Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][NH:12][CH2:11][CH2:10][N:9]1C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:21]=[C:22]1[C:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][N:23]1[CH2:39][C:40](O)=[O:41].C(N(C(C)C)CC)(C)C.Cl>ClCCl>[CH2:1]([CH:8]1[NH:9][CH2:10][CH2:11][N:12]([C:40](=[O:41])[CH2:39][N:23]2[CH2:24][CH2:25][C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:22]2=[O:21])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1Cc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCNC(Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
To tert-butyl 2-benzylpiperazine-1-carboxylate (0.052 g, 0.190 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.051 g, 0.173 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.069 g, 0.181 mmol) in dichloromethane (0.5 mL) was added diisopropylethylamine (0.045 mL, 0.259 mmol), and the reaction was stirred a room temperature. After stirring overnight, the reaction was concentrated, loaded onto a silica gel column (Analogix® SF15-12, Burlington, Wis.) and eluted with a gradient of 5% to 100% ethyl acetate/hexanes. To the resulting product was added HCl (2.0 Min diethyl ether, 3.57 μl, 0.117 mmol), and the reaction was stirred at room temperature overnight. The reaction was centrifuged, and the solvent was decanted away from the solid. Diethyl ether (1 mL) was added, and the suspension was sonicated to give a fine suspension. The reaction was centrifuged, the solvent was decanted and the resulting solid dried to give the title compound as the hydrochloride salt. 1H NMR (300 MHz, pyridine-d5) δ ppm 7.05-7.50 (m, 15H), 4.65-4.80 (m, 2H), 4.25-4.55 (m, 2H), 3.95-4.15 (m, 2H), 3.40-3.75 (m, 5H), 2.95-3.27 (m, 2H), 2.75-2.85 (m, 2H); MS (DCI+) m/z 454.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)=[CH:20][C:19]=3[O:31][CH3:32])[N:12]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].[CH3:35]I>O1CCCC1.CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)=[CH:20][C:19]=3[O:31][CH3:32])[N:12]=2)[N:8]([CH3:35])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)c1c[nH]c(-c2ccnc(Nc3ccc(N4CCN(C)CC4)cc3OC)n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccnc(Nc3ccc(N4CCN(C)CC4)cc3OC)n2)n(C)c1
Reaction time: 12 h
Yield: 74.4 %

Procedure:
To a solution of 5-{2-[2-Methoxy-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1H-pyrrole-3-carboxylic acid ethyl ester (0.5 g, 1.14 mmol) in tetrahydrofuran (25 mL) and dimethylsulfoxide (5 mL) cooled in a ice-water bath, NaH (50 mg, 1.26 mmol) and methyl iodide (0.08 mL, 1.26 mmol) were added. The reaction was continued at room temperature for 12 h, tetrahydrofuran was removed under vacuo, then dichloromethane (25 mL) was added and the organic phase washed with water (25 mL). The aqueous fraction was extracted with dichloromethane (2×20 mL). The organic fractions were combined, dried over sodium sulfate, filtered, and concentered in vacuo. Purification by flash chromatography on silica gel (eluant: dichloromethane/methanol 95/5) provided 382 mg (74%) of the title compound as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2([CH3:21])[CH2:16][C:15]([C:17]([F:20])([F:19])[F:18])=[N:14][NH:13]2)=[S:11])=[CH:5][C:4]=1[C:22]([F:25])([F:24])[F:23])#[N:2].C([O-])([O-])=O.[K+].[K+].[CH3:32][C:33](C)=O>>[CH2:32]([S:11][C:10]([C:12]1([CH3:21])[CH2:16][C:15]([C:17]([F:18])([F:19])[F:20])=[N:14][NH:13]1)=[N:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:22]([F:25])([F:24])[F:23])[CH:5]=1)[CH3:33]
Reactant: CC(C)=O
Reactant: CC1(C(=S)Nc2ccc(C#N)c(C(F)(F)F)c2)CC(C(F)(F)F)=NN1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCSC(=Nc1ccc(C#N)c(C(F)(F)F)c1)C1(C)CC(C(F)(F)F)=NN1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carbothioic acid (4-cyano-3-trifluoromethyl-phenyl)-amide (10 mmoL), K2CO3 (15 mmoL) in acetone was treated with Etl (10 mmoL) at room temperature. The reaction was slightly heated and stirred at 50° C. for 1 hr. The solid was filtrated and the filtrate was concentrated to give the crude product as a brown oil, which was then purified by silica gel column chromatography using hexanes and ethyl acetate as eluent to afford the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:20]C)[N:6]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N>Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:20])[N:6]2[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1nc(N)c2nc(OC)n(Cc3ccccc3)c2n1
Agent: Cl
Agent: N
Product: COc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Yield: 75.3 %

Procedure:
6-Amino-9-benzyl-2,8-dimethoxypurine (53 mg, 0.186 mmol) in concentrated hydrochloric acid (10 ml) was stirred for 3 hours at room temperature. The reaction mixture was made basic with 28% aqueous ammonia, and the resulting crystals were filtered and washed with water to give the subject compound (38 mg, yield 75%).
Reaction SMILES: [CH:1]([N:4]([CH2:12][CH2:13][NH:14]S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].C1(S)C=CC=CC=1>C(#N)C.O>[NH2:14][CH2:13][CH2:12][N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)N(CCNS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CC(C)N(CCN)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.8 %

Procedure:
The compound (34.21 g, 82.60 mmol) obtained in step A was dissolved in acetonitrile (300 ml), cesium carbonate (52.38 g, 161 mmol) and benzenethiol (12 ml, 117 mmol) were added and the mixture was stirred at room temperature for one day. The reaction mixture was diluted with water, and the aqueous layer was extracted with dichloromethane. The obtained organic layer was dried over potassium carbonate, the insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was dissolved in toluene, and the mixture was extracted with 1N aqueous hydrogensulfate potassium solution. An aqueous sodium hydroxide solution was added to the aqueous layer to give a strong alkaline solution, and the suspending oil was extracted. The aqueous layer was extracted with dichloromethane, mixed with oil and dichloromethane solution, and the mixture was dried over sodium sulfate. The insoluble material was filtered off and the solution was concentrated under reduced pressure to give the title compound as a pale-yellow oil (15.0 g, yield 79%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:8])[CH3:7].[Cl-].[Al+3].[Cl-].[Cl-].Br[CH:14]([CH3:16])[CH3:15]>C(Cl)(Cl)Cl>[CH:14]([C:4]1[CH:3]=[C:2]([C:6](=[O:8])[CH3:7])[S:1][CH:5]=1)([CH3:16])[CH3:15]
Reactant: CC(C)Br
Reactant: CC(=O)c1cccs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CC(=O)c1cc(C(C)C)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(Thiophen-2-yl)ethanone (5.4 mL) was added to an ice cold suspension of aluminum chloride (33 g), in dry chloroform (100 mL). 2-Bromopropane (5.2 mL) was then added dropwise over 5 min. The reaction was allowed to warm to RT and stirred overnight. The dark suspension was cautiously poured onto ice and the mixture stirred for 10 min. The layers were separated and the aqueous phase extracted with DCM (100 mL). The combined organic layers were washed with sodium hydroxide solution (2M, 200 mL) and water (200 mL), dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with 2% ethyl acetate in isohexane. The fractions containing product were combined and evaporated to give the subtitled compound as a light yellow oil. Yield 5.4 g.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:4][C:3]=1[CH3:17].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C(C)=CC=CC=1>[CH2:10]([O:9][C:6]1[C:7]2[NH:8][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:1][C:2]=2[C:3]([CH3:17])=[CH:4][CH:5]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1ccc(OCc2ccccc2)c(N)c1N
Solvent: Cc1ccccc1C
Product: Cc1ccc(OCc2ccccc2)c2[nH]c(-c3ccccc3)nc12
Reaction time: 18 h

Procedure:
A mixture of 2,3-diamino-4-benzyloxytoluene (5.0 g) and benzaldehyde (5.52 g, 2 mol. equiv.) in xylene (75 ml) was heated under reflux for 3 h, and then left for 18 h at room temperature. The resulting crystalline product was filtered, washed with ether, and recrystallized from ethanol to afford the title compound, 4.13 g, m.p. 221°-224° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]1[N:14]=[C:13]([NH:15][C:16]2[C:17]3[N:18]([CH:32]=[CH:33][N:34]=3)[N:19]=[C:20]([C:22]3[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=3)[C:25]([O:27]C)=[O:26])[CH:21]=2)[CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>O1CCOCC1.O>[CH3:1][O:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]1[N:14]=[C:13]([NH:15][C:16]2[C:17]3[N:18]([CH:32]=[CH:33][N:34]=3)[N:19]=[C:20]([C:22]3[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=3)[C:25]([OH:27])=[O:26])[CH:21]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: COCC1CCCN1c1cccc(Nc2cc(-c3cccc(C(=O)OC)c3)nn3ccnc23)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COCC1CCCN1c1cccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)n1
Yield: 24.5 %

Procedure:
To a stirred solution of methyl 3-(8-(6-(2-(methoxymethyl)pyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (0.155 g, 0.34 mmol) in dioxane (10 mL) and H2O (4 mL) was added NaOH (135 mg, 3.4 mmol) at 40° C. After 4 h the mixture was washed with ether (10 mL), the aqueous layer adjusted to pH=4 with concentrated HCl, then was concentrated and filtered. The collected solid was washed with ether and dried to afford 3-(8-(6-(2-(methoxymethyl)pyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (0.037 g, 28% over two steps) as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 8.80 (s, 1H), 8.54 (s, 1H), 8.20-8.08 (m, 3H), 7.72 (d, 1H, J=1.5 Hz), 7.59 (t, 1H, J=7.8 Hz), 7.45 (t, 1H, J=7.8 Hz), 6.31 (d, 1H, J=7.5 Hz), 6.17 (d, 1H, J=8.4 Hz), 4.21 (brs, 1H), 3.62-3.58 (m, 1H), 3.51-3.42 (m, 2H), 3.34-3.32 (m, 1H), 3.11 (s, 3H), 2.10-2.00 (m, 4 h). LC-MS: [M+H]+, 445, tR=1.714 min, HPLC: 95.14% at 214 nm, 95.00% at 254 nm, tR=5.9 min.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1)#[CH:2].[F:11][C:12]1[CH:19]=[CH:18][C:17](I)=[CH:16][C:13]=1[C:14]#[N:15].C(N(CC)CC)C>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.[Cu]I>[F:11][C:12]1[CH:19]=[CH:18][C:17]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=2)=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: N#Cc1cc(I)ccc1F
Reactant: C#Cc1cncc(OC)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1cncc(C#Cc2ccc(F)c(C#N)c2)c1
Temperature: 60 °C
Yield: 87.9 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (77 mg, 0.1 mmol), copper (I) iodide (44 mg, 0.23 mmol), and 3-ethynyl-5-methoxypyridine (300 mg, 2.3 mmol), (prepared as described in PREPARATION 10), to a solution of 2-fluoro-5-iodobenzonitrile (670 mg, 2.7 mmol) in triethylamine (3.4 mL, 34 mmol) and heat at 60° C. for 2.75 h. Cool to room temperature and concentrate. Purify the residue by silica gel chromatography, eluting with 100:0 to 80:20 dichloromethane/ethyl acetate followed by a second silica gel chromatography, eluting with 75:25 to 60:40 hexanes:ethyl acetate to give the title compound as a white solid (510 mg, 90%).
Reaction SMILES: O[CH:2]([CH3:16])[C@H:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4].[C:17]1(=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[NH:18]1>>[O:27]=[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[N:18]1[CH:2]([CH3:16])[C@H:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4]
Reactant: CC(O)[C@@H](C)NC(=O)OCc1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Product: CC([C@@H](C)NC(=O)OCc1ccccc1)N1C(=O)c2ccccc2C1=O

Procedure:
Under argon, 0.82 g of benzyl [(2R)-3-hydroxybutan-2-yl]carbamate (Example 134A, 3.3 mmol, 1 equivalent) were reacted with 0.57 g of 1H-isoindole-1,3(2H)-dione (phthalimide, 3.9 mmol, 1.1 equivalents) and worked up analogously to Example 137A. This gave 1.25 g (72% of theory; purity 75%) of the title compound (diastereomer ratio about 3:1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:34])=[C:23]([CH:25]=[N:26][C:27]([O:29][Si](C)(C)C)=[CH2:28])[CH:24]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[NH:8][C:7](=[O:11])[C:6]3([CH:12]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:28][C:27](=[O:29])[NH:26][CH:25]3[C:23]3[CH:24]=[C:19]([F:18])[CH:20]=[CH:21][C:22]=3[CH3:34])[C:5]2=[CH:4][CH:3]=1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Reactant: CC(C)(C)C/C=C1\C(=O)Nc2cc(Cl)ccc21
Product: Cc1ccc(F)cc1C1NC(=O)CC(CC(C)(C)C)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in example 1c, E/Z-6-Chloro-3-(3,3-dimethyl-butylidene)-1,3-dihydro-indol-2-one (0.2 g, 0.80 mmol) prepared in example 1a was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 36a to give racemic (2′R,3R,4′S)-6-chloro-4′-(2,2-dimethylpropyl)-2′-(5-fluoro-2-methyl phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an white solid (7 mg).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[CH3:6][C:7]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[O:17][CH3:18])=[O:8]>O>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:9]=1[C:7](=[O:8])[CH2:6][CH:2]([OH:3])[C:1]([OH:5])=[O:4]
Reactant: O=CC(=O)O
Reactant: COc1ccc(OC)c(C(C)=O)c1
Solvent: O
Product: COc1ccc(OC)c(C(=O)CC(O)C(=O)O)c1

Procedure:
22.2 g of glyoxylic acid, 50 wt.% in water, are heated under reduced pressure until about 80% of the water present has been eliminated; then, after cooling, 54 g of 2,5-dimethoxyacetophenone are added, i.e., an excess of 100% over theoretical.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:23]2[N:27]([CH2:28][CH3:29])[N:26]=[CH:25][CH:24]=2)=[C:12]([F:30])[C:11]=1[F:31])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH2:28]([N:27]1[C:23]([C@H:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]2[O:16][C:13]2[CH:14]=[CH:15][C:10]([S:7]([NH:6][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][N:33]=3)(=[O:8])=[O:9])=[C:11]([F:31])[C:12]=2[F:30])=[CH:24][CH:25]=[N:26]1)[CH3:29]
Reactant: CCn1nccc1[C@H]1CCCC[C@@H]1Oc1ccc(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)c(F)c1F
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1nccc1[C@H]1CCCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1F
Yield: 83.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (0.060 g, 0.09 mmol) prepared in Example 41a, triethylsilane (0.07 mL), trifluoroacetic acid (0.09 mL) and dichloromethane (0.9 mL), to yield the title compound (34.9 mg, 82%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Sn](Cl)(Cl)(Cl)Cl.[C:23](Cl)(=[O:25])[CH3:24].O>ClC(Cl)C>[C:23]([C:8]1[C:7]([O:9][CH3:10])=[CH:6][C:5]([NH:11][C:12](=[O:17])[C:13]([F:14])([F:16])[F:15])=[CH:4][C:3]=1[O:2][CH3:1])(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: COc1cc(NC(=O)C(F)(F)F)cc(OC)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CC(Cl)Cl
Product: COc1cc(NC(=O)C(F)(F)F)cc(OC)c1C(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.7 %

Procedure:
To a solution of N-(3,5-Dimethoxy-phenyl)-2,2,2-trifluoro-acetamide (31.8 g, 130 mmol) in anhydrous dichloroethane (450 mL), cooled in an ice bath, was added a solution of tin (IV) chloride (29.9 mL, 260 mmol dissolved in 30 mL anhydrous dichloroethane) dropwise over 10 minutes. Acetyl chloride (9.1 mL, 130 mmol) was added slowly, maintaining the temperature of the reaction below 5° C. After stirring 3 hours at room temperature, the reaction was cooled in an ice bath. Water (300 mL) was added, maintaining the temperature of the reaction below 25° C., and the reaction was stirred at room temperature for 18 hours. The reaction mixture was extracted with dichloromethane, and the organic layer was separated, washed with water, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 20% to 30% hexanes/ethyl acetate to yield N-(4-Acetyl-3,5-dimethoxy-phenyl)-2,2,2-trifluoro-acetamide (4.8 g, 13%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25](/[CH:27]=[CH:28]/[P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[CH:26][C:4]=2[N:3]=1.[H][H]>C(Cl)Cl.CCO.[Pd]>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH2:27][CH2:28][P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[CH:26][C:4]=2[N:3]=1
Reactant: [H][H]
Reactant: CCOP(=O)(/C=C/c1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OC)cc3C)cc12)OCC
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: CCOP(=O)(CCc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OC)cc3C)cc12)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (E)-diethyl 2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)vinylphosphonate (3-1) (Example 10—Step 1) (1.0 equiv.) in DCM (0.05 M) and EtOH (0.08 M) was added 10% palladium on carbon (0.09 equiv.). A reaction vessel was charged with a hydrogen balloon and stirred at room temperature overnight. After the reaction was complete as monitored by LCMS, solvents were removed, and the resulting residue was purified by a COMBIFLASH® system (ISCO) using a gradient of 0-5% MeOH/DCM to provide diethyl 2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)ethylphosphonate (3-3).
Reaction SMILES: [Br:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[N:6]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[CH:3]=1
Reactant: CCOC(=O)CI
Reactant: FC(F)(F)c1cc(Br)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nc(C(F)(F)F)cc1Br
Temperature: 95 °C
Reaction time: 3 h

Procedure:
A suspension of 5-bromo-3-(trifluoromethyl)-1H-pyrazole (i.e. the product of Example 11, Step B) (2.73 g, 12.7 mmol) and potassium carbonate (2.0 g, 14.5 mmol) in N,N-dimethylformamide (20 mL) was treated with ethyl iodoacetate (3.0 ml, 25.3 mmol), and the resulting mixture was stirred at 95° C. for 3 h. The resulting mixture was diluted with ethyl acetate, washed with water, and dried (MgSO4). The reaction mixture was concentrated in vacuo and further purified by medium-pressure liquid chromatography using 0-50% of ethyl acetate in hexanes as eluant to give 2.84 g of the title compound as a brown oil.
Reaction SMILES: Cl.[OH:2][NH2:3].C(N(CC)CC)C.[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20]3[C:21]4[C:35](=[O:36])[O:34][C:33](=O)[C:22]=4[CH:23]=[C:24]4[C:32]=3[C:28]3[O:29][CH2:30][O:31][C:27]=3[CH:26]=[CH:25]4)=[CH:19][C:14]=2[O:13][CH2:12]1>CCO>[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20]3[C:32]4[C:24](=[CH:25][CH:26]=[C:27]5[O:31][CH2:30][O:29][C:28]5=4)[CH:23]=[C:22]4[C:33](=[O:34])[N:3]([OH:2])[C:35](=[O:36])[C:21]=34)=[CH:19][C:14]=2[O:13][CH2:12]1
Reactant: O=C1OC(=O)c2c1cc1ccc3c(c1c2-c1ccc2c(c1)OCO2)OCO3
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1c2cc3ccc4c(c3c(-c3ccc5c(c3)OCO5)c2C(=O)N1O)OCO4
Reaction time: 0.17 h
Yield: 14.1 %

Procedure:
Hydroxyamine hydrochloride (20.9 mg, 0.3 mmol) and triethylamine (0.04 mL, 0.3 mmol) were dissolved in EtOH (30 mL). After stirring for 10 min, anhydride 1 (109 mg, 0.3 mmol) was added. The mixture was refluxed overnight and then concentrated in vacuo. The resulting product was purified by silica gel column chromatography using CH2Cl2/acetone (2:1, v/v) to afford 24 (16 mg, 15%) as a yellow powder. mp 255° C. (decomp.); 1H NMR (DMSO-d6) δ 10.78 (s, 1H, OH), 8.40 (s, 1H, H4), 7.89 (d, 1H, H5, J=8.7 Hz), 7.54 (d, 1H, H6, J=8.7 Hz), 6.94 (s, 1H, H2′), 6.90 (d, 1H, H5′, J=7.8 Hz), 6.79 (d, 1H, H6′, J=7.8 Hz), 6.08 (s, 2H, 3′,4′-OCH2O—), 5.96 (AB, 2H, 7,8-OCH2O—, Δδ=5.7 Hz); MS (FAB, positive) m/z 378 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=3)[O:15][CH:10]2[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)[CH3:2].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:34][CH2:35][OH:36])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]>ClCCl.B(F)(F)F.CCOCC>[OH:15][CH:10]([C:9]([O:36][CH2:35][CH2:34][C:28]1[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[CH:27]=1)([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=1)[C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: CCc1ccc(C2(c3ccc(CC)cc3)OC2C(=O)OC)cc1
Reactant: COc1ccc(CCO)cc1OC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCc1ccc(C(OCCc2ccc(OC)c(OC)c2)(c2ccc(CC)cc2)C(O)C(=O)OC)cc1
Reaction time: 1.5 h

Procedure:
6 g (19.3 mmol) of methyl 3,3-di(4-ethylphenyl)-2,3-epoxypropionate (crude) and 3.52 g (19.3 mmol) of 2-(3,4-dimethoxyphenyl)ethanol were dissolved in 20 ml of dichloromethane and, at room temperature, 5 drops of boron trifluoride etherate were added. The solution was stirred for 1.5 hours. The solvent was then distilled off, and the residue, a pale yellow oil (8.66 g, 91%), was immediately reacted further.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH2:20]([O:22][C:23]([C:25]1[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([NH2:34])=[CH:29][CH:28]=2)=[O:24])[CH3:21]>>[CH2:20]([O:22][C:23]([C:25]1[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([NH:34][C:2]1[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]4[O:15][CH2:16][CH2:17][O:18][C:11]=4[CH:10]=3)[C:5]([F:19])=[CH:4][N:3]=1)=[CH:29][CH:28]=2)=[O:24])[CH3:21]
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Product: CCOC(=O)c1cc2cc(Nc3ncc(F)c(Nc4ccc5c(c4)OCCO5)n3)ccc2[nH]1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 2-ethoxycarbonyl-5-aminoindole were reacted to yield N2-(2-ethoxycarbonylindol-5-yl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.84 (d, 1H, J=5.4 Hz), 7.76 (d, 1H, J=3.6 Hz), 7.50 (d, 1H, J=9 Hz), 7.23–7.15 (m, 3H), 7.03 (bd, 1H, J=8.7 Hz), 6.78 (d, 1H, J=8.7 Hz), 4.38 (q, 2H, J=7.2 Hz), 4.22 (s, 4H), 1.41 (t, 3H, J=6.9 Hz); LCMS: ret. time: 23.58 min; purity: 100%; MS (m/e): 451 (MH+).