C:44]=5[N:43]=[CH:42]4)[C@H:38]([OH:51])[C@@H:37]3[OH:52])([OH:33])=[O:32])([O-:29])=[O:28])[C@@H:22]([OH:53])[C@H:21]2[OH:54])[CH:17]=[C:16]([C:55]([NH2:57])=[O:56])[CH:15]=1.[N-]=[N+]=[N-].[Na+].C(NCO)C([O-])=O.[Na+]>O>[CH:47]1[N:48]=[C:49]([NH2:50])[C:44]2[N:43]=[CH:42][N:41]([C@@H:39]3[O:40][C@H:36]([CH2:35][O:34][P:31]([O:30][P:27]([O:26][CH2:25][C@H:23]4[O:24][C@@H:20]([N:18]5[CH:17]=[C:16]([C:55]([NH2:57])=[O:56])[CH2:15][CH:14]=[CH:19]5)[C@H:21]([OH:54])[C@@H:22]4[OH:53])([OH:29])=[O:28])([OH:33])=[O:32])[C@@H:37]([OH:52])[C@H:38]3[OH:51])[C:45]=2[N:46]=1
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)([O-])OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: NC(=O)CNCCS(=O)(=O)O
Agent: O=C([O-])CNCO
Agent: [N-]=[N+]=[N-]
Solvent: O
Product: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1

Procedure:
One hundred ml of a second reagent composition were prepared as follows. Approximately 80 ml deionized water were dispensed into a container and 1.82 grams of N-[2-acetamido]-2-aminoethanesulfonic acid (ACES) were added and completely dissolved. The pH was adjusted to 6.0 with 2N sodium hydroxide (NaOH). Then 0.166 gram nicotinamide adenine dinucleotide (NAD) was added, followed by 0.095 gram sodium azide and 0.1 gram SUTTOCIDE A. The volume was adjusted to 100 ml with deionized water.