Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([CH:11]=[N:12][C:13]3[C:18]([F:19])=[C:17]([O:20][CH3:21])[CH:16]=[C:15]([O:22][CH3:23])[C:14]=3[F:24])=[CH:9][N:8]=[C:7]([S:25][CH3:26])[N:6]=2)[CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:1]1([NH:4][C:5]2[C:10]([CH2:11][NH:12][C:13]3[C:18]([F:19])=[C:17]([O:20][CH3:21])[CH:16]=[C:15]([O:22][CH3:23])[C:14]=3[F:24])=[CH:9][N:8]=[C:7]([S:25][CH3:26])[N:6]=2)[CH2:3][CH2:2]1
Reactant: COc1cc(OC)c(F)c(N=Cc2cnc(SC)nc2NC2CC2)c1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)c(F)c(NCc2cnc(SC)nc2NC2CC2)c1F
Reaction time: 2 h
Yield: 97 %

Procedure:
A solution of in 8.61 g (22.6 mmol) of cyclopropyl-(5-[(2,6-difluoro-3,5-dimethoxy-phenylimino)-methyl]-2-methylsulfanyl-pyrimidin-4-yl)-amine in 400 mL of dry THF was cooled in an ice/water bath. To the cooled solution was added dropwise equivalent (22.6 mL, 22.6 mmol) of a 1 M LAH solution in THF. The reaction was stirred cold for 2 hours and then quenched by sequential addition of 0.4 mL water, followed by 1.6 mL of 15% NaOH solution, and finally 0.88 mL of water. The reaction was filtered through Celite and the filter pad was washed well with THF. The THF filtrate was concentrated in vacuo. The residue was dissolved in dichloromethane, washed with a saturated solution of NaCl, and concentrated in vacuo. Stirring the residue with diethyl ether and concentrating the suspension in vacuo gave 8.38 g (97%) of the title compound as a solid: mp 48° C.–50° C. MS (APCI) (m+1)/z 383.4 Analysis calculated for C17H20F2N4SO2: C, 53.39; H, 5.27; N, 14.65. Found: C, 53.44; H, 5.29; N, 14.31.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH:5]([C:25]1[N:26]=[C:27]([N:30]2[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]2)[S:28][CH:29]=1)[N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[C:14]([O:23][CH3:24])=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)[CH2:8][CH2:7]1.[OH-].[Na+].CO>C1COCC1>[OH:36][CH:33]1[CH2:32][CH2:31][N:30]([C:27]2[S:28][CH:29]=[C:25]([CH:5]([N:6]3[CH2:12][CH2:11][CH2:10][N:9]([C:13]4[C:14]([O:23][CH3:24])=[CH:15][CH:16]=[C:17]5[C:22]=4[N:21]=[CH:20][CH:19]=[CH:18]5)[CH2:8][CH2:7]3)[CH2:4][C:3]([OH:37])=[O:2])[N:26]=2)[CH2:35][CH2:34]1
Reactant: COC(=O)CC(c1csc(N2CCC(O)CC2)n1)N1CCCN(c2c(OC)ccc3cccnc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2cccnc2c1N1CCCN(C(CC(=O)O)c2csc(N3CCC(O)CC3)n2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product from step 1 (660 mg, 1.26 mmol) was dissolved in THF (4.20 mL) and 1 N aq. NaOH (2.52 mL, 2.52 mmol) was added, followed by MeOH (2.10 mL). The reaction was stirred at room temp for 3 h, then concentrated. The product was taken up in CH2Cl2 and water, then acidified to pH 4 with AcOH. NH4OH was added to bring the pH to 9, then the aqueous was extracted with CH2Cl2 (3×50 mL). The combined organic was dried over MgSO4, filtered, and concentrated to give the product, which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:17][C:11]3[NH:12][CH:13]=[CH:14][C:15](=O)[C:10]=3[C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C(Cl)(Cl)[Cl:25].C(Cl)(=O)C(Cl)=O>CN(C=O)C>[Cl:25][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[O:17][C:8]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]=12
Reactant: ClC(Cl)Cl
Reactant: O=c1cc[nH]c2oc(-c3ccc(O)cc3)c(-c3ccccc3)c12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: Oc1ccc(-c2oc3nccc(Cl)c3c2-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A 25-ml round bottom flask equipped with a reflux condenser fitted with a nitrogen inlet adapter was charged with 2-(4-hydroxy-phenyl)-3-phenyl-7H-furo[2,3-b]pyridin-4-one (5) (0.280 g, 0.923 mmol) and chloroform (9.0 mL). Oxalyl chloride (0.469 g, 0.32 mL, 3.69 mmol) and DMF (0.05 mL) were added and the mixture stirred at room temperature until the evolution of gas ceased (approx. 1 min). The mixture was heated at reflux for 5 h. The reaction mixture was concentrated to afford an orange brown solid which was purified via column chromatography on silica gel (eluting with 0-25% ethyl acetate-hexane) to afford 4-(4-chloro-3-phenyl-furo[2,3-b]pyridin-2-yl)-phenol 6 as an orange solid. MS (MH+) 322.0; Calculated 321 for C19H12ClNO2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[N:7][CH:8]=1.C(=O)(O)[O-].[Na+].Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29]>C(OCC)(=O)C>[C:31]1([O:30][C:28](=[O:29])[NH:15][C:12]2[CH:13]=[CH:14][C:9]([C:6]3[N:5]=[C:4]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[C:3]([O:2][CH3:1])=[CH:8][N:7]=3)=[CH:10][CH:11]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1cnc(-c2ccc(N)cc2)nc1N1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cnc(-c2ccc(NC(=O)Oc3ccccc3)cc2)nc1N1CCOCC1
Reaction time: 0.08 h
Yield: 40.5 %

Procedure:
A mixture of 4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenylamine (1.50 g, 1.0 eq.) and sodium bicarbonate solution (6 ml) in ethyl acetate (6 ml) stirring 5 min. After dropping phenyl chloroformate (0.98 ml, 1.2 eq) for 4 hrs at room temperature. The resultant mixture extracted with EA and the combined organic layers were washed with brine and dried in vacuo to give a light brown solid (1.80 g, 40.5%) as the product.
Reaction SMILES: C[O:2][S:3]([O-:6])(=[O:5])=[O:4].[CH2:7]([N+:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])([CH3:27])[CH3:26])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].S(=O)(=O)(O)O>C(O)(C)C.O>[S:3](=[O:4])(=[O:2])([OH:6])[O-:5].[CH2:28]([N+:25]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([CH3:27])[CH3:26])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: COS(=O)(=O)[O-]
Agent: CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCCCCCCCC
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Product: O=S(=O)([O-])O
Temperature: 820 °C
Reaction time: 1 h

Procedure:
In a 1 liter 3-necked round bottomed flask equipped with a mechanical stirrer and reflux condenser were suspended 60 grams (90.8 millimoles) of distearyl dimethyl ammonium methylsulfate in a mixture of 168.75 grams of isopropanol and 56.25 grams of deionized water. 9.57 grams of 95 percent sulfuric acid (90.8 millimoles) were then added and the reaction mixture was heated at gentle reflux, at about 820° C., for 4 hours. The resulting clear, orange-yellow solution was then cooled slowly. After about one hour, at about 30° C., crystals started to appear, followed by a massive crystallization with a noticeable exotherm of over 4° C. and the formation of white viscous slurry The crystallization was continued overnight, about 18 hours, under agitation at about 20° to 25° C. The slurry was filtered under vacuum on an 11 centimeter Whatman #4 filter paper with a Buchner funnel. The filtration time recorded was 2 minutes. The excellent filtration rate reflects the excellent crystallization characteristics of the product. A white filter cake was obtained, while a yellowish filtrate was removed. The filter cake was reslurried in 225 grams of a 75/25 mixture of isopropanol and water to remove residual acidity. The mixture of isopropanol and water was used to avoid the formation of gel experienced when water only is used to wash the highly acidic wet cake. A white slurry was obtained, which again required only 2 minutes to filter. Two more reslurry washings were accomplished as described above with filtration times of about 2 minutes each. A final reslurry wash with 200 grams of acetone was accomplished after which the product was recovered by filtration and dried overnight in vacuum at about 50° C. 42.7 grams (72.7 percent yield) of distearyl dimethyl ammonium bisulfate (IR fingerprint) were recovered. Analyticals- melting point (DSC) 94.50° C., H2O content 0.04 percent, bisulfate content (by titration) 15.24 percent.
Reaction SMILES: [OH:1][CH2:2][C:3]([F:23])([F:22])[C@H:4](O)[C@@H:5]([NH:13][C:14]([O:16]C(C)(C)C)=[O:15])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[H-].[Na+]>CN(C=O)C>[CH:7]1([CH2:6][C@H:5]2[C@H:4]([C:3]([F:22])([F:23])[CH2:2][OH:1])[O:16][C:14](=[O:15])[NH:13]2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)C(F)(F)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N[C@@H](CC2CCCCC2)[C@H](C(F)(F)CO)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.3 %

Procedure:
The resultant compound from Example 70 (596 mg, 1.77 mmol) in dry DMF (15 mL) was added to NaH (260 mg, 6.5 mmol, 60% in oil, hexane washed) in DMF (5 mL) at 0° C. The mixture was stirred at room temperature for 16 hours and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution and the organic phase was dried over Na2SO4 and evaporated to afford 472 mg (100%) of product as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:35][CH:36]1[CH2:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]([CH2:46][C:47]([O:49][CH3:50])=[O:48])[C:37]1=[O:51]>O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:35][CH:36]1[CH2:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]([CH2:46][C:47]([O:49][CH3:50])=[O:48])[C:37]1=[O:51])=[O:13])=[CH:5]2
Reactant: COC(=O)CN1C(=O)C(N)Cc2ccccc21
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COC(=O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Reaction time: 18 h

Procedure:
5-Chloro-1H-indole-2-carboxylic acid (493 mg, 2.52 mmol), HOBT (340 mg, 2.52 mmol), DCM (100 mL) and finally EDCI (483 mg, 2.52 mmol) were added to methyl 2-(3-amino-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate (Method 1; 590 mg, 2.52 mmol) and the reaction was stirred for 18 h. The reaction was then diluted with water (50 mL) and stirred vigorously for 30 min. The resultant precipitate was filtered and washed with Et2O (2×20 mL). After filtration the resultant solid was then triturated with refluxing Et2O (25 mL) and after cooling the title compound (608 mg, 59%) was collected again by filtration as a white solid.
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[OH:21].O.[C:24](O)(C(F)(F)F)=[O:25]>>[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[C:18]([CH:24]=[O:25])[CH:17]=[C:16]([CH3:20])[C:15]=1[OH:21]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1cccc(C)c1O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: COC(=O)c1cc(C=O)cc(C)c1O
Temperature: 78 °C
Yield: 86 %

Procedure:
To a solution of HMTA (1,3,5,7-Tetraaza-tricyclo[3.3.1.13,7]decane, 8.43 g, 60.2 mmol) in TFA (100 mL) is added 2-hydroxy-3-methyl-benzoic acid methyl ester (5 g, 30.1 mmol) and the reaction is refluxed (78° C.) overnight. The reaction is cooled to 50° C. and water (400 mL) is added with stirring. The mixture is stirred at 50° C. for 2 h then cooled to RT and extracted with EtOAc (2×200 mL). The combined organic layers are washed with brine (75 mL), dried over anhydrous MgSO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 silica gel, gradient elution: 0-50% EtOAc in heptane) to give product (281) as off-white solid (5.05 g, 86%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])[O:6][CH2:5][CH2:4][O:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O1CCCC1>[CH3:1][C:2]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10][NH2:11])[O:3][CH2:4][CH2:5][O:6]1
Reactant: CC1(c2cccc(C#N)c2)OCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(c2cccc(CN)c2)OCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
A solution of 3-(2-methyl-1,3-dioxolan-2-yl)benzonitrile (65.6 g) in tetrahydrofuran (400 ml) was added to a suspension of lithium aluminum hydride (26.3 g) in tetrahydrofuran (400 ml) with cooling on an ice-water bath under nitrogen stream for 1 hour. The mixture was stirred at room temperature for 2 hours. Ethyl acetate (200 ml) was added slowly with cooling on an ice bath and then ice-water (200 ml) was added very slowly with cooling on an ice bath. The resulting precipitate was removed by filtration. The solvent was removed under reduced pressure. Chloroform (300 ml) was added to the residue. The mixture was washed with water (100 ml) and then dried with magnesium sulfate. The solvent was removed under reduced pressure to afford 3-(2-methyl-1,3-dioxolan-2-yl)benzylamine (57.2 g) (oil).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]2[CH:20]=[N:21][N:22]=[C:16]2[CH2:15]1)=[O:13].Br[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]2[C:20]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[N:21][N:22]=[C:16]2[CH2:15]1)=[O:13]
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2cnnc2C1
Reactant: Brc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(nnc2-c2cccnc2)C1

Procedure:
7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (0.160 g, 0.484 mmol, e.g. see Example 3 for method of preparation), 3-bromopyridine (0.084 g, 0.532 mmol, commercially available e.g. from Sigma-Aldrich or Ryan Scientific), palladium(II) acetate (0.011 g, 0.048 mmol) and cesium carbonate (0.159 g, 0.489 mmol) in anhydrous 1,4-dioxane (2.5 mL) were heated, under argon, at 90° C. for 18 hours. The mixture was cooled, water added and extracted with ethyl acetate (three times). The combined organic phases were washed with water (twice), dried and evaporated. The residue was purified on the mass-directed automated (preparative) HPLC (MDAP) to give 7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(3-pyridinyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (0.015 g).
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[N:9]=[CH:8][N:7]=[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH:5]=1>CCO>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C:6]2[N:7]=[CH:8][N:9]=[C:4]([NH:2][CH3:1])[CH:5]=2)=[CH:12][CH:13]=1
Reactant: CN
Reactant: Nc1ccc(Cc2cc(Cl)ncn2)cc1
Solvent: CCO
Product: CNc1cc(Cc2ccc(N)cc2)ncn1
Temperature: 50 °C

Procedure:
A 4 N solution of HCl in dioxane (11.7 mL, 46.9 mmol, 30 equiv) is added to a solution of [4-(6-chloro-pyrimidin-4-ylmethyl)-phenyl]-carbamic acid tert-butyl ester (Example 117) (0.50 g, 1.56 mmol) in CH2Cl2 (6.7 mL), under an argon atmosphere. The resulting white suspension is stirred at rt for 6.5 h. Additional 4 N HCl solution (1.1 mL, 4.6 mmol, 3.0 equiv) is added. The reaction mixture is allowed to stir for 0.5 h and concentrated in vacuo to afford 0.467 g of crude 4-(6-chloro-pyrimidin-4-ylmethyl)-phenylamine as a white solid. An 8 M solution of methylamine in EtOH (5.1 mL, 40.0 mmol, 30 equiv) Is added to a solution of crude 4-(6-chloro-pyrimidin-4-ylmethyl)phenylamine (0.300 g, 1.37 mmol) in EtOH (2.7 mL), under an argon atmosphere. The mixture Is heated to 50° C. (oil bath temperature) for 5 h, allowed to cool to rt and concentrated in vacuo. The residue is purified by silica gel (48 g) column chromatography (CH2Cl2/MeOH, 85/15) to afford the title compound as a light yellow oil: ES-MS: 215.0 [M+H]+; single peak at tR=3.03 min (System 2); Rf=0.49 (CH2Cl2/MeOH, 85/15).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:15](=[O:18])[CH2:16][Cl:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH2:19]([O:21][C:22](=[O:27])/[CH:23]=[C:24](\[NH2:26])/[CH3:25])[CH3:20]>CCO>[NH2:26][C:24](=[C:23]([C:22]([O:21][CH2:19][CH3:20])=[O:27])[CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:15](=[O:18])[CH2:16][Cl:17])[CH3:25]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: CCOC(=O)C(=Cc1cccc(Cl)c1)C(=O)CCl
Solvent: CCO
Product: CCOC(=O)C(=C(C)N)C(c1cccc(Cl)c1)C(C(=O)CCl)C(=O)OCC
Yield: 57.9 %

Procedure:
A solution of ethyl 2-(m-chlorophenylmethylen)-4-chloro-3-oxobutanoate (5 g) and ethyl-3-aminocrotonate (2.3 g) in EtOH (50 ml) is stirred at room temperature for four hours, then it is evaporated at reduced pressure, the residue dissolved in Et2O (70 ml) washed with water (3×20 ml), dried on Na2SO4 and purified by column-chromatography on silica gel (120 g; eluent hexane/AcOEt 60/40) to give 4.2 g of 2-amino-7-chloro-3,5-dicarboethoxy-6-oxo-4-(m-chlorophenyl)-2-heptene as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH:14]([CH3:16])[CH3:15])[N:4]=[CH:3]1.Cl.Cl.[NH2:20][OH:21].[OH-].[Na+]>O>[CH3:1][C:2]([CH3:17])([CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH:14]([CH3:16])[CH3:15])[NH2:4])[CH:3]=[N:20][OH:21]
Reactant: NO
Reactant: CC(C)C1CC=CCCC=CCC(C)(C)C=N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C(N)CC=CCCC=CCC(C)(C)C=NO
Yield: 92 %

Procedure:
233.4 g (1 mol) of 3,3-dimethyl-12-isopropyl-1-aza-1,5,9-cyclododecatriene is added dropwise to 100 g of 37% hydrochloric acid and 200 ml of water in the course of one hour, in a manner ensuring that the temperature does not exceed 80° C. The mixture is then cooled to 20°-50° C., and 69.5 g (1.0 mol) of hydroxylamine hydrochloride is added. There is subsequently added during one hour, while cooling with a water bath, about 92 g (2.3 mols) of solid sodium hydroxide until the pH value of the aqueous solution is 10-11. The organic phase which precipitates is separated, and washed free from salt with water. Distillation yields 245 g (0.92 mol) of 2,2-dimethyl-11-isopropyl-11-amino-undeca-4,8-dienal-oxime; b.p. 158°-162° C./4 Pa; nD20 =1.4930.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[N:3]=1.[Cl-].[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([NH3+:27])[CH:22]=[C:21]2[CH3:28].CN1CCOCC1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CN(C=O)C.O>[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([NH:27][C:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:11]3[S:12][CH:13]=[CH:14][N:15]=3)=[N:5][CH:6]=1)=[O:10])[CH:22]=[C:21]2[CH3:28]
Reactant: Cc1cn([NH3+])c2ccc(F)cc12
Reactant: Cc1nc(-c2nccs2)ncc1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1nc(-c2nccs2)ncc1C(=O)Nn1cc(C)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68 %

Procedure:
A mixture of 4-methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid (221 mg, 1 mmol), 5-fluoro-3-methyl-indol-1-yl-ammonium chloride (200 mg, 1 mmol) and N-methylmorpholine (101 mg, 1 mmol) in DMF (5 mL) is stirred at rt for 5 min. 4-(4,6-Dimethoxy-[1,3,5]triazin-2-yl)-4-methyl-morpholin-4-ium chloride (277 mg, 1 mmol) is added and the reaction is heated to 50° C. for 4 h. The reaction mixture is then poured into water (50 mL). The precipitate is collected via filtration and dried in vacuo to provide 4-methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid (5-fluoro-3-methyl-indol-1-yl)-amide (68%). MS: 368 (M+H); 1H NMR (300 MHz, CDCl3): δ=2.27 (s, 3H), 2.76 (s, 3H), 7.06 (dt, 1H), 7.35-7.38 (m, 2H), 7.42-7.47 (m, 1H), 8.07 (d, 1H), 8.14 (d, 1H), 9.22 (s, 1H), 11.9 (s, 1H).
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.[CH3:23][NH:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28](Br)[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:23][NH:24][C:25]([C:26]1[CH:27]=[C:28]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C@@H:3]([CH3:14])[C@H:2]([OH:1])[CH2:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:6][CH:7]=2)[C:29]([CH3:32])=[CH:30][CH:31]=1)=[O:34]
Reactant: CNC(=O)c1ccc(C)c(Br)c1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
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
Product: CNC(=O)c1ccc(C)c(-c2ccc(O[C@@H](C)[C@H](O)CCc3cccnc3)cc2)c1
Temperature: 90 °C

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-[2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy]benzeneboronic acid (0.20 g, Example 33 (0.290 g), 3-bromo-4-methylbenzoic acid, methyl amide (0.30 g), 2M aqueous sodium carbonate (0.66 ml) and tetrakis(triphenylphosphine)palladium(0) (0.038 g) in ethanol (3 ml). The reaction mixture was heated at 90° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure, taken up in ethanol and concentrated again (twice). The residue was triturated with acetone and then filtered through silica gel. The filtrate was concentrated under reduced pressure, dissolved in dichloromethane, filtered and purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give an oil, which was further purified by column chromatography over silica gel eluting with ethyl acetate:ethanol (9:1) to give the title compound as a foam(0.20 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[S:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.I[C:19]1[C:24](NC(=O)C(F)(F)F)=C(OC(C)C)C(OC)=C[CH:20]=1>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:20]#[C:19][CH3:24])=[C:3]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1
Reactant: COc1ccc(I)c(SCc2ccccc2)c1
Reactant: COc1ccc(I)c(NC(=O)C(F)(F)F)c1OC(C)C
Product: CC#Cc1ccc(OC)cc1SCc1ccccc1
Reaction time: 72 h
Yield: 69 %

Procedure:
When benzyl 2-iodo-5-methoxyphenyl sulfide (Flynn et al, Org. Lett. 2001, 3(5), 651) was substituted for 6-iodo-2-isopropoxy-3-methoxy-N-trifluoroacetylaniline in Step C of Example 38 and reaction time was extended to 72 h, the similar process provided the title compound in 69% yield as a creamy solid. 1H-NMR (CDCl3) 2.1 (s, 2H); 3.7 (s, 3H); 4.17 (s, 2H); 6.61 (dd, 1H, J=2.53, 8.5 Hz); 6.72 (d, 1H, J=2.53 Hz); 7.2-7.33 (m, 5H); 7.38 (d, 1H, J=8.5 Hz).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>CN(C=O)C>[C:4]([O:3][C:1]([NH:8][C@H:9]([CH2:10][O:11][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=1)[C:12]([OH:14])=[O:13])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](COCc1ccc(F)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of N—BOC-D-serine (2.00 g, 9.75 mmol) in DMF (25 ml) was cooled to 0° C. under nitrogen atmosphere and sodium hydride (60% in mineral oil) (0.82 g, 20.47 mmol) was added portionwise over 15 minutes. After stirring at 0° C. for 30 minutes, 4-fluorobenzyl bromide (1.82 g, 9.75 mmol) in DMF (5 ml) was added. The ice bath was removed and the reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc (100 ml) and water (50 ml). The aqueous phase was separated and washed with DCM (2×50 ml). The organic washings were discarded. The aqueous layer was acidified with 5% citric acid aqueous solution and back-extracted with DCM (2×100 ml). The combined organic portions were washed with brine (50 ml), dried (MgSO4) and concentrated in vacuo to yield the title compound as pale yellow oil.