Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:6](=[O:18])[CH:5]2[C:19]1[C:28]([OH:29])=[CH:27][C:22]2[O:23][CH2:24][CH2:25][O:26][C:21]=2[CH:20]=1.[C:30](=O)([O-])[O-].[Cs+].[Cs+].ClCI.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:6](=[O:18])[C:5]12[C:19]2[C:28](=[CH:27][C:22]3[O:23][CH2:24][CH2:25][O:26][C:21]=3[CH:20]=2)[O:29][CH2:30]1
Reactant: O=C([O-])[O-]
Reactant: O=C1C(c2cc3c(cc2O)OCCO3)c2cc(Br)ccc2N1Cc1ccccn1
Agent: ClCI
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1N(Cc2ccccn2)c2ccc(Br)cc2C12COc1cc3c(cc12)OCCO3
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.3 %

Procedure:
To a solution of 5-bromo-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-(pyridin-2-ylmethyl)-1,3-dihydro-2H-indol-2-one (2.00 g, 4.40 mmol) in anhydrous N,N-dimethylformamide (25 mL) was added cesium carbonate (4.30 g, 13.2 mmol) and chloroiodomethane (0.85 g, 4.9 mmol). The solution was stirred at ambient temperature for 16 h and poured into water (100 mL). The mixture was extracted with ethyl acetate (3×50 mL) and the combined ethyl acetate extracts were washed with brine (2×35 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated in dichloromethane/diethyl ether (2/5, 14 mL) to afford 5′-bromo-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (1.44 g, 72%) as a beige solid: mp>250° C. (dichloromethane/diethyl ether); 1H NMR (300 MHz, CDCl3) δ 8.57-8.52 (m, 1H), 7.69-7.61 (m, 1H), 7.33-7.27 (m, 3H), 7.26-7.16 (m, 1H), 6.77 (d, J=8.3 Hz, 1H), 6.49 (s, 1H), 6.30 (s, 1H), 5.16 (d, J=15.8 Hz, 1H), 4.97-4.87 (m, 2H), 4.64 (d, J=9.0 Hz, 1H), 4.22-4.08 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 176.9, 155.2, 155.1, 149.6, 144.9, 141.1, 138.4, 137.2, 134.2, 131.7, 127.0, 122.9, 121.7, 120.4, 116.1, 111.7, 111.1, 99.5, 80.0, 64.5, 63.9, 58.2, 46.1; MS (ES+) m/z 465.0 (M+1), 467.0 (M+1).
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2.[C:23]1([Si:29]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)Cl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C=CC=CC=1>C1C=CC=CC=1>[C:37]1([Si:29]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:1][CH2:2][C@@:3]23[C@@H:20]4[C@H:11]([C@H:12]5[C@@:16]([CH2:18][CH2:19]4)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]5)[CH2:10][CH2:9][C:8]2=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]3)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO[Si](c3ccccc3)(c3ccccc3)c3ccccc3)[C@@H]1CCC2=O

Procedure:
A solution of 19-hydroxy-4-androstene-3,17-dione, triphenylchlorosilane and pyridine contained in 100 ml of benzene is refluxed for a period of 18 hours. The resulting suspension is filtered and concentrated in vacuo to a yellow oil. The oil is placed on a silica gel chromatographic column packed in chloroform which is further eluted with chloroform. The chloroform eluant is evaporated to dryness in vacuo and the residue is recrystallized from methanol to yield 19-triphenylsiloxy-4-androstene-3,17-dione.
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1.[C:24]([C:27]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([OH:26])=[O:25]>CO>[C:2]1([CH3:12])[CH:3]=[CH:4][C:5]([S:8]([OH:11])(=[O:9])=[O:10])=[CH:6][CH:7]=1.[CH3:13][O:25][C:24]([C:27]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]1)=[O:26]
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)C1(c2ccccc2)CCNCC1
Yield: 453.8 %

Procedure:
1 g of para-toluenesulfonic acid monohydrate is added to a solution of 10 g of 4-carboxy-4-phenylpiperidine p-toluenesulfonate in 300 ml of MeOH and the mixture is refluxed for 3 days. The reaction mixture is concentrated under vacuum, the residue taken up in acetone and ether is added until precipitation occurs. After spinning the precipitate formed, 9.34 g of the expected product are obtained.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([NH2:12])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.COC(=O)CCC1C(=O)N(N)C(=O)NC=1.[F:28][C:29]1[CH:30]=[C:31]([C:35]2[N:40]=[CH:39][C:38]([C:41](O)=[O:42])=[CH:37][N:36]=2)[CH:32]=[CH:33][CH:34]=1.C1(N2CCN([NH-])CC2)CCCC1>>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([NH:12][C:41]([C:38]3[CH:39]=[N:40][C:35]([C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([F:28])[CH:30]=4)=[N:36][CH:37]=3)=[O:42])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NN1CCN(C2CCCC2)CC1
Reactant: O=C(O)c1cnc(-c2cccc(F)c2)nc1
Agent: COC(=O)CCc1c[nH]c(=O)n(N)c1=O
Agent: [NH-]N1CCN(C2CCCC2)CC1
Product: O=C(NN1CCN(C2CCCC2)CC1)c1cnc(-c2cccc(F)c2)nc1

Procedure:
Following procedures similar to those of Example 64 but using substituting 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid for 2-phenyl-4-yl-pyrimidine-5-carboxylic acid, and substituting 4-cyclopentyl-piperazin-1-ylamine for 3-{3-amino-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-propionic acid methyl ester, there is prepared 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (4-cyclopentyl-piperazin-1-yl-amide (64%) as a solid. MS: 370 (M+H).
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9]3[CH:10]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:13][C:14]=3[C:6]=2[C:5](=[O:19])[NH:4][CH:3]=1.[CH3:20][N:21]1CCCC1=O>>[CH3:18][O:17][C:15]([C:11]1[CH:12]=[CH:13][C:14]2[C:6]3[C:5](=[O:19])[NH:4][CH:3]=[C:2]([C:20]#[N:21])[C:7]=3[NH:8][C:9]=2[CH:10]=1)=[O:16]
Reactant: CN1CCCC1=O
Reactant: COC(=O)c1ccc2c(c1)[nH]c1c(Br)c[nH]c(=O)c12
Product: COC(=O)c1ccc2c(c1)[nH]c1c(C#N)c[nH]c(=O)c12
Temperature: 200 °C

Procedure:
A stirred mixture of methyl 4-bromo-1-oxo-2,5-dihydro-1H-pyrido[4,3-b]indole-7-carboxylate (0.820 g, 2.55 mmol) and Cuprous cyanide (0.229 g, 2.55 mmol) in N-Methyl-2-pyrrolidinone (25 mL) was heated at 200° C. for 2-4 hours. LC-MS showed complete conversion to the desired product plus minor debrominated product. The reaction mixture was cooled to room temperature then concentrated in vacuo. The residue was slurred in water and filtered. The solid residue was dried overnight under vacuum to give methyl-4-cyano-1-oxo-2,5-dihydro-1H-pyrido[4,3-b]indole-7-carboxylate as a brown solid. [0.672 g product, 2.51 mmol, 98% yield]. The product had an HPLC Retention Time=2.537 min [4 min grad, 10% MeOH/water to 90% MeOH/water, 0.1% TFA, YMC COMBISCREEN® ODS-A, 4.6×50 mm, 220 nM]; LC/MS+1 268.2
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:48]=[CH:47][C:26]([C:27]([N:29]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3/[C:33](=[CH:40]\[C:41]([O:43][CH3:44])=[O:42])/[C:32]([F:46])([F:45])[CH2:31][CH2:30]2)=[O:28])=[CH:25][CH:24]=1>>[F:46][C:32]1([F:45])[CH2:31][CH2:30][N:29]([C:27](=[O:28])[C:26]2[CH:25]=[CH:24][C:23]([NH:22][C:9](=[O:11])[C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:48][CH:47]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2/[C:33]/1=[CH:40]\[C:41]([O:43][CH3:44])=[O:42]
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: COC(=O)/C=C1\c2ccccc2N(C(=O)c2ccc(N)cc2)CCC1(F)F
Agent: O=C(Cl)C(=O)Cl
Product: COC(=O)/C=C1\c2ccccc2N(C(=O)c2ccc(NC(=O)c3ccccc3-c3ccccc3)cc2)CCC1(F)F
Yield: 96.7 %

Procedure:
Using 127 mg of o-phenylbenzoic acid, 0.141 ml of oxalyl chloride and 200 mg of methyl (E)-[1-(4-aminobenzoyl)-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-5ylidene]acetate, a similar procedure as in Reference Example 8 was repeated to obtain 287 mg of methyl (E)-[4,4-difluoro-1-[4-(2-phenylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ylidene]acetate.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[NH:32]([CH2:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])[CH2:33][CH2:34][CH2:35][N:36]([CH3:38])[CH3:37]>C(Cl)Cl>[CH3:43][N:42]([CH3:44])[CH2:41][CH2:40][CH2:39][N:32]([CH:18]=[C:17]1[C:16]2[C:15]([CH3:30])([C:14]3[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]4([CH3:31])[CH:8]([C:13]=3[C:21](=[O:22])[C:20]=2[OH:19])[CH2:9][CH2:10][CH:11]4[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]1=[O:24])[CH2:33][CH2:34][CH2:35][N:36]([CH3:37])[CH3:38]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: CN(C)CCCNCCCN(C)C
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN(CCCN(C)C)CCCN(C)C)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added 3,3′-iminobis(N,N-dimethylpropylamine) (104 μL, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 619 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](O)([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]=[C:10]([C:14]2[N:15]=[CH:16][CH:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)(c2ncccn2)C1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC=C(c2ncccn2)C1
Reaction time: 16 h

Procedure:
1.56 g of the compound of step 1 of Example 29 was dissolved in 15 ml of pyridine, 0.8 ml (1.5 equivalents) of phosphorus oxychloride was added under ice cooling and the result was agitated for 16 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:16]([CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])=[N:15][O:14][N:13]=2)=[S:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH:29](N(CC)C(C)C)(C)C.FC(F)(F)S(OC)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]([C:12]2[C:16]([CH2:17][O:18][Si:19]([CH:23]([CH3:25])[CH3:24])([CH:26]([CH3:28])[CH3:27])[CH:20]([CH3:21])[CH3:22])=[N:15][O:14][N:13]=2)[S:11][CH3:29])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)[Si](OCc1nonc1C(=S)Nc1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Reactant: CCN(C(C)C)C(C)C
Agent: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CSC(=Nc1ccc(F)c(Cl)c1)c1nonc1CO[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 2 h

Procedure:
To a solution of N-(3-chloro-4-fluorophenyl)-4-[(triisopropylsilyl)oxy]methyl-1,2,5-oxadiazole-3-carbothioamide (3.3 g, 7.4 mmol) in anhydrous DCM (148 mL) under N2 was added N,N-diisopropylethylamine (DIPEA) (1.4 mL). Methyl trifluoromethanesulfonate (900 μL, 8.2 mmol) was then added dropwise and stirred for 2 hrs. The reaction was stripped to dryness and purified on a 330 g silica ISCO cartridge, eluting with 25% EtOAc/hexane to yield the desired product as a yellow oil that solidified upon standing. (2.97 g, 87%). 1H NMR (400 MHz, DMSO-d6) δ: 11.32 (s, 1H), 8.01 (dd, J=7.1, 2.7 Hz, 1H), 7.45 (dd, J=9.5, 9.5 Hz, 1H), 7.67 (m, 1H), 4.4 (s=3H), 5.13 (s, 2H), 1.1 (m, 3H); 0.99 (m, 18H); MF=C20H29ClFN3O2SSi; LCMS calculated for C20H30ClFN3O2SSi(M+H)+: m/z=458.150.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:26])[CH2:22][C:23](O)=[O:24])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.N.CC#[N:36]>CN(C=O)C.C1(C)C=CC=CC=1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:26])[CH2:22][C:23]([NH2:36])=[O:24])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC#N
Reactant: COc1ccc(C2CCN(C(=O)CC(=O)O)CC2)cc1OC1CCCC1
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(C2CCN(C(=O)CC(N)=O)CC2)cc1OC1CCCC1

Procedure:
In the same manner as Example, 9, 3-[4-(3-cyclopentyloxy-4-methoxyphenyl)piperidin-1-yl]-3-oxo-propionic acid (0.70 mmol, 0.25 g), oxalyl chloride (0.77 mmol, 0.385 mL; 2M solution in CH2Cl2), DMF (4 drops) and saturated NH3 /CH3CN solution (10 mL) in dry toluene (10 mL) afforded a solid which was triturated in Et2O/hexane to give the title compound as a white solid, mp=132°-133° C. (0.40 mmol, 0.150 g, 60%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]3)=[CH:19][CH:18]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc2cc(OCc3ccc(Br)cc3)ccc2[nH]1
Yield: 60.9 %

Procedure:
A solution of ethyl 5-hydroxy-1H-indole-2-carboxylate (508 mg, 2.48 mmol), 1-bromo-4-(bromomethyl)benzene (681 mg, 2.72 mmol) and potassium carbonate (684 mg, 4.95 mmol) in acetonitrile (12 ml) was stirred at 80° C. for 3 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added to the resulting oil, the mixture was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After the solvent was concentrated under reduced pressure, the resulting residue was purified by alumina column chromatography (developing solvent: ethyl acetate), and converted into powders with isopropyl ether to obtain ethyl 5-[(4-bromobenzyl)oxy]-1H-indole-2-carboxylate (565 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[OH-].[Na+].Cl[C:11]1[N:16]=[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=2)[N:14]=[C:13]([NH:27][CH:28]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[N:12]=1>C1C=CC=CC=1>[Cl:26][C:20]1[CH:19]=[C:18]([NH:17][C:15]2[N:14]=[C:13]([NH:27][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[N:12]=[C:11]([N:4]3[CH2:5][CH2:6][CH2:7][CH:2]([OH:1])[CH2:3]3)[N:16]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Reactant: OC1CCCNC1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(N3CCCC(O)C3)n2)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 3-hydroxypiperidine (0.198 g, 1.96 mmol) and sodium hydroxide (79 mg, 1.96 mmol) in benzene (10 mL) was heated to reflux for 2 hours with stirring under nitrogen atmosphere and then cooled to 25° C. followed by the addition of compound 133 (0.25 g, 0.65 mmol) at same temperature. The mixture was heated to reflux for 6 hours, concentrated under vacuum and diluted with water (10 mL). The precipitated solid was filtered off and purified by column chromatography (1-2% MeOH—CHCl3) to afford the title compound E23 as an off-white solid (0.06 g, 21%). mp 100-102° C.; HPLC: Hichrom RPB (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 5.5); solvent B=CH3CN], Gradient elution program: T/% B=0/20, 10/20,25/80, 40/80, 55/60, 65/20, 70/20; 270 nm, Rt 41.95 min, 98.43% purity; MS (CI): m/z 447 (M+H, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:31][C:32]1[CH:37]=[C:36]([C:38](Cl)=[O:39])[CH:35]=[CH:34][N:33]=1.C1C2C(=CC=C(NC3N=C(C4C(C5C=C(NC(=O)C6C=CC=CC=6)C=CC=5)=NN5C=CC=CC=45)C=CN=3)C=2)CCN1>>[Cl:31][C:32]1[CH:37]=[C:36]([C:38]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[C:16]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]5[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=5)[N:18]=4)=[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][N:10]4[N:9]=3)[CH:3]=2)=[O:39])[CH:35]=[CH:34][N:33]=1
Reactant: O=C(Cl)c1ccnc(Cl)c1
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1
Agent: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1)c1ccnc(Cl)c1

Procedure:
In a manner analogous to Example 66, 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-fluorophenyl)-2-pyrimidinamine and 2-chloro-4-pyridinecarbonyl chloride are used to prepare the title compound. HRMS calcd for C29H19ClFN7O: 535.1324, found: 536.1392 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:29][O:30][C:31](=[O:44])[CH:32]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:34]Br>CN(C=O)C.C(OCC)(=O)C>[CH3:29][O:30][C:31](=[O:44])[CH:32]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:34][O:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:15]([O:14][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:16])=[CH:23][CH:24]=1
Reactant: COC(=O)C(CCBr)NC(=O)OC(C)(C)C
Reactant: O=C(NCCCCc1ccc(O)cc1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(CCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 14 h
Yield: 82.6 %

Procedure:
Potassium carbonate (935 mg, 6.77 mmol) was added in one portion to a solution of 4-[4-(benzyloxycarbonylamino)butyl]phenol (506 mg, 1.69 mmol) and N-Boc bromide 30 (501 mg, 1.69 mmol) in anhydrous DMF (10 mL). The reaction mixture was stirred at 70° C. (oil bath) for 14 h, cooled to room temperature, and diluted with ethyl acetate (100 mL) and hexanes (20 mL). The mixture was washed with water (4×20 mL) and brine (40 mL) and concentrated under reduced pressure. Flash silica gel column chromatography using ethyl acetate/CH2Cl2 (1:25, 1:20, v/v) gave the desired product 31 as a thick yellow oil (718 mg, 83% yield). 1H NMR (300 MHz, CDCl3) δ 1.44 (s, 9H), 1.48-1.68 (m, 4H), 2.12-2.38 (m, 2H), 2.48-2.60 (m, 2H), 3.10-3.24 (m, 2H), 3.75 (s, 3H), 3.97-4.06 (m, 2H), 4.41-4.52 (m, 1H), 4.70 (br s, 1H), 5.09 (s, 2H), 5.25-5.37 (m, 1H), 6.70-6.80 (m, 2H), 6.95-7.09 (m, 2H), 7.30-7.38 (m, 5H). m/z (ESI) 515 [C28H38N2O7+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH:15]([CH3:17])[CH3:16])[C:11]([Cl:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:48])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[CH:38][N:37]=[N:36]2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH:15]([CH3:16])[CH3:17])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:48])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[CH:38][N:37]=[N:36]2)[CH:30]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Reactant: CC(C)Nc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: CC(C)Nc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-isopropylamino-phenyl)-carbamic acid tert-butyl ester (Example J40) (300 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (401 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (375 mg, 60%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1.[C:18]([NH2:21])(=[S:20])[CH3:19]>>[CH3:1][O:2][C:3]([C:4]1[N:21]=[C:18]([CH3:19])[S:20][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)=[O:17]
Reactant: COC(=O)C(=O)C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1cccc([N+](=O)[O-])c1

Procedure:
prepared by reaction of 3-chloro-3-(3-nitro-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.94 min; [M+H]+=279.3.
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][C:4]([OH:6])=[O:5].C(N(CC)CC)C.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[OH:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][C:4]([O:6][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:5]
Reactant: CCCCCCCCCCCCCC(O)CC(=O)O
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCC(O)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 3-hydroxyhexadecanoic acid (1.90 g) and triethylamine (0.97 ml) in DMF (20 ml) was added benzyl bromide (0.83 ml) and the mixture was stirred at room temperature for 3 days. After the solvent was removed in vacuo, ethyl acetate and water were added to the residue. The separated ethyl acetate layer was washed twice with water and then dried over anhydrous sodium sulfate. After concentration, the residue was purified by a silica gel column chromatography (silica gel 15 g, chloroform: methanol=100:0-8) to afford 1.22 g of benzyl 3-hydroxyhexadecanoate.
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=O)[CH3:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH3:15][O:16][CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)[CH2:18][NH2:19].Cl>C1C=CC=CC=1>[ClH:26].[CH:1]([S:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH:19][CH2:18][CH:17]([O:16][CH3:15])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[CH3:13])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)Cc1ccc(SC(C)C)cc1
Reactant: COC(CN)c1cccc(Cl)c1
Agent: Cl
Solvent: c1ccccc1
Product: COC(CNC(C)Cc1ccc(SC(C)C)cc1)c1cccc(Cl)c1
Reaction time: 1 h

Procedure:
1-(4-Isopropylthiophenyl)propan-2-one (4.16 g) and 2-methoxy-2-(3-chlorophenyl)ethanamine (3.71 g) in dry benzene (100 ml) was boiled under reflux for two hours in an apparatus incorporating a water trap. The solution was cooled and the solvent removed under reduced pressure. The residue was dissolved in ethanol (80 ml), cooled to less than 10° C. and treated portionwise with sodium borohydride (3.0 g) over 30 minutes. The mixture was stirred for one hour and the solvent removed under reduced pressure. The residue was dissolved in dichloromethane, washed with water, dried over magnesium sulphate, filtered and evaporated. Chromatography of the residue on silica gel in 2-4% methanol-dichloromethane gave an oil which was converted to its hydrochloride salt by addition of ethereal hydrogen chloride. Crystallisation from methanol-ethyl acetate-hexane gave the title compound, m.p. 133°-9° C., as a 70:30 mixture of diastereoisomers.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.[CH3:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][C:42](Cl)=[O:43]>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19](=[O:20])[NH:18][C:15]2[CH:14]=[CH:13][C:12]([N:7]3[CH:6]=[N:5][C:4]4[C:8]3=[N:9][CH:10]=[N:11][C:3]=4[NH:2][C:42](=[O:43])[CH2:41][O:40][CH2:39][CH2:38][O:37][CH2:36][CH2:35][O:34][CH3:33])=[CH:17][CH:16]=2)=[CH:23][C:24]=1[C:29]([F:31])([F:32])[F:30]
Reactant: COCCOCCOCC(=O)Cl
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: Cl
Product: COCCOCCOCC(=O)Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and 2-[2-(2-methoxyethoxy)ethoxy]acetyl chloride by using the same method as in Example 107.