Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:35])[CH2:3][CH2:4][CH2:5][S:6]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[C:23]3[C:18](=[C:19]([C:32]([NH2:34])=[O:33])[CH:20]=[C:21]([C:24]4[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][CH:25]=4)[CH:22]=3)[NH:17][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])=[O:7].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:35][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][S:6]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[C:23]3[C:18](=[C:19]([C:32]([NH2:34])=[O:33])[CH:20]=[C:21]([C:24]4[CH:29]=[CH:28][C:27]([CH2:30][N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[CH:26][CH:25]=4)[CH:22]=3)[NH:17][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])=[O:7]
Reactant: C1COCCN1
Reactant: CN(C)CCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(C=O)cc4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CN(C)CCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CN5CCOCC5)cc4)cc23)CC1
Yield: 26.4 %

Procedure:
Following the general procedure of example (99), 3-(1-{[3-(dimethylamino)propyl]sulfonyl}-4-piperidinyl)-5-(4-formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.1 mmol), morpholine (9 mg, 0.1 mmol) and NaBH(OAc)3 (64 mg, 0.3 mmol) were reacted to give the title compound (15 mg, 30%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:26]=[C:25]([CH3:27])[C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[C:17]([CH3:28])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)[CH3:2].[CH2:30](CNC1N=C(C(O)=O)C=C(C)N=1)C>>[CH2:1]([N:3]([CH3:30])[C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:26]=[C:25]([CH3:27])[C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[C:17]([CH3:28])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)[CH3:2]
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(C)c3)no2)n1
Reactant: CCCNc1nc(C)cc(C(=O)O)n1
Product: CCN(C)c1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(C)c3)no2)n1

Procedure:
rac-3-{4-[5-(2-(Ethyl-methylamino)-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol is prepared in analogy to rac-3-{4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol using 2-(ethyl-methyl)amino-6-methyl-pyrimidine-4-carboxylic acid; LC-MS: tR=0.96 min*; [M+H]+=414.10.
Reaction SMILES: [Mg].Br[C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:4]=1[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.[CH:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2[C:4]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:3]([CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[OH:29])[N:7]([CH3:8])[N:6]=2)=[CH:10][CH:11]=1
Reactant: Cn1nc(-c2ccc(F)cc2)c(-c2ccncc2)c1Br
Reactant: O=Cc1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Product: Cn1nc(-c2ccc(F)cc2)c(-c2ccncc2)c1C(O)c1ccccc1
Temperature: 40 °C
Yield: 12 %

Procedure:
To solid magnesium (60 mg, 5 mmol) under nitrogen was added a solution of 4-[5-bromo-3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine (450 mg, 1.35 mmol) (prepared in accordance with Example A-214) in tetrahydrofuran (7 mL). The mixture was heated at 40° C. for 2 hours. Benzaldehyde (1 mL) was added. The mixture was heated to 45° C. for 2 hours. It was quenched with HCl (10 mL, 1N) and washed with ethyl acetate. The aqueous acid layer was basified and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over MgSO4, filtered and concentrated to give a residue. The residue was purified with a silica gel column to give the title compound (59 mg, 12% yield). MS: m/z=360 (M+1); 1H NMR was consistent with the proposed structure. Anal. Calc'd for C22H18N2OF.0.6EtOAC: C, 71.1; H, 5.6; N, 10.2; Found: C, 70.9; H, 5.47; N, 10.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1Br)([CH3:7])[CH3:6])[CH3:2].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH2:1]([O:3][C:4](=[O:24])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccccc2)cc1Br
Reactant: OB(O)c1ccccc1
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: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccccc2)cc1-c1ccccc1

Procedure:
2-(4-Benzyloxy-2-bromo-phenoxy)-2-methyl-propionic acid ethyl ester (3.00 g, 7.63 mmol) and phenyl boronic acid (1.12 g, 9.15 mmol) were dissolved in toluene (75 mL)/ethanol (75 mL). The solution was degassed (2×), and tetrakis(triphenylphosphine)palladium (70 mg, 0.061 mmol) was added followed by aqueous 2M Na2CO3 solution (7.63 mL, 15.3 mmol). The reaction mixture was degassed (2×) and heated to reflux under argon for 16 h. The reaction mixture cooled and partitioned between ethyl acetate (200 mL) and H2O (75 mL). The organic layer was washed with brine (75 mL), dried (Na2SO4), and concentrated to a light brown oil (3.58 g). The crude product was used directly in the next reaction: 1H NMR (400 MHz, CDCl3) δ1.266 (t, 3H, J=7.1 Hz), 1.273 (s, 6H), 4.20 (q, 2H, J 7.1 Hz), 5.03 (s, 2H), 6.82 (dd, 1H, J=3.2, 9.0 Hz), 6.92 (d, 1H, J=8.8 Hz), 6.97 (d, 1H, J=3.0 Hz), 7.28-7.44 (m, 8H), 7.51-7.60 (m, 2H); MS (ES) m/e #[M+1].
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[S:21][C:22]([NH:30]C(=O)OC(C)(C)C)=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:12]=2[CH:11]=[CH:10]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:30][C:22]1[S:21][C:13]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9](=[O:8])[CH:10]=[CH:11][C:12]=2[C:23]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)Nc1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of the compound of Example 80 (170 mg, 0.406 mmol) in DCM (2 mL) and the reaction mixture stirred for 2 h at r.t. The mixture was added to saturated NaHCO3(aq) (20 mL) and the product extracted with DCM (2×20 mL). The combined organic fractions were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica (EtOAc), followed by radial chromatography (20% EtOH in DCM) to give the title compound as a buff solid (30 mg, 23%). δH (CDCl3) 7.8–7.3 (13H, m), 6.58 (1H, d, J 9 Hz). m/z (ES+) 319 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30][O:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:16][CH:15]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
To a slurry of NaH (562 mg, 8.44 mmol, 60% dispersion in mineral oil) in anhydrous DMF (5 mL) at 0° C. was added p-benzyloxy phenol (1.41 g, 7.0 mmol) in anhydrous DMF (5 mL) dropwise over 30 min under N2 atmosphere. The resulting slurry was stirred at 0° C. for 30 minutes, warmed to ambient temperature and stirred for 1 h before a solution of (S)-2-(Toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (2.5 g, 7.0 mmol) in DMF (10 mL) was added dropwise over 30 min at 0° C. The subsequent mixture was stirred at 85° C. 16 h. The reaction mixture was poured over ice-water, precipitated yellow solid was removed by filtration, washed with water and dried under reduced pressure. The crude product was crystallized from ether/hexane to obtain the title compound (1.2 g, 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C([O:20][C:21]([C:23]1[CH:24]=[N:25][N:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:27]=1[NH2:28])=O)C.CCOC(C)=O>ClC(Cl)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)=[N:28][C:27]3[N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:25]=[CH:24][C:23]=3[C:21]=2[OH:20])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnn(-c2ccccc2)c1N
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: Oc1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)nc2c1cnn2-c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 1,2-bis-(4-chloro-phenyl)-ethanone (100 mg, 0.38 mmol) in dichloroethane (1 mL) is stirred at room temperature while TiCL4 (143 mg, 0.75 mmol) is added in dropwise. After the addition, the mixture is stirred at room temperature for 5 min and a solution of 5-amino-1-phenyl-1H-pyrazole-4-carboxilic acid ethyl ester (97 mg, 0.42 mmol) in dichloroethane (1 mL) is added dropwise. After the addition, the mixture is heated to 125° C. for 5 h. After cooling down the mixture, it is poured into a mixture of ice cold saturated aqueous NaHCO3 solution (15 mL) and EtOAc (15 mL). The resulted mixture is filtered through celite to remove the precipitate and washed with EtOAc (2×5 mL). The filtrate is extracted by EtOAc (3×5 mL). The organic layers are combined and washed with brine and dried (MgSO4). After filtering off the drying agent, the filtrate is concentrated and purified by preparative LC/MS to provide the titled compound 5,6-bis-(4-chloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-ol as light yellow solid. (55 mg, 31%). 1H NMR (MeOD) δ(ppm) 8.37 (s, 1H), 8.23 (d, 2H), 7.53 (t, 2H), 7.34 (t, 1H), 7.31 (d, 2H), 7.29 (d, 2H), 7.23 (d, 2H), 7.15 (d, 2H); HPLC-MS calculated for C24H15C12N3O (M+1+): 432.1. Found: 432.2.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].[C:8]1(=O)[CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH2:8]1[C:12]2([O:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2][O:1]2)[CH2:11][CH2:10][CH2:9]1
Reactant: O=C1CCCC1
Reactant: OCC(CO)CO
Product: OCC1COC2(CCCC2)OC1
Yield: 87 %

Procedure:
The same procedure as in the step (7a) of Example 7 was repeated using 2-(hydroxymethyl)-1,3-propanediol and cyclopentanone to obtain the title compound (2.8 g, yield: 87%) as yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]([NH2:17])=[O:16])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Br)[CH2:8][C:9]=1[NH:10]2.[H-].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]([NH2:17])=[O:16])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:25])[CH2:8][C:9]=1[NH:10]2
Reactant: NC(=O)c1ccc(Br)c2c3c([nH]c12)CC(CNC(=O)CCCBr)CC3
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Br)c2c3c([nH]c12)CC(CN1CCCC1=O)CC3
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Step 5 A solution of 5-bromo-2-((4-bromobutanamido)methyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (80 mg, 0.170 mmol) in DMF (1 mL) was treated with NaH (60% in mineral oil, pre-washed with hexane, 34 mg, 0.849 mmol). The mixture was stirred at rt for 30 min, the was diluted with water and extracted three times with DCM. The combined organic phases were dried and concentrated, and the residue was purified by column chromatography (eluting with 5% aqueous ammonium hydroxide-methanol-DCM) to provide 5-bromo-2-((2-oxopyrrolidin-1-yl)methyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide as a light yellow solid, used without further purification (40 mg, 60%). Mass spectrum m/z 390, 392 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][C:5]1([CH3:24])[O:22][C:8]2=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]2[CH:6]1[CH3:23])[NH:13][C:12](=[O:18])[C:11]([CH:19]([CH3:21])[CH3:20])=[CH:10]3)=[N+]=[N-].[H][H].[ClH:27].CO>CN(C)C=O.CO.[Pd]>[NH2:1][CH2:4][C:5]1([CH3:24])[O:22][C:8]2=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]2[CH:6]1[CH3:23])[NH:13][C:12](=[O:18])[C:11]([CH:19]([CH3:20])[CH3:21])=[CH:10]3.[ClH:27]
Reactant: [H][H]
Reactant: Cc1cc2c(c3cc(C(C)C)c(=O)[nH]c13)OC(C)(CN=[N+]=[N-])C2C
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc2c(c3cc(C(C)C)c(=O)[nH]c13)OC(C)(CN)C2C
Yield: 83.7 %

Procedure:
2-Azidomethyl-8-isopropyl-2,3,5-trimethyl-6,7-dihydrofuro[2,3-f]quinoline-7-one (1.25 g, 3.83 mmol) was dissolved in dimethylformamide (200 ml). To the solution, 10% palladium-on-carbon (1.45 g) was added, followed by stirring at room temperature for 90 minutes in the atmosphere of hydrogen. The reaction mixture was filtered, and the filtrate was condensed under reduced pressure. The resultant residue was suspended in methanol (50 ml), and the suspension was dissolved with 1.37 N HCl-methanol (4 ml, 5.31 mmol). The reaction mixture was condensed under reduced pressure, and the residue was recrystallized from methanol-ether to obtain 1.08 g of the title compound as colorless powdery crystals (83.7%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.O.B1([O-])O[O:20]1.O.O.O.O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C1COCC1>[O:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]1[N:10]1[CH:11]=[C:7]([C@H:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]2[OH:20])[CH:8]=[N:9]1
Reactant: C1=C(c2cnn(C3CCCCO3)c2)CCCC1
Reactant: [O-]B1OO1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O[C@H]1CCCC[C@@H]1c1cnn(C2CCCCO2)c1
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
To a solution of the 4-cyclohex-1-en-1-yl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (775 mg, 3.34 mmol) prepared in Example 33a in THF (4 mL), a borane-THF complex (0.95 M; 3.4 mL, 3.23 mmol) was added with cooling on ice, and the reaction solution was stirred for 30 minutes with cooling on ice. To the reaction solution, a borane-THF complex (0.95 M; 3.4 mL, 3.23 mmol) was added again, and the mixture was stirred at room temperature for 90 minutes. To the reaction solution, water (5 mL) and subsequently sodium perborate tetrahydrate (1.00 g, 6.50 mmol) were added, and the mixture was stirred for 5 hours. To the reaction solution, sodium thiosulfate (2.0 g) was added, followed by extraction with ethyl acetate (50 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with column chromatography (dichloromethane/methanol=97:3) to yield the title compound (590 mg, 71%) as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)C2(C3C4=NON=C4C=CC=3OC2)C1=O.[F:44][CH:45]([F:53])[C:46]1[O:50][C:49]([CH2:51]O)=[CH:48][CH:47]=1.Cl.CO>>[F:44][CH:45]([F:53])[C:46]1[O:50][C:49]([CH2:51][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])=[CH:48][CH:47]=1
Reactant: OCc1ccc(C(F)F)o1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: Cl
Agent: O=C1Nc2ccccc2C12COc1ccc3nonc3c12
Solvent: CO
Product: O=C1N(Cc2ccc(C(F)F)o2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure described in EXAMPLE 11.107 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one and (5-(difluoromethyl)furan-2-yl)methanol to replace 3-trifluoromethyl-pyridin-2-yl)methanol hydrochloride, 1′-{[5-(difluoromethyl)furan-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (35%) as a colorless solid: mp 173-175° C.; 1H NMR (300 MHz, CDCl3) δ7.33-7.25 (m, 1H), 7.21-7.14 (m, 1H), 7.11-6.96 (m, 2H), 6.63-6.58 (m, 1H), 6.57 (t, JH-F=54.3 Hz, 1H), 6.50 (s, 1H), 6.37-6.34 (m, 1H), 6.20 (s, 1H), 5.04 (d, J=16.2 Hz, 1H), 4.94-4.83 (m, 2H), 4.65 (d, J=9.0 Hz, 1H), 4.23-4.07 (m, 4H); 13C NMR (75 MHz, CDCl3) δ177.1, 155.2, 151.1 (t, JC-F=2.2 Hz), 146.5, 144.6, 141.5, 138.3, 132.1, 128.9, 123.9, 123.7, 120.8, 111.5, 111.3 (t, JC-F=4.1 Hz), 109.2, 108.9, 108.2 (t, JC-F=233.6 Hz), 99.4, 80.0, 64.5, 63.9, 57.9, 37.0; MS (ES+) m/z 425.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][C@@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([O:17]C)=O)[C:5]([CH2:11]Cl)=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[NH2:24][CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:24]([CH2:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)[C:15](=[O:17])[C@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:13][C:4]=2[CH:3]=1
Reactant: NCc1ccncc1
Reactant: COC(=O)C[C@H](Cc1cc(Cl)c2[nH]ncc2c1CCl)C(=O)OC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 48 %

Procedure:
(S)-Dimethyl 2-((7-chloro-4-(chloromethyl)-1H-indazol-5-yl)methyl)succinate (120 mg, 0.33 mmol) was dissolved in DMF (1.0 mL). 4-Aminomethylpyridine (100 μL, 1.0 mmol) was added to the mixture. Reaction stirred at room temperature for 24 hours. Mixture was diluted with ethyl acetate. Mixture was washed twice with water and once with brine. Organic was dried (magnesium sulfate), filtered and concentrated in vacuo. Residue was dissolved in toluene (4 mL). Acetic acid (1 mL) was added to the mixture. Reaction was heated at reflux for 3.5 hours. Mixture was cooled to room temperature then diluted with ethyl acetate. Material was washed once with water and twice with aqueous sodium bicarbonate. Aqueous was made basic with sodium bicarbonate. Back extracted from the aqueous twice with ethyl acetate. Combined organics were dried (magnesium sulfate), filtered and concentrated in vacuo. Residue was purified with silica gel chromatography eluting dichloromethane and 2N ammonia in methanol. Title compound was obtained as yellow solid in 48% yield.
Reaction SMILES: [F:1][C:2]([F:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]1[C:6](=[O:16])[N:7]([CH2:12][CH2:13][CH2:14]O)[C:8]([CH3:11])=[CH:9][N:10]=1.C(Br)(Br)(Br)[Br:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[F:1][C:2]([F:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]1[C:6](=[O:16])[N:7]([CH2:12][CH2:13][CH2:14][Br:25])[C:8]([CH3:11])=[CH:9][N:10]=1
Reactant: Cc1cnc(NCC(F)(F)c2ccccc2)c(=O)n1CCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cnc(NCC(F)(F)c2ccccc2)c(=O)n1CCCBr
Reaction time: 2 h
Yield: 97.6 %

Procedure:
To a magnetically stirred solution of 3-(2,2-difluoro-2-phenylethylamino)-1-(3-hydroxypropyl)-6-methylpyrazinone (2-12) (0.267 g, 0.82 mmol) and carbon tetrabromide (0.328 g, 0.99 mmol) in dichloromethane (10 mL), was added triphenylphosphine (0.26 g, 0.99 mmol) portionwise with ice-bath cooling. After the addition was complete, the mixture was stirred for an additional 2 hours. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography using ethyl acetate/n-hexane (2:1 to 1:1 gradient) as eluent to afford the title compound (0.309 g, 96.9%) as a yellow solid. Rf 0.45 ((EtOAc/hexane 1/1); 1H-NMR (CDCl3): δ 2.20 (d, J=1.2 Hz, 3H), 2.19-2.26 (m, 2H), 3.44 (t, J=6.4 Hz, 2H), 4.01-4.10 (m, 4H 6.12 (t, J=6.4 Hz, 1H), 6.62(d, J=1.2 Hz, 1H), 7.37-7.41 (m, 3H), 7.50-7.53 (m, 2H).
Reaction SMILES: [OH:1][C:2]1C=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])C=3)[C:12]([F:23])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.ClC1N=C(Cl)C(F)=CN=1.C(N)C1OC=CC=1>>[CH2:4]([NH:8][C:9]1[N:14]=[C:13]([NH:15][CH2:16][C:21]2[O:22][CH:18]=[CH:19][CH:20]=2)[C:12]([F:23])=[CH:11][N:10]=1)[C:5]1[O:1][CH:2]=[CH:7][CH:6]=1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Agent: Fc1cnc(Cl)nc1Cl
Agent: NCc1ccco1
Product: Fc1cnc(NCc2ccco2)nc1NCc1ccco1

Procedure:
In a manner similar to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and furfurylamine were reacted to yield N2,N4-bis(furfuryl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.72 (bs, 1H), 7.38 (dd, 2H, J=1.8 and 7.5 Hz), 6.34–6.30 (m, 2H), 6.22 (dd, 2H, J=2.4 and 9.9 Hz), 5.163 (bs, 2H), 4.63 (d, 2H, J=6.0), 4.54 (d, 2H, J=6.0).; 19F NMR (CDCl3): −48621; LCMS: ret. time: 97.27 min.; purity: 97%; MS (m/e): 289 (MH+).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.[Cl:13][C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=1)[O:17][CH2:18][C:19](OCC)=[O:20]>C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=1)[O:17][CH2:18][C:19](=[O:20])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: CCOC(=O)COc1cccc(Cl)c1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)COc1cccc(Cl)c1)OC
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To 20.6 g (166 mmol, 238 mol %) of dimethyl methylphosphonate in 110 mL of THF at −78° C. was added dropwise 65 mL (162 mmol, 232 mol %) of a 2.5M solution of n-BuLi in hexanes. After addition was complete, the mixture was stirred for an additional 1 h, after which 15.0 g (69.9 mmol) of aryloxyester 10 in 40 mL of THF was added dropwise. The reaction was stirred for 1 h and then quenched by the addition of 100 mL of saturated NH4Cl. The mixture was poured into 200 mL of a 1/1 mixture of saturated NaCl/ethyl acetate, layers were separated, and the aqueous layer was further extracted with ethyl acetate (2×100 mL). Combined organic layers were dried over MgSO4, filtered, and concentrated, to afford 20.5 g (100%) of 11 as a viscous oil. 1H NMR δ 7.22 (t, J=8.1 Hz, 1 H), 7.05-6.90 (m, 2 H), 6.85-6.78 (m, 1 H), 4.72 (s, 2 H), 3.84 (s, 3 H), 3.78 (s, 3 H), 3.27 (d, J=22.8 Hz, 2 H).
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([C:7](Cl)=[O:8])[N:6]=1.ClC1SC=C(C(O)=O)N=1.S(Cl)(Cl)=O.[Br:23][C:24]1[CH:30]=[C:29]([C:31]([F:40])([C:36]([F:39])([F:38])[F:37])[C:32]([F:35])([F:34])[F:33])[CH:28]=[C:27]([C:41]([F:44])([F:43])[F:42])[C:25]=1[NH2:26]>>[Br:23][C:24]1[CH:30]=[C:29]([C:31]([F:40])([C:32]([F:34])([F:35])[F:33])[C:36]([F:37])([F:39])[F:38])[CH:28]=[C:27]([C:41]([F:42])([F:43])[F:44])[C:25]=1[NH:26][C:7]([C:5]1[N:6]=[C:2]([Cl:1])[S:3][CH:4]=1)=[O:8]
Reactant: O=C(Cl)c1csc(Cl)n1
Reactant: Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F
Agent: O=C(O)c1csc(Cl)n1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F)c1csc(Cl)n1

Procedure:
According to the method of 4-3 of Example 4, a target compound was prepared from 2-chlorothiazole-4-carbonylchloride prepared from 2-chlorothiazole-4-carboxylic acid and thionyl chloride, and 2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)aniline obtained in 1-2 of Example 1.