Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH2:24][CH3:25])[C:3](=[O:23])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11](=[O:22])[CH2:12][CH2:13][CH:14]=[CH:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:5].C(OCC)(=O)C.C(O)C.C(O)C.C(OCC)(=O)C>CO.[Pt]=O.[Pd]>[CH3:1][C:2]([CH3:26])([CH2:24][CH3:25])[C:3](=[O:23])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11](=[O:22])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:5]
Reactant: CCC(C)(C)C(=O)C(=O)N1CCCC1C(=O)CCC=Cc1cccnc1
Agent: O=[Pt]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCC(C)(C)C(=O)C(=O)N1CCCC1C(=O)CCCCc1cccnc1
Reaction time: 2.5 h

Procedure:
Platinum oxide (12 mg) was added to a solution of 3,3-dimethyl-1-[2-(5-(3-pyridyl)pent-4-enoyl) pyrrolidinyl]pentane-1,2-dione (300 mg; 0.84 mmol) in methanol (8 ml). The mixture was hydrogenated at 1 atm. for 2.5 hours. TLC indicated that the reaction was complete, and it was filtered through Celite and concentrated. Eluting through a plug of silica gel (ethyl acetate) furnished analytically pure material, 260 mg (87%). 1H NMR (CDCl3, 400 MHz): δ 0.87 (t, 3H, J=7.5); 1.21 (s, 6H); 1.64 (m, 4H); 1.69 (m, 2H); 1.78 (m, 1H); 1.96 (m, 2H); 2.15 (m, 1H); 2.53 (m, 1H); 2.63 (m, 2H); 3.49 (m, 1H); 3.53 (m, 1H); 4.57 (dd, 1H, J=8.8, 4.8); 7.20 (m, 1H); 7.49 (m, 1H, J=7.8); 8.44 (m, 2H). Anal. Calcd. for C21H30N2O3: C, 70.36; H, 8.44; N, 7.81. Found: C, 70.15; H, 8.54; N, 7.76. TLC: R1=0.80 (ethyl acetate:ethanol 4:1). Note: this final hydrogenation step may be done using 10% Pd/C, and hydrogenating for 5 hours at 60 psi. Ethanol or ethyl acetate may be used instead of methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[C:21]([CH3:28])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH:6]=1>C(O)(=O)C.C(OCC)(=O)C.[Zn]>[NH2:25][C:23]1[CH:22]=[C:21]([CH3:28])[C:3]([O:4][C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:6]=2)=[C:2]([Cl:1])[CH:24]=1
Reactant: Cc1cc([N+](=O)[O-])cc(Cl)c1Oc1ccc(O)c(COc2ccc(F)cc2)c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cc(N)cc(Cl)c1Oc1ccc(O)c(COc2ccc(F)cc2)c1
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
To a warm (100° C.) solution of 4-(2-chloro-6-methyl-4-nitro-phenoxy)-2-(4-fluorophenoxymethyl)-phenol (100 mg) in glacial acetic acid (2.5 mL) was added zinc dust (243 mg) and heating was continued for 30 min. The reaction mixture was cooled, diluted with ethyl acetate and filtered through Celite®. The filtrate was washed with 1 M aqueous sodium bicarbonate, dried over sodium sulfate, concentrated in vacuo and flashed chromatographed (30% ethyl acetate/hexanes) to afford 4-(4-amino-2-chloro-6-methyl-phenoxy)-2-(4-fluoro-phenoxymethyl)-phenol (90 mg) as a tan solid.
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[CH3:11][C:12]1([CH3:20])[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[O:13]1.[NH2:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([Br:28])[CH:27]=1>C(O)C>[Br:28][C:26]1[CH:27]=[C:22]([N:21]=[CH:1][CH:15]2[C:16](=[O:18])[O:17][C:12]([CH3:20])([CH3:11])[O:13][C:14]2=[O:19])[CH:23]=[N:24][CH:25]=1
Reactant: CCOC(OCC)OCC
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: Nc1cncc(Br)c1
Solvent: CCO
Product: CC1(C)OC(=O)C(C=Nc2cncc(Br)c2)C(=O)O1
Temperature: 92 °C
Yield: 300.8 %

Procedure:
A mixture of triethyl orthoformate (10 mL, 60.1 mmol) and 2,2dimethyl-1,3-dioxane-4,6-dione (40.9 g, 0.23 mol) (Meldrum's acid) was heated at 92° C. for 90 minutes and then cooled to 70° C. over one hour. 3-Amino-5-bromopyridine (40.9 g, 0.20 mol) was slowly added over 10 minutes with an ethanol rinse while maintaining the reaction temperature between 60 and 70° C. The reaction was then heated for an additional 20 minutes and allowed to cool to room temperature. The reaction mixture was filtered and washed with ethanol (150 mL) yielding a tan solid. The solid was dried under vacuum for 2 hours to yield 59.14 g of 5-{[(5-bromopyridin-3-yl)imino]methyl}-2,2-dimethyl-1,3-dioxane-4,6-dione as a light yellow crystalline solid, mp 200-202° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH:31]([C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)=[O:32].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.O.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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:20]=[C:2]([C:36]2[CH:37]=[N:38][C:33]([CH:31]=[O:32])=[CH:34][CH:35]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21]
Reactant: O=Cc1ccc(B(O)O)cn1
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(c1cc(-c2ccc(C=O)nc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 80 °C
Yield: 55.5 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (1 g, 2.15 mmol) and (6-formylpyridin-3-yl) boronic acid (0.539 g, 2.31 mmol) in dioxane/water mixture (15 mL+3 mL), Na2CO3 (0.82 g, 7.74 mmol) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.288 g, 0.25 mmol) was added and argon was purged again for 10 min. Reaction mass was heated at 80° C. for 2 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the desired compound (0.60 g, 57%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[CH3:11])=[CH:5][CH:4]=1.[OH:13][CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:15][NH2:16].C(O)C.C(O)(=O)/C=C/C(O)=O>C1C=CC=CC=1.CC(O)C.[Pt]=O>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:16][CH2:15][CH:14]([OH:13])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:11])=[CH:5][CH:4]=1
Reactant: NCC(O)c1ccccc1
Reactant: CC(=O)Cc1ccc(CO)cc1
Agent: O=[Pt]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: c1ccccc1
Solvent: CC(C)O
Product: CC(Cc1ccc(CO)cc1)NCC(O)c1ccccc1

Procedure:
A mixture of 1-(4-hydroxymethylphenyl)propan-2-one (3.0 g) and 2-hydroxy-2-phenylethanamine (2.5 g) in benzene (200 ml) was refluxed for 4 hours under Dean and Stark conditions. The solvent was replaced with ethanol (200 ml), platinum oxide (200 mg) was added and the mixture was hydrogenated at ambient temperature and pressure. The solution was filtered and evaporated to give an oil which was taken up in propan-2-ol and treated with the theoretical amount of fumaric acid. The title compound was obtained as the hemi-fumarate salt m.p. 67°-70° (60:40 mixture of diastereoisomers).
Reaction SMILES: C(O[C@@H:5]1[O:18][C@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:7]([O:8][C:9](=[O:11])[CH3:10])[C@H:6]1[N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34])(=O)C.B(F)(F)F.CCOCC.[C:44]1([SH:50])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(OCC)(=O)C>ClCCl>[C:9]([O:8][C@H:7]1[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:18][C@@H:5]([S:50][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C@@H:6]1[N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34])(=[O:11])[CH3:10]
Reactant: Sc1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](Sc2ccccc2)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3.82 g (0.008 Mol) of 1,3,4,6-tetra-O-acetyl-2-deoxy-2-phthalimido-β-D-glucopyranose was dissolved in 80 ml of anhydrous dichloromethane and stirred at 0° C. under an atmosphere of nitrogen. To this solution, 4.0 ml (0.032 Mol) of boron trifluoride diethyl etherate was slowly added. This was followed by 2.2 ml (0.021 Mol) of thiophenol. The resulting solution was stirred at 0° C. for 4 hr. and at RT for 2 hr. and then poured into a mixture of ethyl acetate (500 ml) and ice-cold saturated sodium bicarbonate solution (200 ml).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:6]2[CH2:7][NH:8][CH2:9][CH2:10][N:5]2[C:4](=[O:11])[O:3]1.C(N(CC)CC)C.[C:20](Cl)(=[O:28])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>O1CCCC1>[CH3:1][C:2]1([CH3:12])[CH:6]2[CH2:7][N:8]([C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:28])[CH2:9][CH2:10][N:5]2[C:4](=[O:11])[O:3]1
Reactant: CC1(C)OC(=O)N2CCNCC21
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)OC(=O)N2CCN(C(=O)Oc3ccccc3)CC21
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
Hexahydro-1,1-dimethyl-3H-oxazolo[3,4-a]pyrazin-3-one (0.10 g, 0.59 mmol) was dissolved in tetrahydrofuran (10 mL). Triethylamine (0.17 mL, 1.2 mmol) and phenyl chlorocarbonate (0.11 mL, 0.88 mmol) were added, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1 to 1:2). After purification, the crystals, which were precipitated while concentrating under reduced pressure, were collected by filtration to obtain the title compound (0.14 g, yield 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C@H:9]2[CH2:22]OS(C)(=O)=O)=[CH:4][C:3]=1[F:28].[Cl:29][C:30]1[C:31](=[O:36])[NH:32][CH:33]=[CH:34][CH:35]=1>>[ClH:1].[Cl:29][C:30]1[C:31](=[O:36])[N:32]([CH2:22][C@H:9]2[C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:28])[CH:4]=3)[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:33]=[CH:34][CH:35]=1
Reactant: O=c1[nH]cccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](COS(C)(=O)=O)C1
Product: Cl
Product: O=c1c(Cl)cccn1C[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(F)c1

Procedure:
Using tert-butyl (6S,7R)-7-(4-chloro-3-fluorophenyl)-6-{[(methylsulfonyl)oxy]methyl}-1,4-oxazepane-4-carboxylate and 3-chloropyridin-2(1H)-one, and by a method similar to that in Example 31, steps C and E, the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([N:15]([CH:25]3[CH2:27][CH2:26]3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:12]3=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:11]3[N:10]=2)=[CH:6][C:5]([C:33]#[N:34])=[CH:4][C:3]=1[N:35]1[CH2:40][CH2:39][NH:38][CH:37]([C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[CH2:36]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:53][CH:54]([F:56])[F:55]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([N:15]([CH:25]3[CH2:27][CH2:26]3)[CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[C:12]3=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:11]3[N:10]=2)=[CH:6][C:5]([C:33]#[N:34])=[CH:4][C:3]=1[N:35]1[CH2:40][CH2:39][N:38]([CH2:53][CH:54]([F:56])[F:55])[CH:37]([C:41]([N:43]([CH3:44])[CH3:45])=[O:42])[CH2:36]1
Reactant: FC(F)CBr
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCNC(C(=O)N(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCN(CC(F)F)C(C(=O)N(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 80 °C
Yield: 87.9 %

Procedure:
4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-N,N-dimethylpiperazine-2-carboxamide (38 mg, 0.061 mmol, Example 563D) was taken up in DMF (0.5 mL) and Cs2CO3 (39.5 mg, 0.121 mmol) and 2-bromo-1,1-difluoroethane (5.79 μl, 0.073 mmol) were added. The reaction was heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was extracted 2× with water and once with brine, then dried over Na2SO4, filtered, and concentrated. 4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-1-(2,2-difluoroethyl)-N,N-dimethylpiperazine-2-carboxamide (37 mg) was obtained as an orange glass. The crude material was taken onto the next step.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:6]([NH:7][C:8](=[O:10])[CH3:9])=[CH:5][CH:4]=1)[CH3:2].[N+:13]([O-])([OH:15])=[O:14]>C(OC(=O)C)(=O)C.C(O)(=O)C>[CH2:1]([C:3]1[CH:12]=[CH:11][C:6]([NH:7][C:8](=[O:10])[CH3:9])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(NC(C)=O)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A stirred solution of 4-ethyl-N-acetyl-aniline [3 g, Reference Example 33(a)] in acetic anhydride (8 mL) and acetic acid (4 mL), at −5° C., was treated dropwise with a mixture of acetic acid (1.75 mL) and concentrated nitric acid (1.22 mL). The mixture was warmed to 0° C., then stirred at 0° C. for 2 hours and then poured onto water. This mixture was evaporated and the resulting oil was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate and then evaporated. The residual oil was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and petroleum ether (2:5) to give 4-ethyl-2-nitro-N-acetyl-aniline (1.4 g) as an orange solid.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[F:11][C:12]1[CH:13]=[C:14]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][C:19]=2[CH:28]([NH2:30])[CH3:29])[CH:15]=[CH:16][CH:17]=1.C(N(CC)C(C)C)(C)C>C(O)C>[F:11][C:12]1[CH:13]=[C:14]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][C:19]=2[CH:28]([NH:30][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:29])[CH:15]=[CH:16][CH:17]=1
Reactant: CC(N)c1ccc2ccccc2c1-c1cccc(F)c1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1ccc2ccccc2c1-c1cccc(F)c1

Procedure:
A mixture of 6-bromo-9H-purine (0.02696 g, 0.1355 mmol), 1-[1-(3-fluorophenyl)-2-naphthyl]ethanamine (0.030 g, 0.11 mmol), and N,N-diisopropylethylamine (0.024 mL, 0.14 mmol) in ethanol (0.9 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resultant residue was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/minute) to give the product as a TFA salt. LCMS calculated for C23H19FN5(M+H)+: m/z=384.2; found: 384.3. 1H NMR (DMSO-d6, 400 MHz) δ 8.92 (1H, br s), 8.30 (2H, m), 7.97 (1H, d, J=9.2 Hz), 7.90 (1H, d, J=7.6 Hz), 7.79 (1H, m), 7.57 (1H, m), 7.47 (1H, m), 7.40 (2H, m), 7.31 (1H, m), 7.19 (2H, m), 5.23 (1H, m), 1.49 (3H, m) ppm. 19F NMR (DMSO-d6, 376.28 MHz) δ −74.6 ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:11][O:12][CH2:13]Cl.C([Li])CCC.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C>>[CH3:11][O:12][CH2:13][O:8][C:5]1[CH:6]=[CH:7][C:2]([B:20]([OH:25])[OH:21])=[CH:3][CH:4]=1
Reactant: COCCl
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Oc1ccc(Br)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Product: COCOc1ccc(B(O)O)cc1

Procedure:
In a manner similar to that of Example 1(g), by reaction of 10 g (57.8 mmol) of 4-bromophenol with 2.55 g (63.6 mmol) of 60% sodium hydride and 4.83 mL (63.6 mmol) of methoxymethyl chloride, followed by 25.4 mL (63.6 mmol) of 2.5M butyllithium solution and 15 mL (65 mmol) of triisopropyl borate, a brown solid is obtained (m.p.=65° C., m=6.2 g; Y=7.3%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9](OS(C(F)(F)F)(=O)=O)=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2.[NH:30]1[C:38]2[C:33](=[CH:34][C:35](B(O)O)=[CH:36][CH:37]=2)[CH:32]=[CH:31]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[NH:30]1[C:38]2[C:33](=[CH:34][C:35]([C:9]3[C:8]([N:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]4[CH3:1])=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=4)[N:10]=3)=[CH:36][CH:37]=2)[CH:32]=[CH:31]1
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCC[C@@H]3C)nc2c1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]ccc4c3)c(N3CCCC[C@@H]3C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 34.2 %

Procedure:
To a solution of (S)-methyl 3-(2-methylpiperidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (250 mg, crude) in dioxane (5 mL) was added Pd(PPh3)4 (33 mg, 0.03 mmol), 1H-indol-5-ylboronic acid (234 mg, 1.45 mmol), K3PO4 (367 mg, 1.74 mmol) and water (5 drops). The resulting solution was stirred for 1 h at 90° C. with an inert atmosphere of nitrogen and then concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with 1%-10% ethyl acetate in petroleum ether to afford (S)-methyl 2-(1H-indol-5-yl)-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylate as a yellow solid (79 mg).
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[O:7])=[CH:4][N:3]=1.[CH3:20][O:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:18]=[CH:19][C:2]([N:27]3[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][O:21][CH3:20])[CH2:25][CH2:26]3)=[N:3][CH:4]=2)=[CH:12][CH:13]=1
Reactant: COCCN1CCNCC1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(Cl)nc1
Product: COCCN1CCN(c2ccc(C(=O)NCCc3ccc(Cl)cc3)cn2)CC1

Procedure:
In analogy to example 21.b 6-chloro-N-[2-(4-chloro-phenyl)-ethyl]-nicotinamide was reacted with 1-(2-methoxyethyl)piperazine. Light yellow solid. MS (ISP): 403.3 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)(=[O:24])=[O:23])[CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[ClH:1].[Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[CH:26]=2)(=[O:23])=[O:24])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(S(=O)(=O)c4cccc(C(F)(F)F)c4)cc3c2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)c1cc(Cl)c2oc3c(c2c1)CNCC3
Reaction time: 3 h
Yield: 49.5 %

Procedure:
To the product of step A (130 mg, 0.25 mmol) in dichloromethane, was added trifluoroacetic acid (0.48 mL) at 0° C. After stirring for 3 h, the reaction mixture was concentrated in vacuo, treated with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic extract was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography in (SiO2, 90:10 dichloromethane/methanol) and the free base treated directly with 1.25M HCl in methanol to give 6-chloro-8-(3-trifluoromethylphenylsulfonyl)-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine hydrochloride (28 mg, 27%) as a white solid: 1H NMR (DMSO-d6, 300 MHz) δ 9.51 (s, 2H), 8.51 (d, J=1.5 Hz, 1H), 8.37-8.34 (m, 2H), 8.18 (d, J=1.5 Hz, 1H), 8.10 (d, J=7.8 Hz, 1H), 7.89 (t, J=7.8 Hz, 1H), 4.38 (s, 2H), 3.52 (t, J=5.2 Hz, 2H), 3.17 (t, J=5.4 Hz, 2H); APCI MS m/z 416 [M+H]+.
Reaction SMILES: N[C@H:2]([C:10]([OH:12])=[O:11])CC1C=CC=CC=1.[NH2:13][C@H:14]([C:16]([OH:18])=[O:17])[CH3:15].N[C@H](C(O)=O)CC1C=CC(O)=CC=1.N[C@H](C(O)=O)CC(C)C.N[C@H](C(O)=O)CCCNC(=N)N>>[NH2:13][C@H:14]([C:16]([OH:18])=[O:17])[CH2:15][CH2:2][C:10](=[O:11])[OH:12]
Reactant: C[C@H](N)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)C[C@H](N)C(=O)O
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Agent: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
1.02 His: 0.95 Phe: 0.95 Ala: 2.00 Tyr: 0.91 Leu: 1.00 Arg: 0.90 Pro: 0.96
Reaction SMILES: [CH3:1][N:2]1[C:6](=[NH:7])[C:5](=[O:8])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]1=[O:15].O=[CH:17][C:18]([Cl:21])([Cl:20])[Cl:19].S(Cl)([Cl:24])=O>COCCOC>[CH3:1][N:2]1[C:6](=[N:7][CH:17]([Cl:24])[C:18]([Cl:21])([Cl:20])[Cl:19])[C:5](=[O:8])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]1=[O:15]
Reactant: CN1C(=N)C(=O)N(c2ccccc2)C1=O
Reactant: O=S(Cl)Cl
Reactant: O=CC(Cl)(Cl)Cl
Solvent: COCCOC
Product: CN1C(=O)N(c2ccccc2)C(=O)C1=NC(Cl)C(Cl)(Cl)Cl
Yield: 40 %

Procedure:
In this preparation 1-methyl-3-phenyl-5-imino-1,3-diazolidine-2,4-dione (10.15 g; 0.05 mol) was dissolved in 80 ml 1,2-dimethoxyethane. Chloral (13.7 g, 1.0 mol) was added followed by the addition of thionyl chloride (11.9 g, 1.0 mol). The temperature of the reaction mixture rose to 45° C. due to the exothermicity of the reaction. One hour later the temperature was back to 23° C. and a solid had formed. The solid (1.1 g) had a melting point 140-150 with some not melting at all. The filtrate was stripped to give 9.6 g of a crude material which was recrystallized from benzene and washed with ether to give 8.2 g (0.02 mol) of 1-methyl-3-phenyl-5-(1,2,2,2-tetrachloroethyl)imino-1,3-diazolidine-2,4-dione melting at 158°-160° C.
Reaction SMILES: O1CCCC1.[H-].[Na+].[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.F[C:17]1[CH:18]=[C:19]([CH:56]=[C:57]([C:59]([F:62])([F:61])[F:60])[CH:58]=1)[CH2:20][N:21]([CH2:34][C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:36]=1[C:45]1[CH:50]=[C:49]([CH:51]([CH3:53])[CH3:52])[CH:48]=[CH:47][C:46]=1[O:54][CH3:55])[C:22]1[N:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:24][N:23]=1>[Cl-].[Na+].O>[CH2:8]([O:15][C:17]1[CH:18]=[C:19]([CH:56]=[C:57]([C:59]([F:62])([F:60])[F:61])[CH:58]=1)[CH2:20][N:21]([CH2:34][C:35]1[CH:40]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:38]=[CH:37][C:36]=1[C:45]1[CH:50]=[C:49]([CH:51]([CH3:53])[CH3:52])[CH:48]=[CH:47][C:46]=1[O:54][CH3:55])[C:22]1[N:27]=[CH:26][C:25]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)=[CH:24][N:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCc1ccccc1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(OCc2ccccc2)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Reaction time: 0.5 h

Procedure:
To tetrahydrofuran (6 ml) is added sodium hydride (60%) (390 mg) under nitrogen atmosphere, followed by an addition dropwise of benzyl alcohol (1.01 ml) under water-cooling, and the mixture is stirred at the same temperature for 30 minutes. To this reaction mixture is added a mixture of (3-fluoro-5-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amine (430 mg) and tetrahydrofuran (4 ml) and the mixture is stirred under nitrogen atmosphere at 70° C. overnight. To the reaction solution are added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=97:3→17:3) to give (3-benzyloxy-5-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amine (221 mg). MS (m/z): 751 [M+H]+