Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCCCC1.BrC1OC(C=O)=CC=1.[N:15]1([C:21]2[O:25][C:24]([CH:26]=O)=[CH:23][CH:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:33][C:34]#[N:35]>>[CH3:28][O:29][C:30]1[CH:31]=[C:32](/[C:33](=[CH:26]/[C:24]2[O:25][C:21]([N:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)=[CH:22][CH:23]=2)/[C:34]#[N:35])[CH:36]=[CH:37][C:38]=1[O:39][CH3:40]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1ccc(N2CCCCC2)o1
Agent: O=Cc1ccc(Br)o1
Solvent: C1CCNCC1
Product: COc1ccc(/C(C#N)=C/c2ccc(N3CCCCC3)o2)cc1OC
Yield: 29.6 %

Procedure:
Through the procedure as employed in Production step 1, an amine moiety derived from piperidine (1.28 g) was introduced into 5-bromo-2-furaldehyde (875 mg), to thereby yield 5-piperidin-1-yl-furan-2-carbaldehyde (yield: 650 mg, 73%). The produced 5-piperidin-1-yl-furan-2-carbaldehyde (179 mg) was condensed with 3,4-dimethoxybenzyl cyanide (177 mg) through Method A (production step 2), to thereby yield the target product (yield: 100 mg, 30%).
Reaction SMILES: C([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2Br)[CH2:8][CH:7]([CH2:22][O:23]C(=O)C)[CH:6]1[O:27]C(=O)C)(=O)C.[CH:31]1([NH2:34])[CH2:33][CH2:32]1.CO.N>C(O)C>[Cl:19][C:17]1[C:16]([Cl:20])=[CH:15][C:14]2[N:10]([CH:9]3[CH:5]([OH:4])[CH:6]([OH:27])[CH:7]([CH2:22][OH:23])[CH2:8]3)[C:11]([NH:34][CH:31]3[CH2:33][CH2:32]3)=[N:12][C:13]=2[CH:18]=1
Reactant: NC1CC1
Reactant: CC(=O)OCC1CC(n2c(Br)nc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Agent: N
Solvent: CO
Solvent: CCO
Product: OCC1CC(n2c(NC3CC3)nc3cc(Cl)c(Cl)cc32)C(O)C1O
Reaction time: 18 h

Procedure:
(±)(1R*, 2S*, 3S*, 5S*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (500 mg, 0.958 mmol) was dissolved in absolute ethanol (5 mL) and cyclopropylamine (0.66 mL, 9.6 mmol) was added. The solution was refluxed under nitrogen for two hours. Additional cyclopropylamine (0.66 mL) was added and reflux continued for an additional 18 hours. The solution was cooled and methanol saturated with ammonia at 0° C. (5 mL) was added. After two days at ambient temperature, volatiles were removed in vacuo and the residue chromatographed on silica gel. (±)-(1R*, 2S*, 3S*, 5S*)-5-[5,6-Dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol was eluted with 7% methanol-chloroform and solidified from ethyl acetate-hexanes to white powder (210 mg, 59%), m.p. 223°-224° C.; 1H-NMR(DMSO-d6)δ: 7.64 and 7.46 (both s, 2, aromatic CH), 7.11 (m, 1, NH), 5.11 (t, J=4.3 Hz, 1, OH), 4.77 (d, J=7.0 Hz, 1, OH), 4.67 (d, J=3.7 Hz, 1, OH), 4.65-4.30 (m, 2, OCH and NCH), 3.85-3.75 (m, 1, OCH), 3.7-3.4 (m, 2, OCH2), 2.85-2.70 (m, 1, NCH of cyclopropyl), 2.15-1.80 (m, 3, CH2 and CH of cyclopentane), 0.80-0.50 (m, 4, 2 CH2 of cyclopropyl); mass spectrum (CI): 372(M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.C1N2CN3CN(C2)CN1C3.C(=O)([O-])[O-:26].[Na+].[Na+]>C(O)(=O)C>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1)=[O:26]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)Cc1ccc(CBr)cc1
Agent: C1N2CN3CN1CN(C2)C3
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccc(C=O)cc1
Temperature: 100 °C

Procedure:
25.7 g of ethyl 4-bromomethylphenylacetate and 28 g of hexamethylenetetramine are dissolved in 200 ml of 20% acetic acid, heated to 100° C. with stirring and stirred for four hours. The reaction solution is allowed to cool and sufficient sodium carbonate is added until a saturated solution is obtained. This solution is extracted with ether, dried and the ether is then removed. The residue is purified by chromatography (silica gel/methyl t-butyl ether/ether 1:1).
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][C:9](=O)[C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][O:21][CH3:22].CCOCC>C1C=CC=CC=1>[CH3:22][O:21][CH2:20][CH:16]1[CH2:17][CH2:18][CH2:19][N:15]1[N:14]=[C:9]1[CH2:10][CH2:11][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]1=[O:13]
Reactant: COCC1CCCN1N
Reactant: O=C1CCN(c2ccccc2)C1=O
Solvent: CCOCC
Solvent: c1ccccc1
Product: COCC1CCCN1N=C1CCN(c2ccccc2)C1=O

Procedure:
A solution of the product of Example 61 and chiral 1-amino-2-methoxymethylpyrrolidine (SAMP or RAMP; 1 equiv) in benzene is refluxed under Dean-Stark conditions for 20 h. After cooling, Et2O is added and the mixture is washed with water. The organic layer is dried (MgO4) and evaporated to give a residue which is chromatographed on silica gel to give the title compound.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][N:9]=2)[CH2:4][CH2:3]1.[CH3:17][C:18]1[NH:19][C:20]2[C:25]([C:26]=1[CH2:27][CH2:28][CH2:29]S(C1C=CC=CC=1)(=O)=O)=[CH:24][CH:23]=[CH:22][CH:21]=2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[O:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH2:29][CH2:28][CH2:27][C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][C:18]=3[CH3:17])[CH2:7][CH2:6]2)=[N:9]1
Reactant: c1ccc2c(C3CCNCC3)noc2c1
Reactant: Cc1[nH]c2ccccc2c1CCCS(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1[nH]c2ccccc2c1CCCN1CCC(c2noc3ccccc23)CC1
Reaction time: 4 h
Yield: 61.2 %

Procedure:
A mixture of 1.67 g of 3-(4-piperidyl)-1,2-benzisoxazole hydrochloride, 2.47 g of 2-methyl-3-(phenylsulfonylpropyl)indole, 40 ml of dimethylformamide and 5.0 g of potassium carbonate was stirred under nitrogen at 90° for 4 hrs. The reaction mixture was poured into water. The precipitate was extracted with ethyl acetate and the ethyl acetate was washed with brine, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to yield an oil. The oil was combined with 1.39 g of previously prepared material and the sample was chromatographed in 120 g of silica gel, using 1% methanol-chloroform as eluent. The eluent was evaporated and the residue was recrystallized two times from ethanol-water to yield 1.60 g (15.4%) of the product, mp 110°-112°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[CH3:21][OH:22].S(=O)(=O)(O)O>O>[C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:21][OH:22])[CH:4]=1)#[N:2]
Reactant: N#Cc1ccncc1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: N#Cc1ccnc(CO)c1
Yield: 46 %

Procedure:
A mixture of 4-cyanopyridine (31.2 g), ammonium persulphate (136.8 g), methanol (450 ml), concentrated sulphuric acid (16.2 ml) and water (210 ml) was heated under reflux for 24 hours, and the methanol was removed by distillation. Crushed ice (450 g) was added and the mixture was adjusted to pH 12 with 10 M sodium hydroxide and extracted with chloroform. The chloroform extracts were combined and evaporated and the residue was purified by elution from a silica gel column with methanol-chloroform (7.5% v/v) to give 4-cyano-2-hydroxymethylpyridine (18.5 g, 46%) m.p. 92°-94°.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([S:15]([NH:18][C@H:19]([CH2:23][CH2:24][CH2:25][NH2:26])[C:20]([OH:22])=[O:21])(=[O:17])=[O:16])[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1.[CH:27](=O)[C:28]1[C:29](=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH:30]=[O:31]>C(O)(=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([S:15]([NH:18][C@H:19]([CH2:23][CH2:24][CH2:25][N:26]2[CH2:27][C:28]3[C:29](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]2=[O:31])[C:20]([OH:22])=[O:21])(=[O:17])=[O:16])[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: O=Cc1ccccc1C=O
Reactant: NCCC[C@@H](NS(=O)(=O)c1cc(Cl)ccc1-c1ccccc1)C(=O)O
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)[C@@H](CCCN1Cc2ccccc2C1=O)NS(=O)(=O)c1cc(Cl)ccc1-c1ccccc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
0.32 g (0.76 mmol) of 2-(2R)-(4-chlorobiphenylsulfonylamino)-5-amino-pentanoic acid hydrochloride is dissolved in 30 ml of glacial acetic acid with 0.186 g (1.35 mmol) of phthalaldehyde and stirred at 100° C. for 3 hours. The solution is cooled to 0° C., and the precipitate which is deposited is filtered off with suction and chromatographed on a silica gel column (eluent: ethyl acetate/petroleum ether/glacial acetic acid 10/10/2).
Reaction SMILES: OC1C2C(=O)C(OC)=CC(=O)C=2C(O)=C2C(=O)[C@]3(C4C(O)=C5C(C=C(/C=N/O[C@@H]6O[C@H](CO)[C@@H](O)[C@H](O)[C@H]6O)NC5=O)=CC=4CC3)C(=O)C=12.[CH3:50]/[CH:51]=[CH:52]/[CH:53]=[CH:54]/[C:55]1[NH:65][C:63](=[O:64])[C:62]2[C:57](=[CH:58][C:59]3[CH2:69][CH2:68][C:67]4([C:78](=[O:79])[C:77]5[C:72](=[C:73]([OH:89])[C:74]6[C:85](=[O:86])[CH:84]=[C:83](OC)[C:81](=[O:82])[C:75]=6[C:76]=5[OH:80])[C:70]4=[O:71])[C:60]=3[C:61]=2[OH:66])[CH:56]=1.[NH2:90][CH2:91][CH:92]1[CH2:97][CH2:96][NH:95][CH2:94][CH2:93]1>CN(C=O)C>[OH:80][C:76]1[C:75]2[C:81](=[O:82])[C:83]([NH:90][CH2:91][CH:92]3[CH2:97][CH2:96][NH:95][CH2:94][CH2:93]3)=[CH:84][C:85](=[O:86])[C:74]=2[C:73]([OH:89])=[C:72]2[C:70](=[O:71])[C@:67]3([C:60]4[C:61]([OH:66])=[C:62]5[C:57]([CH:56]=[C:55](/[CH:54]=[CH:53]/[CH:52]=[CH:51]/[CH3:50])[NH:65][C:63]5=[O:64])=[CH:58][C:59]=4[CH2:69][CH2:68]3)[C:78](=[O:79])[C:77]=12
Reactant: NCC1CCNCC1
Reactant: C/C=C/C=C/c1cc2cc3c(c(O)c2c(=O)[nH]1)C1(CC3)C(=O)c2c(O)c3c(c(O)c2C1=O)C(=O)C(OC)=CC3=O
Agent: COC1=CC(=O)c2c(O)c3c(c(O)c2C1=O)C(=O)[C@]1(CCc2cc4cc(/C=N/O[C@@H]5O[C@H](CO)[C@@H](O)[C@H](O)[C@H]5O)[nH]c(=O)c4c(O)c21)C3=O
Solvent: CN(C)C=O
Product: C/C=C/C=C/c1cc2cc3c(c(O)c2c(=O)[nH]1)[C@@]1(CC3)C(=O)c2c(O)c3c(c(O)c2C1=O)C(=O)C(NCC1CCNCC1)=CC3=O

Procedure:
Ten (10) mg (18.6 μmol) fredericamycin are dissolved in 1 ml DMF under argon, then 2.7 PI (22.3 μmol) 4-aminomethylpiperidine are added at room temperature. The reaction mixture is concentrated at high vacuum until dry after 24 h.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:15])=[N:12][CH:13]=2)[CH:7]=1.[CH3:26][C:27]1(C)[C:31](C)(C)OB(C(C)=C)O1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1(C)C=CC=CC=1.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:24]([C:5]1[CH:4]=[CH:3][C:2]([C:27]([CH3:31])=[CH2:26])=[CH:7][C:6]=1[C:8]1[CH:9]=[CH:10][C:11]([C:14]([NH:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:15])=[N:12][CH:13]=1)=[O:25]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C=O)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=C(C)c1ccc(C=O)c(-c2ccc(C(=O)NCCC(=O)OCC)nc2)c1
Temperature: 90 °C

Procedure:
Ethyl 3-(5-(5-chloro-2-formylphenyl)picolinamido)propanoate (180 mg, 0.50 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (126 mg, 0.75 mmol), Pd(OAc)2 (11 mg, 0.05 mmol), S-PHOS (41 mg, 0.10) K3PO3 (318 mg, 1.50 mmol) were dissolved in toluene (2 mL) and the resulting mixture was heated to 90° C. After 16 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [NH3:1].CO.[CH3:4][S:5][C:6]1[N:7]=[N:8][C:9]([C:23]([O:25]CC)=O)=[C:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][CH:17]=[CH:16]3)[N:11]=1>C1COCC1>[CH3:4][S:5][C:6]1[N:7]=[N:8][C:9]([C:23]([NH2:1])=[O:25])=[C:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][CH:17]=[CH:16]3)[N:11]=1
Reactant: N
Reactant: CCOC(=O)c1nnc(SC)nc1Nc1ccc2ncccc2c1
Solvent: CO
Solvent: C1CCOC1
Product: CSc1nnc(C(N)=O)c(Nc2ccc3ncccc3c2)n1
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
A 2 M ammonia-methanol solution (3 ml) was added to a solution of ethyl 3-(methylthio)-5-(quinolin-6-ylamino)-1,2,4-triazine-6-carboxylate obtained in the above-described Step 1 (150 mg) in THF (0.5 ml), and then the reaction solution was stirred in a microwave reactor at 130° C. for 30 minutes. The precipitate was filtrated to obtain 3-(methylthio)-5-(quinolin-6-ylamino)-1,2,4-triazine-6-carboxamide as a crude white solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)=[O:16])[CH2:6][CH2:5]2
Reactant: NCCc1ccc(O)cc1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCc1ccc(O)cc1)O2
Yield: 72.8 %

Procedure:
Following the amide coupling procedure described in protocol A, 500 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.0 mmol), 356 mg CDI (2.2 mmol) and 548 mg tyramine (4.0 mmol) produced 537.8 mg of 6-hydroxy-N-(4-hydroxyphenethyl)-2,5,7,8-tetramethylchroman-2-carboxamide as a brown solid.
Reaction SMILES: FC(F)(F)C([O-])=O.[F:8][C:9]1[CH:10]=[C:11]([CH2:16][C@H:17]([NH3+:51])[C:18](=[O:50])[NH:19][C@H:20]2[CH2:41][O:40][C:39](=[O:42])[C@H:38]3[N:34]([CH2:35][CH2:36][CH2:37]3)[C:33](=[O:43])[C@H:32]([CH3:44])[NH:31][C:30](=[O:45])[C@H:29]([CH3:46])[N:28]([CH3:47])[C:27](=[O:48])[C@H:26]3[N:22]([CH2:23][CH2:24][CH2:25]3)[C:21]2=[O:49])[CH:12]=[C:13]([F:15])[CH:14]=1.[C:52](O)(=[O:59])/[CH:53]=[CH:54]/[CH2:55][CH2:56][CH2:57][CH3:58].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>ClCCl>[F:8][C:9]1[CH:10]=[C:11]([CH2:16][C@H:17]([NH:51][C:52](=[O:59])/[CH:53]=[CH:54]/[CH2:55][CH2:56][CH2:57][CH3:58])[C:18](=[O:50])[NH:19][C@H:20]2[CH2:41][O:40][C:39](=[O:42])[C@H:38]3[N:34]([CH2:35][CH2:36][CH2:37]3)[C:33](=[O:43])[C@H:32]([CH3:44])[NH:31][C:30](=[O:45])[C@H:29]([CH3:46])[N:28]([CH3:47])[C:27](=[O:48])[C@H:26]3[N:22]([CH2:23][CH2:24][CH2:25]3)[C:21]2=[O:49])[CH:12]=[C:13]([F:15])[CH:14]=1
Reactant: C[C@@H]1NC(=O)[C@H](C)N(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](NC(=O)[C@@H]([NH3+])Cc2cc(F)cc(F)c2)COC(=O)[C@@H]2CCCN2C1=O
Reactant: CCCC/C=C/C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCC/C=C/C(=O)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)N[C@H]1COC(=O)[C@@H]2CCCN2C(=O)[C@H](C)NC(=O)[C@H](C)N(C)C(=O)[C@@H]2CCCN2C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.89 g (2.75 mmol) of the compound from example 13A and 458.8 mg (3.58 mmol) of trans-2-heptenoic acid are introduced into dichloromethane (20 ml), cooled to 0° C., then treated with 2.09 g (5.51 mmol) of HATU and 462.7 mg (3.58 mmol) of ethyldiisopropylamine. The solution is stirred at 0° C. for 30 min, then a further 925.3 mg (7.16 mmol) of ethyldiisopropylamine are added, and it is stirred at room temperature for 18 h. The reaction solution is evaporated, and the residue is taken up using ethyl acetate and washed with aq. citric acid, aq. sodium hydrogencarbonate solution and sat. aq. sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness. The residue is chromatographed on silica gel using ethyl acetate/cyclohexane 1/2. 1.51 g (56% of th.) of the product are obtained.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([CH2:18][CH2:19][OH:20])[CH2:13]1.[H-].[Na+].I[CH3:24].O>C1COCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([CH2:18][CH2:19][O:20][CH3:24])[CH2:13]1
Reactant: CI
Reactant: OCCC1CCCN(CC2COc3ccccc3O2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCC1CCCN(CC2COc3ccccc3O2)C1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A solution of 2-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]ethanol (0.1 g, 0.36 mmol) in THF (5 ml) was added NaH (79.0 mg, 1.79 mmol), which was previously washed with heptane. The reaction mixture was stirred at 70° C. for 1 h followed by a dropwise addition of a solution of iodomethane (0.034 ml, 0.54 mmol) in THF (1 ml). Stirring was continued for 1 h. Water was slowly added and the reaction mixture was extracted with DCM (3×20 ml). The combined organic phases were dried (Na2SO4), filtered and the filtrate was evaporated to give the title compound, which was purified by column chromatography (DCM/MeOH, 90:10).
Reaction SMILES: [CH:1]1([N:7]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:30][O:31][C:32](=[O:37])[C:33]([NH2:36])([CH3:35])[CH3:34]>>[CH:1]1([N:7]([CH2:25][CH:26]2[CH2:27][CH2:28]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][NH:36][C:33]([CH3:35])([C:32]([O:31][CH3:30])=[O:37])[CH3:34])=[CH:21][CH:22]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C(C)(C)N
Reactant: O=Cc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Agent: Cl
Product: COC(=O)C(C)(C)NCc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1

Procedure:
Following the general method as outlined in Example 73, starting from 6-[cyclohexyl(cyclopropylmethyl)amino]-N-(4-formylphenyl)pyrimidine-4-carboxamide (Intermediate 24) and 2-aminoisobutyric acid methyl ester hydrochloride (Sigma), the title compound was obtained as a colorless oil after purcation by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:29][C:30](O)=[O:31])[C:18]([C:33]([F:36])([F:35])[F:34])=[CH:17][N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.C[N:38](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl-].[NH4+]>CN(C=O)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:29][C:30]([NH2:38])=[O:31])[C:18]([C:33]([F:35])([F:34])[F:36])=[CH:17][N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CN1CCN(c2cccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)O)n3)c2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(2-(2-(2-((3-(4-Methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetic acid (I68) (75.0 mg, 169 μmol) was dissolved in DMF (1 mL) then HATU (129 mg, 339 μmol), DIPEA (57 uL, 339 μmol) and ammonium chloride (181 mg, 3.39 mmol) were added. The resulting mixture was stirred at room temperature overnight then the volatiles were evaporated under reduced pressure.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](O)=O.N>>[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1ccccc1F
Agent: N
Product: Fc1ccccc1-c1nc(-c2cccnc2)no1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 2-fluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.38-7.49 (m, 2H), 7.64 (ddd, J=8.0, 4.9, 1.0 Hz, 1H), 7.70-7.79 (m, 1H), 8.28 (td, J=7.5, 1.9 Hz, 1H), 8.57 (dt, J=8.1, 1.9 Hz, 1H), 8.74 (dd, J=4.7, 1.7 Hz, 1H), 9.31 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCl/NH3) m/z 242 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([F:40])([F:39])[C:29]1[CH:34]=[CH:33][C:32](OB(O)O)=[CH:31][CH:30]=1.O>O1CCOCC1.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>[C:1]([O:5][C:6](=[O:26])[C:7]([CH3:9])([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:32]3[CH:33]=[CH:34][C:29]([C:28]([F:40])([F:39])[F:27])=[CH:30][CH:31]=3)=[CH:21][CH:20]=2)[N:15]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(COCc2ccc(Br)cc2)cs1
Reactant: OB(O)Oc1ccc(C(F)(F)F)cc1
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: CC(C)(C)OC(=O)C(C)(C)Sc1nc(COCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cs1
Yield: 78.8 %

Procedure:
Under nitrogen atmosphere, 2-[(4-{[(4-bromobenzyl)oxy]methyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (1.0 g) synthesized in Example 152-1 and 4-(trifluoromethyl)phenylboric acid (621 mg) were dissolved in dioxane (10 mL) and sodium hydrogen carbonate aqueous solution (2 mol/L, 5 mL), tetrakis(triphenylphosphine)palladium (162 mg) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=5:1) to give the title compound (900 mg) as a colorless oil.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[C:18](N1C=CN=C1)(N1C=CN=C1)=[S:19]>CN(C)C=O>[N:17]([C:14]1[CH:13]=[CH:12][C:11]([N:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH2:6][CH2:7]2)=[CH:16][CH:15]=1)=[C:18]=[S:19]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(N2CCN(CC3CC3)CC2)cc1
Solvent: CN(C)C=O
Product: S=C=Nc1ccc(N2CCN(CC3CC3)CC2)cc1
Temperature: -15 °C
Reaction time: 0.33 h

Procedure:
A solution of 4-[4-(cyclopropylmethyl)-1-piperazinyli]benzenamine (3.7 g, 16 mmol) (from Step B above) in N,N-dimethylformamide (50 mL) was added dropwise over 20 min to a cooled (−15° C.) solution of thiocarbonyidiimidazole (2.87 g, 16.1 mmol) (Aldrich) in N,N-dimethylformamide (25 mL). After the addition was complete, the mixture was stirred at −15° C. for 20 min, then the cooling bath was removed and the solution was stirred for 1 h. Ice-water (1000 mL) was added and the mixture was stirred for 30 min. The solid was filtered off and washed with water and dried under vacuum. (4 g, 91%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[CH:4][C:3]=1[Cl:9].[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=2[O:25][CH3:26])[C:19](Cl)=[O:20])[CH2:14][CH2:13][CH2:12][CH2:11]1>>[Cl:9][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([Cl:8])[C:2]=1[NH:1][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:16]([O:15][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:17]=1
Reactant: COc1ccc(C(=O)Cl)cc1OC1CCCC1
Reactant: Nc1c(Cl)cncc1Cl
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1OC1CCCC1
Reaction time: 0.17 h
Yield: 20 %

Procedure:
4-Amino-3,5-dichloropyridine (4.0 g) and 3-cyclopentyloxy-4-methoxybenzoyl chloride (6.26 g) are intimately ground together in a mortar with a pestle, and transferred to a round-bottomed flask. The mixture is melted, using a hot air gun external to the flask, stirring with a magnetic stirrer. After 10 minutes, heating is ceased and the melt is allowed to cool. The resulting material is triturated with dichloromethane and the residual solid is filtered off. The filtrate is concentrated to give a fawn solid, which is subjected to flash chromatography on silica gel, eluting with diethyl ether, to give N-(3,5-dichloro-pyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide (1.87 g), m.p. 155-157° C. [Elemental analysis: C,56.3; H,4.7; N,7.2; Cl,18.4%; calculated: C,56.7; H,4.76; N,7.35; Cl,18.6%; IR spectrum: 1661 cm-1, 3244 cm-1 ].