Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([N:10]1[CH:14]=[C:13]([C:15]2[C:16]3[CH:23]=[CH:22][N:21](COCC[Si](C)(C)C)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH:12]=[N:11]1)[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40](Cl)(=[O:42])=[O:41])#[N:33]>>[N:18]1[C:17]2[NH:21][CH:22]=[CH:23][C:16]=2[C:15]([C:13]2[CH:12]=[N:11][N:10]([CH:2]([CH3:1])[CH2:3][N:4]3[CH2:5][CH2:6][N:7]([S:40]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[C:32]#[N:33])(=[O:42])=[O:41])[CH2:8][CH2:9]3)[CH:14]=2)=[N:20][CH:19]=1
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: CC(CN1CCNCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Product: CC(CN1CCN(S(=O)(=O)c2ccccc2C#N)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1

Procedure:
This compound was prepared according to the procedure of Example 92, using 4-[1-(1-methyl-2-piperazin-1-ylethyl)-1H-pyrazol-4-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine and 2-cyanobenzenesulfonyl chloride as the starting materials. 1H NMR (300 MHz, DMSO-D6): δ 12.05 (s, 1H); 8.61 (s, 1H); 8.58 (s, 1H); 8.21 (s, 1H); 8.07 (m, 1H); 7.95-7.78 (m, 3H); 7.53 (m, 1H); 6.88 (d, 1H); 4.62 (m, 1H); 2.98 (m, 4H); 2.82 (m, 1H); 2.59 (m, 3H); 2.36 (m, 2H); 1.40 (d, 3H); LCMS calculated for C23H25N8O2S(M+H)+: m/z=477.0.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:22])=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.[CH3:23][N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]1.CC([O-])(C)C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:22][C:3]1[C:2]([O:31][CH2:30][CH:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)=[N:7][N:6]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=3)=[CH:9][N:10]=[C:5]2[CH:4]=1
Reactant: Cc1cc2ncc(-c3cccc(OC(F)(F)F)c3)n2nc1Cl
Reactant: CN1CCC(CO)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cc2ncc(-c3cccc(OC(F)(F)F)c3)n2nc1OCC1CCN(C)CC1
Temperature: 165 °C
Yield: 118.4 %

Procedure:
To the toluene (5 mL) solvent was added Compound 11 (80 mg, 0.224 mmol), (1-methylpiperidine-4-yl)methanol 14 (47.3 mg, 0.366 mmol), ligand (14.41 mg, 0.037 mmol), NaOtBu (33.3 mg, 0.347 mmol) and Pd2(dba)3 (16.77, 0.018 mmol). The resulting reaction mixture was degassed for 10 min under argon and then was heated with microwave at 165° C. Concentration and preparative TLC (10% MeOH/DCM) afforded 111.5 mg (11.2%) of Compound 7-34.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].CCCCCC.[CH2:17]([C@H:24]1[CH2:28][O:27][C:26](=[O:29])[N:25]1[C:30](=[O:35])[CH2:31][CH2:32][CH2:33][CH3:34])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Br[CH2:37]/[CH:38]=[CH:39]/[CH2:40][O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:17]([C@H:24]1[CH2:28][O:27][C:26](=[O:29])[N:25]1[C:30](=[O:35])[C@H:31]([CH2:32][CH2:33][CH3:34])[CH2:37]/[CH:38]=[CH:39]/[CH2:40][O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: BrC/C=C/COCc1ccccc1
Reactant: CCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC[C@H](C/C=C/COCc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
165 ml of a solution of sodium bis(trimethylsilyl)amide in n-hexane (1.03 mol/l) (169 mmol) was added to a solution of 37.0 g of (S)-4-benzyl-3-pentanoyloxazolidin-2-one obtained in Reference Example 6 (142 mmol) in tetrahydrofuran (330 ml) under a nitrogen atmosphere and at −78° C. over 45 minutes, and the mixture was stirred at the same temperature for 30 minutes. Then, a solution of 35.8 g of [(E)-4-bromobut-2-enyloxymethyl]benzene obtained in Reference Example 4 (148 mmol) in tetrahydrofuran (80 ml) was added to the solution obtained above over 30 minutes, and the mixture was stirred at the same temperature for 30 minutes. Thereafter, the mixture was raised to −40° C. and further stirred for four hours. 90 ml of an ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was further stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure and diluted with 500 ml of water, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=7/1-2/1) to obtain 47.3 g of the title compound (yield: 79%).
Reaction SMILES: [H][H].C([O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])=[CH:13][CH:12]=1)C1C=CC=CC=1>[Pd].C(O)(=O)C>[C:22]1(=[O:31])[N:21]([CH2:20][CH2:19][CH2:18][O:17][C:14]2[CH:15]=[CH:16][C:11]([OH:10])=[CH:12][CH:13]=2)[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]12
Reactant: O=C1c2ccccc2C(=O)N1CCCOc1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1CCCOc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a hydrogen bottle containing 0.5 g of 10% palladium on carbon and acetic acid (250 ml) was added the above 1-benzyloxy-4-(3-phthalimidopropoxy)benzene (16 g). The mixture was shaken at 50° in the Parr hydrogenation apparatus for about 4 hours and cooled to room temperature. The mixture was filtered and the solvent distilled in vacuo. The residue was crystallized from toluene to yield 10.8 g (88%), mp 135°-7° of 4-(3-phthalimidopropoxy)phenol.
Reaction SMILES: [C:1]1([C:16]([OH:17])=[C:12]([N+:13]([O-:15])=[O:14])[CH:11]=[C:7]([N+:8]([O-:10])=[O:9])[C:5]=1[OH:6])[N+:2]([O-:4])=[O:3].C(=O)([O-])[O-].[Mg+2:22]>O>[C:1]1([C:5]([O-:6])=[C:7]([N+:8]([O-:10])=[O:9])[CH:11]=[C:12]([N+:13]([O-:15])=[O:14])[C:16]=1[O-:17])[N+:2]([O-:4])=[O:3].[Mg+2:22]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1O
Agent: O=C([O-])[O-]
Agent: [Mg+2]
Solvent: O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c([O-])c([N+](=O)[O-])c1[O-]
Temperature: 45 °C

Procedure:
A magnesium styphnate solution was prepared by the steps of adding 27.5 kg (dry weight) of styphnic acid to 70 liters of distilled water, warming the solution to 45°C, and then adding 11.3 Kg magnesium carbonate (heavy) in small quantities with stirring. The temperature was increased to 55°-60°C and stirring was continued until solution was complete. The solution was cooled, the volume adjusted to 110 liters, filtered and the pH was found to be above 7.2. An analysis of this solution showed that it contained 245g styphnate ion (as styphnic acid) per liter. 330 ml of nitric acid (sp gr 1.42) was then added with stirring.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].C(O[C:20]([N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]([NH:31][C:32]2[CH:33]=[CH:34][C:35]3[NH:36][C:37]4[N:53]=[C:41]([NH:42][C:43]5[CH:44]=[CH:45][CH:46]=[C:47]([CH:52]=5)[CH2:48][CH2:49][C:50]=2[CH:51]=3)[N:40]=[CH:39][C:38]=4[Cl:54])=[O:30])[CH2:24][CH2:23]1)=[O:21])(C)(C)C.[CH3:55][C:56]1[O:60][N:59]=[C:58](C(Cl)=O)[CH:57]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:54][C:38]1[CH:39]=[N:40][C:41]2[NH:42][C:43]3[CH:44]=[CH:45][CH:46]=[C:47]([CH:52]=3)[CH2:48][CH2:49][C:50]3[CH:51]=[C:35]([NH:36][C:37]=1[N:53]=2)[CH:34]=[CH:33][C:32]=3[NH:31][C:29](=[O:30])[CH2:28][N:25]1[CH2:26][CH2:27][N:22]([C:20]([C:58]2[CH:57]=[C:56]([CH3:55])[O:60][N:59]=2)=[O:21])[CH2:23][CH2:24]1
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2CCN(CC(=O)Nc3ccc4cc3CCc3cccc(c3)Nc3ncc(Cl)c(n3)N4)CC2)no1
Yield: 56 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using tert-butyl-4-(2-[{6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}-2-oxoethyl)piperazine-1-carboxylate bis(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as starting materials in 56% yield. LCMS for C29H30ClN8O3 (M+H)+: m/z=573.2.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=O)[O:3]1.[CH3:23][S:24]([NH2:27])(=[O:26])=[O:25]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4]([NH:27][S:24]([CH3:23])(=[O:26])=[O:25])=[O:3])=[CH:15][CH:16]=1
Reactant: CS(N)(=O)=O
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Product: CON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)NS(C)(=O)=O
Yield: 29 %

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide was treated with methane sulfonamide as described in the preparation of compound 1 to yield 100 mg solid (29% yield), mp=137° C. (decomposition). HRMS (M−H) cacld for C13H14FN2O6S: 345.056. Found: 345.0570. Anal calcd for C13H15FN2O6S: C, 45.08; H, 4.36; N, 8.08. Found: C, 45.20; H, 4.29; N, 7.92. 1H NMR (500 MHz, CDCl3) δ: 3.36 (s, 3), 3.71 (s, 3), 4.81 (s, 2), 6.56 (s, 1), 7.04 (m, 2), 7.32 (m, 2), 8.97 (s, 1). 13C NMR (125 MHz, CDCl3) δ: 41.60, 48.27, 63.16, 92.57, 115.65, 115.81, 130.19, 130.24, 130.97, 158.99, 160.05, 161.65, 163.61, 170.79.
Reaction SMILES: [CH3:1][O:2][C:3](Cl)=[O:4].[NH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH:17]([OH:23])[CH2:18][NH:19][CH:20]([CH3:22])[CH3:21])=[N:13][CH:14]=1>C(O)(C)C.O>[CH:20]([NH:19][CH2:18][CH:17]([OH:23])[CH2:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][NH:6][C:3]([O:2][CH3:1])=[O:4])=[CH:14][N:13]=1)([CH3:22])[CH3:21]
Reactant: CC(C)NCC(O)COc1ccc(CCN)cn1
Reactant: COC(=O)Cl
Solvent: O
Solvent: CC(C)O
Product: COC(=O)NCCc1ccc(OCC(O)CNC(C)C)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.4 ml of chloroformic acid methyl ester are added dropwise, whilst stirring, to 12.4 g of 5-(2'-aminoethyl)-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyridine, dissolved in a mixture of 45 ml of isopropanol and 45 ml of water, at a temperature of 20°-35° C., with cooling by means of ice water, if necessary. The reaction mixture is stirred further for one hour at room temperature and is evaporated in vacuo, and the evaporation residue is dissolved in approx. 30 ml of water. This solution is extracted with 20 ml of ethyl acetate and the acid aqueous phase is rendered alkaline with concentrated sodium hydroxide solution. The oil which precipitates is extracted with dichloromethane. After drying the solution over magnesium sulphate and evaporating off the solvent, 2-(3'-isopropylamino-2'-hydroxy-propoxy)-5-(2'-methoxycarbonylaminoethyl)-pyridine is obtained, melting at 97°-99° C. after recrystallisation from a little butanone.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:5]=1[CH:6]=[O:7].[N+:13]([CH3:16])([O-:15])=[O:14].C(O)(=O)C>CO.C(OCC)C>[F:3][C:4]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:5]=1[CH:6]([OH:7])[CH2:16][N+:13]([O-:15])=[O:14]
Reactant: O=Cc1cc(F)ccc1F
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: CC(=O)O
Product: O=[N+]([O-])CC(O)c1cc(F)ccc1F

Procedure:
To sodium hydroxide (1N, 3L) and methanol (1500 mL) at 5° C. was added a solution of 2,5-difluorobenzaldehyde (350 g, 2.46 mol) and nitromethane (157 mL, 2.9 mol) in methanol (350 mL) dropwise over a period of 1 h. The reaction mixture was then neutralized with glacial acetic acid (165 mL). Diethyl ether (1500 mL) was added and the layers separated. The organic layer was washed successively with saturated aqueous sodium carbonate solution (1000 mL), and saturated aqueous brine (1000 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to afford 1-(2,5-difluorophenyl)-2-nitroethanol that was used without further purification in Step B.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[NH2:7][C:8]1[C:13]2=[C:14]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=4)=[O:27])=[CH:21][CH:20]=3)[C:15]([CH:17]=O)=[CH:16][N:12]2[N:11]=[CH:10][N:9]=1.O>O1CCOCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:7][C:8]1[C:13]2=[C:14]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=4)=[O:27])=[CH:21][CH:20]=3)[C:15]([CH:17]=[CH2:1])=[CH:16][N:12]2[N:11]=[CH:10][N:9]=1
Reactant: CC(C)(C)[O-]
Reactant: Nc1ncnn2cc(C=O)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccn4)cc3)c12
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1cn2ncnc(N)c2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium tert-butoxide (1.0 g, 9.06 mmol) was suspended in 1,4-dioxane (20 mL) and treated with methyltriphenylphosphonium bromide (3.2 g, 9.06 mmol). The mixture was allowed to stir at rt for 30 min. A yellow suspension formed then Intermediate AF (1-[4-(4-amino-6-formylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-3-[4-(trifluoromethyl)-pyridin-2-yl]urea) (2.0 g, 4.53 mmol) in 1,4-dioxane (10 mL) was slowly added and the reaction was stirred at rt for 4 hr. The reaction was slowly poured into vigorously stirring water. The mixture was allowed to stir for 1 hr. The solid was filtered and rinsed with water and MeOH. A light brown solid was isolated (1.2 g, 60%). 1H-NMR (DMSO-d6) δ 9.90 (s, 1H), 9.77 (s, 1H), 8.53 (d, J=5.2 Hz, 1H), 8.06-8.05 (m, 2H), 7.84 (s, 1H), 7.64 (d, J=8.5 Hz, 2H), 7.36 (d, J=5.4 Hz, 1H), 7.31 (d, J=8.5 Hz, 2H), 6.39 (dd, J1=11.3, J2=17.6 Hz, 1H), 5.63 (dd, J1=1.7, J2=17.5 Hz, 1H), 5.12 (dd, J1=1.5, J2=11.1 Hz, 2H). MS [M+H]+=440.0; LCMS RT=2.88.
Reaction SMILES: [NH2:1][C:2]1[N:14]=[C:5]2[N:6]=[C:7]([O:12][CH3:13])[CH:8]=[C:9]([O:10][CH3:11])[N:4]2[N:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[S:23](Cl)(=[O:25])=[O:24].N1C=CC=CC=1.CS(C)=O>C(#N)C>[CH3:13][O:12][C:7]1[CH:8]=[C:9]([O:10][CH3:11])[N:4]2[N:3]=[C:2]([NH:1][S:23]([C:17]3[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:16]=3[Cl:15])(=[O:25])=[O:24])[N:14]=[C:5]2[N:6]=1
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Reactant: COc1cc(OC)n2nc(N)nc2n1
Solvent: CS(C)=O
Solvent: c1ccncc1
Solvent: CC#N
Product: COc1cc(OC)n2nc(NS(=O)(=O)c3c(Cl)cccc3Cl)nc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.8 %

Procedure:
2-Amino-5,7-dimethoxy[1,2,4]triazolo[1,5-a]-pyrimidine (0.75 g, 3.8 mmol) and 2,6-dichlorobenzene-sulfonyl chloride (1.86 g, 7.6 mmol) were mixed in dry acetonitrile (15 mL). To this mixture was added dry pyridine (0.61 mL) and dry DMSO (54 μL, 0.7 mmol). The mixture was allowed to stir at room temperature. After 24 hours, the solvent was removed in vacuo, the residue was partitioned between CH2Cl2 (300 mL) and 2N HCl and the solids were collected by vacuum filtration to give a white solid A. The CH2Cl2 was dried (MgSO4) and removed in vacuo to give a white solid B. Both HPLC and NMR indicated that solid A and B are product. The solids were combined to afford the product as a white powder (1.41 g, 92%). mp 211-213° C. Anal: Cacld for C13H11Cl2N5O4S: C, 38.63; H, 2.74; N, 17.33; S, 7.93; found: C, 38.11; H, 2.68; N, 16.83; S, 7.77. 1H NMR (DMSO-d6): δ 12.4 (bs, 1H); 7.64-7.54 (m, 3H); 6.26 (s, 1H); 4.07 (s, 3H); 3.88 (s, 3H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[O:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=O)[CH2:13][CH2:12]1>>[F:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:14]1[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[O:11][CH2:12][C:13]2=1
Reactant: O=C1CCOc2ccccc21
Reactant: NNc1ccc(F)cc1
Agent: Cl
Product: Fc1ccc2[nH]c3c(c2c1)COc1ccccc1-3

Procedure:
Following the procedure described in Example 4, using (4-fluoro-phenyl)-hydrazine hydrochloride salt and chroman-4-one (2.5 g, 17 mmol) as the starting material, the title compound was prepared as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH2:16]O)[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>C(#N)C>[Cl:20][CH2:16][C:14]1[CH:15]=[C:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[O:9])[CH:11]=[N:12][CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(c1ccc(F)cc1)c1cncc(CO)c1
Solvent: CC#N
Product: O=C(c1ccc(F)cc1)c1cncc(CCl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
To a solution of (4-fluoro-phenyl)-(5-hydroxymethyl-pyridin-3-yl)-methanone (1I) (410 mg, 1.8 mmol) in 25 mL of acetonitrile at 0° C., is added thionyl chloride (0.65 mL, 8.9 mmol) drop wise. After being stirred at room temperature for 2 hours, the reaction mixture is concentrated to remove most of thionyl chloride and acetonitrile. The residue is dissolved in 30 mL of CH2Cl2 and basified by saturated sodium bicarbonate to PH˜8.0. The organic layer is dried over sodium sulfate and concentrated to give (5-chloromethyl-pyridin-3-yl)-(4-fluoro-phenyl)-methanone (1J) (390 mg, yield 87%) as light yellow waxy solid. MS (ESI) m/e 250 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.[CH2:22]([N:24]=[C:25]=[O:26])[CH3:23]>ClCCl>[CH2:22]([NH:24][C:25]([NH:1][CH2:2][CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1)=[O:26])[CH3:23]
Reactant: CCN=C=O
Reactant: CC(C)(C)OC(=O)NC(CN)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: CCNC(=O)NCC(NC(=O)OC(C)(C)C)c1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
A solution of 500 mg (1.64 mmol) of the compound from Example 101A in 15 ml of dichloromethane was admixed at 0° C. with 260 μl (3.29 mmol) of ethyl isocyanate. The ice bath was removed and the reaction mixture was stirred for a further 1 h. Then all of the volatile constituents were removed on a rotary evaporator. The residue was purified by preparative HPLC [Method 23]. The product fraction was freed from the solvent on a rotary evaporator. Drying of the residue in an HV gave 546 mg (89% of theory) of the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C=[CH: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][CH2:24][CH2:25][CH:26]([C:32]([O:34]CC)=O)[C:27]([O:29]CC)=O.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH3:54]COCC>>[CH2:54]=[C:24]([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8])[CH2:25][CH:26]([CH2:27][OH:29])[CH2:32][OH:34]
Reactant: CCOCC
Reactant: C=CCCCCCCCCCCCCCCCCCC(C(=O)OCC)C(=O)OCC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Product: C=C(CCCCCCCCCCCCCCCC)CC(CO)CO
Temperature: 25 °C

Procedure:
A solution of 1.03 g of lithium aluminum hydride in 50 ml of ether is cooled in a water bath. A mixture of 6.78 g of 2-(methyleneoctadecyl)propanedioic acid, diethyl ester in 50 ml of ether is added. This mixture is stirred at reflux for 2 hours, then overnight at room temperature and finally at reflux for 4 hours. The mixture is stirred with sodium sulfate decahydrate, then filtered and recrystallized from ethyl acetate/hexane, to give 4.87 g of the desired compound as white crystals, mp. 64°-65° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.[NH2:51][C:52]1[C:61]2[C:56](=[CH:57][CH:58]=[C:59]([O:62][Si:63]([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64])[CH:60]=2)[C:55]([Br:70])=[CH:54][CH:53]=1.C(N(CC)C(C)C)(C)C>>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:10][CH2:11][S:12][CH3:13])[C:14]([NH:51][C:52]1[C:61]2[C:56](=[CH:57][CH:58]=[C:59]([O:62][Si:63]([C:66]([CH3:68])([CH3:67])[CH3:69])([CH3:64])[CH3:65])[CH:60]=2)[C:55]([Br:70])=[CH:54][CH:53]=1)=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(Br)ccc(N)c2c1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Product: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Br)c2ccc(O[Si](C)(C)C(C)(C)C)cc12
Reaction time: 3 h

Procedure:
To (R)-N-(tert-butoxycarbonyl)methionine (1.33 g, 5.48 mmol) in dry H2Cl2 (5 mL) under argon were added PYBOP (2.85 g, 5.48 mmol), 1-amino-4-bromo-7-(tert-butyldimethylsilyloxy)naphthalene hydrochloride, as described above Step E, (800 mg, 2.19 mmol), and N,N-diisopropylethylamine (1.7 mL, 9.9 mmol). The reaction mixture was stirred for 3 hours, then partitioned between 10% aqueous citric acid (100 mL) and CH2Cl2 (100 mL). The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of hexane—5% EtOAc to hexane—20% EtOAc to yield the product as a pale foam.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8]([S:10][CH2:11][C:12]3[N:17]=[C:16]([NH2:18])[CH:15]=[CH:14][CH:13]=3)=[N:9][C:5]=2[CH:4]=1.[OH2:21]>>[OH:1][CH2:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8]([S:10]([CH2:11][C:12]3[N:17]=[C:16]([NH2:18])[CH:15]=[CH:14][CH:13]=3)=[O:21])=[N:9][C:5]=2[CH:4]=1
Reactant: Nc1cccc(CSc2nc3cc(CO)ccc3[nH]2)n1
Reactant: O
Product: Nc1cccc(CS(=O)c2nc3cc(CO)ccc3[nH]2)n1

Procedure:
The title compound was prepared by the method of Example 85 using 350 mg of 6-[[[5-(hydroxymethyl)-1H-benzimidazol-2-yl]thio]methyl]-2-pyridinamine (see Example 104) instead of 6-[(1H-benzimidazol-2-ylthio)methyl]-2-pyridinamine. Structure assignment was supported by the nmr and infrared spectra and by elemental analysis. Analysis. Calc'd. for C14H14N4SO2*¼ H2O: C, 54.80; H,4.60; N, 18.25; S, 10.44. Found: C, 54.85; H, 4.70; N, 18.01; S, 10.26.
Reaction SMILES: C([N:4](CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].[CH3:36][N:37]1[CH2:42][CH2:41][CH:40]([C:43]2[CH:48]=[CH:47][C:46]([NH:49][C:50]3[N:51]=[CH:52][C:53]4[S:58][C:57]([C:59]([OH:61])=O)=[C:56]([C:62]5[CH:63]=[N:64][NH:65][CH:66]=5)[C:54]=4[N:55]=3)=[C:45]([O:67][CH:68]([CH3:70])[CH3:69])[CH:44]=2)[CH2:39][CH2:38]1>CN(C)C=O.CO>[CH3:36][N:37]1[CH2:38][CH2:39][CH:40]([C:43]2[CH:48]=[CH:47][C:46]([NH:49][C:50]3[N:51]=[CH:52][C:53]4[S:58][C:57]([C:59]([NH2:4])=[O:61])=[C:56]([C:62]5[CH:66]=[N:65][NH:64][CH:63]=5)[C:54]=4[N:55]=3)=[C:45]([O:67][CH:68]([CH3:70])[CH3:69])[CH:44]=2)[CH2:41][CH2:42]1
Reactant: CC(C)Oc1cc(C2CCN(C)CC2)ccc1Nc1ncc2sc(C(=O)O)c(-c3cn[nH]c3)c2n1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)Oc1cc(C2CCN(C)CC2)ccc1Nc1ncc2sc(C(N)=O)c(-c3cn[nH]c3)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.7 %

Procedure:
123 mg of N,N-diisopropylethylamine, 181 mg of HATU and 14 mg of ammonium chloride are added to a solution of 117 mg of 2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-6-carboxylic acid in 6 ml of dimethylformamide. The reaction medium is stirred for 16 hours at ambient temperature and then concentrated to dryness under reduced pressure. Purification is carried out by flash chromatography on alumina, elution being carried out with a mixture of dichloromethane and methanol (+10% NH4OH) (95/5). The product resulting from the column purification is taken up in methanol and is purified by preparative thin layer chromatography (eluent: dichloromethane/methanol (+10% NH4OH) (95/5)), so as to give 23 mg of 2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}-7-(1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-6-carboxamide in the form of a yellow solid.