Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:9]([O:21][CH3:22])[CH:8]=1)=[O:5].[NH2:33]C1C=C(OC2C=CC=CC=2)C=CC=1C(NC1C=CC(OCCN2CCCC2)=C(OC)C=1)=O>>[CH3:22][O:21][C:9]1[CH:8]=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[CH:23]=[CH:24][C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:26][C:2]=3[N:1]=[N:33]2)[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COc1cc(NC(=O)c2ccc(-c3ccccc3)cc2N)ccc1OCCN1CCCC1
Reactant: COc1cc(NC(=O)c2ccc(Oc3ccccc3)cc2N)ccc1OCCN1CCCC1
Product: COc1cc(-n2nnc3cc(-c4ccccc4)ccc3c2=O)ccc1OCCN1CCCC1

Procedure:
This amine was treated in the manner of 2-amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-phenoxy-benzamide in Example C1 to give the title compound;
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1F.[CH2:15]([NH2:18])[CH2:16][NH2:17].C(N(C(C)C)CC)(C)C.[Cl-].[NH4+]>O1CCOCC1>[N+:10]([C:9]1[C:4]2[C:3](=[O:14])[NH:18][CH2:15][CH2:16][NH:17][C:5]=2[CH:6]=[CH:7][CH:8]=1)([O-:12])=[O:11]
Reactant: COC(=O)c1c(F)cccc1[N+](=O)[O-]
Reactant: NCCN
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NCCNc2cccc([N+](=O)[O-])c21
Yield: 25.9 %

Procedure:
2-fluoro-6-nitrobenzoic acid methyl ester (4.54 g, 22.8 mmol), ethylenediamine (1.50 mL, 22.4 mmol) and diisopropylethylamine (8.71 mL, 50 mmol) were dissolved in 1,4-dioxane (40 mL). The reaction mixture was then irradiated at 140° C. for 40 minutes. After cooling, the reaction mixture was poured over saturated ammonium chloride (50 mL), and organics were extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried over Na2SO4, filtered and reduced. The residue was then purified by flash column chromatography (0% MeOH/DCM-20% MeOH/DCM over 35 minutes) to afford 1.2 grams of 6-Nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one as a yellow oil. LC/MS (ESI)=208.24 (M+H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:36])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[CH:17]=[C:18]([C:26]5[CH:31]=[CH:30][C:29]([S:32][CH:33]6[CH2:35][CH2:34]6)=[CH:28][CH:27]=5)[N:19]=[C:20]([NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:15]4=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[O:37]1CO1>ClCCl.CC(C)=O>[CH:1]1([NH:4][C:5](=[O:36])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[N:16]4[CH:17]=[C:18]([C:26]5[CH:27]=[CH:28][C:29]([S:32]([CH:33]6[CH2:35][CH2:34]6)=[O:37])=[CH:30][CH:31]=5)[N:19]=[C:20]([NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:15]4=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: C1OO1
Reactant: CC(C)CNc1nc(-c2ccc(SC3CC3)cc2)cn2c(-c3ccc(C(=O)NC4CC4)cc3)cnc12
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(C)CNc1nc(-c2ccc(S(=O)C3CC3)cc2)cn2c(-c3ccc(C(=O)NC4CC4)cc3)cnc12
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 59 %

Procedure:
A solution of 50 mg (100 μmol) N-cyclopropyl-4-{6-[4-(cyclopropylsulfanyl)phenyl]-8-(isobutylamino)imidazo[1,2-a]pyrazin-3-yl}benzamide in 5.0 mL dichloromethane was cooled to −30° C. and 1.16 mL of a 0.15 molar dioxirane solution in acetone were added. After 15 minutes of stirring the mixture was warmed to 23° C., the solvent removed and the residue was purified by chromatography to give 33.3 mg (59%) of the title compound. 1H-NMR (CDCl3): δ=0.67 (2H), 0.86-1.05 (5H), 1.06 (3H), 1.07 (3H), 1.25 (1H), 2.09 (1H), 2.28 (1H), 2.95 (1H), 3.56 (2H), 6.36 (1H), 6.54 (1H), 7.60 (1H), 7.63 (2H), 7.70 (2H), 7.94 (2H), 7.96 (1H), 8.02 (2H) ppm.
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].[NH2:7][C:8]1[C:9]2[CH:15]=[C:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[S:13][C:10]=2[NH:11][N:12]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[NH2:7][C:8]1[C:9]2[CH:15]=[C:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[S:13][C:10]=2[N:11]([C:1]([O:2][CH2:3][CH3:4])=[O:5])[N:12]=1
Reactant: CC(C)(C)OC(=O)c1cc2c(N)n[nH]c2s1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)n1nc(N)c2cc(C(=O)OC(C)(C)C)sc21
Reaction time: 0.08 h
Yield: 87.7 %

Procedure:
A solution of ethyl chlorocarbonate (4.90 mL, 51.7 mmol) in tetrahydrofuran (THF, 60 mL) was slowly added to a mixture of tert-butyl 3-amino-1H-thieno[2,3-c]pyrazole-5-carboxylate (12.0 g, 50.2 mmol) and diisopropylethylamine (DIEA, 51.5 mL, 301 mmol) in THF (300 mL), maintaining the temperature between −5 and −10° C. The reaction was kept at the same temperature for 5 minutes then allowed to reach room temperature. The obtained mixture was evaporated to dryness under vacuum and the residue extracted with ethyl acetate (AcOEt) and water. The organic layer was separated, dried over sodium sulfate and evaporated to dryness. The resulting raw material was triturated with diethyl ether to give 13.7 g of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:12]([CH3:14])[CH3:13].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Sc1ccc(Br)cc1
Temperature: 0 °C
Yield: 89.8 %

Procedure:
Dissolve 4bromo-benzenethiol (1.0 g, 5.3 mmol) in dry dimethylformamide (50 mL) and cool to 0° C. under nitrogen. Add dry sodium hydride (153 mg, 6.4 mmol) in portions. After the vigorous gas evolution stops, add 2-bromo-propane (0.60 mL, 6.4 mmol) and stir the reaction overnight at room temperature. Slowly pour the reaction into water (300 mL) and extract with ethyl acetate (2×150 mL). Wash the combined organic layers with water (100 mL) and brine (100 mL). Dry the organic layer with sodium sulfate, filter and concentrate in vacuo. Chromatograph the resultant residue on a SiO2 column with 5% ethyl acetate in hexanes to yield 1.1 g of 1-bromo-4-isopropylsulfanyl-benzene (92%).
Reaction SMILES: [CH2:1]([CH:3]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([CH3:24])[CH:17]=2)(=[O:15])=[O:14])[C:11]2[C:6](=[CH:7][C:8](F)=[C:9]([F:25])[CH:10]=2)[N:5]2[CH:27]=[CH:28][CH:29]=[C:4]12)[CH3:2].[CH3:30]C1C=C(S(Cl)(=O)=O)C=C(C)C=1OC>>[CH2:1]([CH:3]1[N:12]([S:13]([C:16]2[CH:17]=[C:18]([CH3:24])[C:19]([O:22][CH3:23])=[C:20]([CH3:30])[CH:21]=2)(=[O:15])=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:25])[CH:10]=2)[N:5]2[CH:27]=[CH:28][CH:29]=[C:4]12)[CH3:2]
Reactant: CCC1c2cccn2-c2cc(F)c(F)cc2N1S(=O)(=O)c1ccc(OC)c(C)c1
Reactant: COc1c(C)cc(S(=O)(=O)Cl)cc1C
Product: CCC1c2cccn2-c2ccc(F)cc2N1S(=O)(=O)c1cc(C)c(OC)c(C)c1

Procedure:
The title compound was prepared from the product of Example 4 using 3,5 dimethyl-4-methoxy benzenesulfonyl chloride to yield crystals, mp 140-142° C.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.CCN(C(C)C)C(C)C.[Si:31]([O:38][C@@H:39]1[C@@H:43]([CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[O:42][C@@H:41]([N:53]2[C:62]3[N:61]=[CH:60][N:59]=[C:57]([OH:58])[C:56]=3[N:55]=[CH:54]2)[CH2:40]1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].[CH:63]1[CH:64]=[CH:65][C:66]2[N:71](O)[N:70]=[N:69][C:67]=2[CH:68]=1>C(Cl)Cl>[N:69]1([O:58][C:57]2[C:56]3[N:55]=[CH:54][N:53]([C:62]=3[N:61]=[CH:60][N:59]=2)[C@@H:41]2[O:42][C@H:43]([CH2:44][O:45][Si:46]([C:49]([CH3:50])([CH3:51])[CH3:52])([CH3:47])[CH3:48])[C@@H:39]([O:38][Si:31]([C:34]([CH3:36])([CH3:37])[CH3:35])([CH3:33])[CH3:32])[CH2:40]2)[C:67]2[CH:68]=[CH:63][CH:64]=[CH:65][C:66]=2[N:71]=[N:70]1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
In a 50 mL round-bottom flask equipped with a stirring bar were placed PPh3 (0.823 g, 3.138 mmol) and I2 (0.800 g, 3.152 mmol) in dry CH2Cl2 (11.0 mL) and the mixture was stirred at room temperature for 20 min. DIPEA (1.5 mL, 8.62 mmol) and 3′,5′-bis-O-(tert-butyldimethylsilyl)-2′-deoxyinosine (1a) (0.500 g, 1.040 mmol) were added, and the mixture was allowed to stir at room temperature for 26 h. To this mixture was added HOBT (0.211 g, 1.561 mmol) and the reaction was allowed to continue and was complete in 22 h. The crude material was evaporated and chromatographic purification (SiO2, elution with 20% EtOAc in hexanes) afforded 0.578 g (93%) of compound 26 as a beige foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[C:5]#[N:6].[F:12][C:13]1[CH:14]=[CH:15][C:16]([OH:36])=[C:17]2[C:21]=1[C@H:20]([O:22][C:23]1[CH:35]=[CH:34][C:26]3[C@H:27]([CH2:30][C:31]([OH:33])=[O:32])[CH2:28][O:29][C:25]=3[CH:24]=1)[CH2:19][CH2:18]2.COC(=O)C[C@H]1C2C=CC(O[C@H]3C4C(=C(O)C=CC=4F)CC3)=CC=2OC1>>[C:5]([C:4]1[CH:7]=[C:8]([F:11])[C:9]([O:36][C:16]2[CH:15]=[CH:14][C:13]([F:12])=[C:21]3[C:17]=2[CH2:18][CH2:19][C@H:20]3[O:22][C:23]2[CH:35]=[CH:34][C:26]3[C@H:27]([CH2:30][C:31]([OH:33])=[O:32])[CH2:28][O:29][C:25]=3[CH:24]=2)=[C:2]([F:1])[CH:3]=1)#[N:6]
Reactant: N#Cc1cc(F)c(F)c(F)c1
Reactant: O=C(O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: N#Cc1cc(F)c(Oc2ccc(F)c3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)O)c(F)c1

Procedure:
The title compound is prepared from 3,4,5-trifluoro-benzonitrile and {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid (prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester using the procedure described for Example 1) following a procedure analogous to that described for Intermediate 12. LC (method 4): tR=1.11 min; Mass spectrum (ESI−): m/z=480 [M−H]−.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:35]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1)(=[O:37])[CH3:36]>CN(C1C=CN=CC=1)C>[C:35]([NH:38][C:39]1[CH:40]=[CH:41][C:42]([S:45]([N:23]2[CH2:24][CH2:25][CH:20]([C:11]3[C:10]4[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[CH:9]=4)[NH:13][N:12]=3)[CH2:21][CH2:22]2)(=[O:47])=[O:46])=[CH:43][CH:44]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(S(=O)(=O)N2CCC(c3n[nH]c4c(C(N)=O)cc(-c5ccccc5)cc34)CC2)cc1
Yield: 27.6 %

Procedure:
Following the general procedure of Example 11, 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (Example 2) (50 mg, 0.14 mmol), diisopropylethylamine (100 uL, 0.56 mmol), DMAP (25 mg, 0.014 mmol) and 4-(acetylamino)benzenesulfonyl chloride (44 mg, 0.168 mmol) were reacted to give the title compound (20 mg, 28%).
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])#[CH:15].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(#N)C>[Cl:13][C:11]1[CH:10]=[CH:9][C:3]([O:4][CH2:5][C:6]([OH:8])=[O:7])=[C:2]([C:15]#[C:14][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[CH:12]=1
Reactant: O=C(O)COc1ccc(Cl)cc1Br
Reactant: C#Cc1ccccc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccccc1C#Cc1cc(Cl)ccc1OCC(=O)O
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A solution of (2-bromo-4-chlorophenoxy)acetic acid (200 mg; 0.75 mmol, Intermediate 4) and 2-ethynylanisole (Aldrich, 107 μL; 0.83 mmol) in anhydrous, degassed ACN (2 mL) was treated with dichlorobis(triphenylphosphine)palladium(II) (38 mg; 0.05 mmol) followed after 5 minutes by copper iodide (10 mg; 0.05 mmol) and triethylamine (0.45 mL; 3.3 mmol). The reaction mixture was heated at 50° C. under stirring for 16 hours. The solvents were removed under vacuum, the residue was then taken up in EtOAc and washed with HCl (1N aqueous solution), the organic phase was washed with water (750 mL) then with brine (750 mL), dried over MgSO4, filtered and concentrated under vacuum to give a brown oily residue which was purified by preparative HPLC to afford the title compound as a brown oil.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:26]=2[CH2:25][CH:24]=[CH:23]3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[O:9]1[CH:24]2[CH2:25][C:26]3[C:22]([CH:23]12)=[CH:21][CH:20]=[CH:19][C:18]=3[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C1=Cc2cccc(-c3ccccc3)c2C1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: c1ccc(-c2cccc3c2CC2OC32)cc1
Reaction time: 2 h
Yield: 97.9 %

Procedure:
A stirred solution of 47.5 g (0.234 mole) of m-chloroperbenzoic acid (85% purity) in 390 ml of chloroform was cooled to 0° C. To this was added dropwise a solution of 45 g (0.234 mole) of 7-phenyl-1H-indene (which may be prepared as in Step G above) in 110 ml of chloroform. After complete addition, the mixture was stirred for 21/2 hours, then was allowed to stand for 21 hours at 0° C. With the temperature in the range of 0°-5° C., 100 ml of a 10% aqueous solution of sodium hydroxide, then 50 ml of a 10% aqueous solution of sodium sulfate, were added dropwise with stirring. Afte complete addition the two-phase mixture was stirred for 30 minutes. The organic phase was separated, washed first with a dilute aqueous solution of sodium bicarbonate, then with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 47.7 g of 1,2-epoxy-4-phenylindane as a pale yellow oil, 97% purity by gas chromatographic analysis.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][O:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[OH:11].[H-].[Na+].[CH3:18]I.CO>O1CCOCC1>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][O:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[O:11][CH3:18]
Reactant: CI
Reactant: O[C@H]1CCC[C@H]1OCc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CO[C@H]1CCC[C@H]1OCc1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
6.3 g (0.03 mol) of cis-1-(2-fluorobenzyloxy)-cyclopentan-2-ol (Example 2) in 100 ml of absolute dioxan were added dropwise to a suspension of 0.72 g (0.03 mol) of sodium hydride (0.9 g of 80% pure sodium hydride in toluene) in 100 ml of absolute dioxan at 5° C. under nitrogen. After stirring the mixture at room temperature for 30 minutes, it was warmed to 70° C. for 45 minutes and cooled, 1.26 g (0.03 mol) of methyl iodide in dioxan were added dropwise and the mixture was then heated to the boil for 4 hours. After cooling the mixture to room temperature, 5 ml of methanol were added dropwise and the suspension was concentrated on a rotary evaporator. The residue was taken up in water and the mixture was extracted again with methylene chloride. The combined methylene chloride phases were dried over sodium sulphate and filtered and the solvent was stripped off from the filtrate on a rotary evaporator. The oily residue was distilled. 5 g (75% of theory) of cis-1-(2-fluorobenzyloxy)-2-methoxy-cyclopentane of boiling point 90° C./0.1 mm Hg were obtained.
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(C)(C)C.[NH2:12][CH2:13]CCO.C=O.P(=O)(O)(O)O>C(O)C.O>[OH:11][C:8]1[CH:7]=[CH:6][CH:5]=[CH:10][C:9]=1[CH2:13][NH2:12]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: NCCCO
Agent: C=O
Agent: O=P(O)(O)O
Solvent: O
Solvent: CCO
Product: NCc1ccccc1O

Procedure:
An o-hydroxybenzylamine compound of the present invention composition is prepared according to the procedure of Example 1, except that 50 g of 4-t-butylphenol is employed in place of the Bisphenol-A, 25 g of 3-aminopropanol is employed in place of the 2-(methylamino)ethanol and that heating of the reactants was only begun after the formaldehyde addition was completed. A 0.5 g sample of the product is dissolved in 500 ml of ethanol/water (1:4 by volume) and the pH of the solution is adjusted to 3.0 with phosphoric acid.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:12]2[CH2:15][O:14][CH2:13]2)[CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH2:24][C:25]([N:27]1[C:35]2[C:30](=[CH:31][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:34]=2)[CH2:29][CH2:28]1)=[O:26].C([O-])(O)=O.[Na+]>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.O1CCOCC1>[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH2:24][C:25]([N:27]1[C:35]2[C:30](=[CH:31][C:32]([C:2]3[C:10]4[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=4[N:4]([CH:12]4[CH2:15][O:14][CH2:13]4)[CH:3]=3)=[CH:33][CH:34]=2)[CH2:29][CH2:28]1)=[O:26]
Reactant: Nc1ncnc2c1c(Br)cn2C1COC1
Reactant: CC1(C)OB(c2ccc3c(c2)CCN3C(=O)Cc2cc(F)ccc2F)OC1(C)C
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: C1COCCO1
Product: Nc1ncnc2c1c(-c1ccc3c(c1)CCN3C(=O)Cc1cc(F)ccc1F)cn2C1COC1
Temperature: 100 °C
Yield: 61.7 %

Procedure:
To 5-bromo-7-(3-oxetanyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50 mg, 0.186 mmol) and 1-[(2,5-difluorophenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (104 mg, 0.260 mmol) were added 1,4-Dioxane (2 mL) and sat. NaHCO3 solution (1 mL) in a 5 ml sealable vial. N2 gas was bubbled through the mixture for 10 minutes then Pd(Ph3P)4 (21.47 mg, 0.019 mmol) was added and bubbled N2 for 5 minutes. The mixture was then capped and heated 100° C. overnight. The reaction was diluted with water (3 ml) then extracted with EtOAc (4×5 ml). The organics were then combined, washed with brine, dried over MgSO4, filtered and concentrated. The residual was then diluted with 3 ml of DMSO and purified on HPLC: (HPLC condition: Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 ml/min, 15% ACN/H2O, 0.1% TFA to 40% ACN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined and the volume was reduced to remove most of the MeCN. The water left behind was added saturated NaHCO3 and then extracted with EtOAc (3×15 mL). The organic was combined wash with saturated NaCl solution, dried over MgSO4, filtered and concentrated. The material was then transferred into a 40 mL vial with MeCN then water was added and the solution was freeze-dried to give 5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-(3-oxetanyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (53 mg, 61.8% yield) as a white power. LC-MS (ES) m/z=462.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J=3.28 Hz, 1H), 8.08-8.13 (m, 1H), 7.70 (d, J=3.03 Hz, 1H), 7.41 (br. s., 1H), 7.15-7.33 (m, 4H), 6.17 (br. s., 2H), 5.82-5.93 (m, 1H), 4.95-5.07 (m, 4H), 4.30 (br. s., 2H), 3.96 (br. s., 2H), 3.29 (d, J=1.01 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH3:36][C:37]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:40])[CH:38]=O.N1CCCCC1>O1CCOCC1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[C:32]([C:33]#[N:34])=[CH:40][C:37]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:36])[CH3:38])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: C1CCNCC1
Solvent: C1COCCO1
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Yield: 46.8 %

Procedure:
A solution of 3-((R)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile (141 mg, 0.30 mmol, 1.0 equiv), tert-butyl 2-methyl-1-oxopropan-2-ylcarbamate (1.12 g, 6.00 mmol, 20.0 equiv), piperidine (255 mg, 3.0 mmol, 10.0 equiv) in 1,4-dioxane (15 mL) was refluxed for 2 h. The resulting mixture was concentrated under vacuum. The residue was submitted to flash chromatography eluting with ethyl acetate to give (R)-tert-butyl (5-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl)carbamate 90 mg as a pale yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.Br[C:9]1[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13]([Br:15])[N:14]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Br:15][C:13]1[N:14]=[C:9]([NH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=1
Reactant: Cn1cc(Br)nc(Br)c1=O
Reactant: Nc1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cn1cc(Br)nc(Nc2cccnc2)c1=O
Temperature: 25 °C
Yield: 49.8 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with pyridin-3-amine (940 mg, 10 mmol), 3,5-dibromo-1-methylpyrazin-2(1H)-one (5.4 g, 20 mmol), i-propanol (50 mL), and di-i-propylethylamine (10 mL). The mixture was heated at reflux for 5 h. After the completion of the reaction, it was cooled to room temperature. The solvent was removed under reduced pressure. The crude was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 186a (1.4 g, 50%) as a yellow solid. MS-ESI: [M+H]+ 281.6.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[C:22]([C:23]#[N:24])=[CH:21][CH:20]=[CH:19][N:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH:15][C:17]1[C:22]([C:23]#[N:24])=[CH:21][CH:20]=[CH:19][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CN
Reactant: N#Cc1cccnc1Cl
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1CNc1ncccc1C#N
Yield: 28.9 %

Procedure:
The title compound (0.66 g) was prepared from (S)-2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (1.55 g) and 2-chloro-3-cyanopyridine (1.0 g) according to the method of D28.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][CH2:4][NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)=[CH:11][C:10]=1[F:29])=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][CH2:40][Cl:41]>CN(C)C=O>[Cl:41][CH2:40][CH2:39][O:28][C:22]1[CH:21]=[C:20]2[C:25]([C:16]([O:15][C:12]3[CH:13]=[CH:14][C:9]([NH:8][C:6]([NH:5][CH2:4][CH2:3][C:2]([CH3:31])([CH3:30])[CH3:1])=[O:7])=[C:10]([F:29])[CH:11]=3)=[CH:17][CH:18]=[N:19]2)=[CH:24][C:23]=1[O:26][CH3:27]
Reactant: ClCCBr
Reactant: COc1cc2c(Oc3ccc(NC(=O)NCCC(C)(C)C)c(F)c3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)NCCC(C)(C)C)c(F)c3)ccnc2cc1OCCCl
Temperature: 25 °C
Reaction time: 20 h
Yield: 74 %

Procedure:
A crude product of 1-(3,3-dimethyl-butyl)-3-[2-fluoro-4-(7-hydroxy-6-methoxy-quinolin-4-yloxy)-phenyl]-urea was dissolved in dimethylformamide (100 ml) to prepare a solution. Potassium carbonate (18 g) and 1-bromo-2-chloroethane (11 g) were added to the solution, and the mixture was stirred at room temperature for 20 hr. The mixture was extracted with ethyl acetate, was then washed with saturated brine, and was dried over anhydrous sodium sulfate. The solvent was removed by evaporation under the reduced pressure. The residue was washed with a mixed solvent of n-hexane: ethyl acetate (2:1) and was then collected by filtration to give 1-{4-[7-(2-chloroethoxy)-6-methoxy-quinolin-4-yloxy]-2-fluorophenyl}-3-(3,3-dimethyl-butyl)urea (7.7 g, yield 74%).