Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[N:6]1[CH:11]=[CH:10][CH:9]=[N:8][C:7]=1[C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH:23]=2)=[N:16][CH:17]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][CH2:2][C:3]([N:21]1[CH2:22][CH:23]=[C:18]([C:15]2[CH:14]=[CH:13][C:12]([C:7]3[N:6]=[CH:11][CH:10]=[CH:9][N:8]=3)=[CH:17][N:16]=2)[CH2:19][CH2:20]1)=[O:4]
Reactant: C1=C(c2ccc(-c3ncccn3)cn2)CCNC1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1CC=C(c2ccc(-c3ncccn3)cn2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
Added chloroacetyl chloride (0.35 g, 4.39 mmol) in MeCl2 (15 ml) to a solution of 5-Pyrimidin-2-yl-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl (3Q) (0.4 g, 1.68 mmol) and triethylamine (0.4 g, 2.87 mmol) in MeCl2 (10 ml) at 0° C., then stirred 2 hours at 0° C. Added saturated NaHCO3 solution and stirred an additional hour at 0° C. MeCl2 (100 ml) was added, organic layer separated, dried over Na2SO4, filtered and solvent evaporated yielding 4Q as a pale yellow solid (0.53 g, 100%) ESMS (MH 315).
Reaction SMILES: [CH2:1]([N:8]1[N:12]=[N:11][C:10]([CH:13]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[N:12]=[N:11][C:10]([C:13]2([S:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(CCCCCO)c1nnn(Cc2ccccc2)n1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)C1(c2nnn(Cc3ccccc3)n2)CCCCC1
Temperature: 25 °C
Yield: 57.6 %

Procedure:
To a toluene (3 ml) solution of 6-(2-benzyl-2H-tetrazol-5-yl)-6-[(4-chlorophenyl)sulfonyl]-1-hexanol (145 mg, 0.33 mmol) was added a toluene (3 ml) solution of cyanomethylenetri-n-butylphosphorane (179 mg, 0.67 m=ol). The resulting mixture was heated under reflux for 7 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography and the fraction obtained from the hexane:ethyl acetate=4:1 eluate was concentrated under reduced pressure. The resulting solid was washed with hexane/diethyl ether and collected by filtration, whereby the title compound (78 mg, 0.19 mmol, 56%) was obtained as a white solid.
Reaction SMILES: [C:1]([O:4][C:5]1([CH2:8][O:9]C2CCCCO2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CO>[C:1]([O:4][C:5]1([CH2:8][OH:9])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1(COC2CCCCO2)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: CC(=O)OC1(CO)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 50.8 %

Procedure:
To a mixture of 1-((tetrahydro-2H-pyran-2-yloxy)methyl)cyclopropyl acetate (149 mg, 0.696 mmol) in 10 mL of methanol was added PPTS (18 mg, 0.07 mmol, Aldrich) in portions. After stirring for 5 hrs at rt, the mixture was quenched with 10 mL of water and extracted with dichloromethane (20 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE: EtOAc=10:1) to give the title compound as pale yellow oil (46 mg, 35.5%).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH:19]3[CH2:24][CH2:23][N:22]([CH:25]([CH3:29])[CH2:26][CH2:27][NH2:28])[CH2:21][CH2:20]3)[O:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)=[CH:6][CH:5]=1.[CH3:32][C:33]1[N:41]=[CH:40][CH:39]=[C:38]([CH3:42])[C:34]=1[C:35](O)=[O:36]>>[CH3:32][C:33]1[N:41]=[CH:40][CH:39]=[C:38]([CH3:42])[C:34]=1[C:35]([NH:28][CH2:27][CH2:26][CH:25]([N:22]1[CH2:21][CH2:20][CH:19]([C:10]2([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:30])[F:31])=[CH:5][CH:6]=3)[O:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)[CH2:24][CH2:23]1)[CH3:29])=[O:36]
Reactant: Cc1ccnc(C)c1C(=O)O
Reactant: CC(CCN)N1CCC(C2(c3ccc(OC(F)(F)F)cc3)Oc3ccccc3O2)CC1
Product: Cc1ccnc(C)c1C(=O)NCCC(C)N1CCC(C2(c3ccc(OC(F)(F)F)cc3)Oc3ccccc3O2)CC1
Yield: 31.1 %

Procedure:
Using general procedure E, 3-{4-[2-(4-trifluoromethoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine (see EXAMPLE 275) (135 mg, 0.31 mmol) and 2,4-dimethylnicotinic acid (51 mg, 0.34 mmol) afforded COMPOUND 276 (55 mg, 31%). 1H NMR (CDCl3) δ 0.83-1.17 (m, 2H), 0.95 (d, 3H, J=6.6 Hz), 1.46-1.63 (m, 3H), 1.67-1.80 (m, 1H), 1.86-1.99 (m, 2H), 2.31 (s, 3H), 2.33-2.40 (m, 1H), 2.54 (s, 3H), 2.67-2.81 (m, 3H), 3.25-3.35 (m, 1H), 3.79-3.89 (m, 1H), 6.76-6.86 (m, 4H), 6.99 (d, 1H, J=5.1 Hz), 7.17 (d, 2H, J=8.1 Hz), 7.40-7.44 (m, 2H), 8.11 (br s, 1H), 8.42 (d, 1H, J=4.8 Hz). 13C NMR (CDCl3) δ 13.57, 19.19, 22.63, 25.94, 26.56, 31.64, 40.02, 44.32, 45.92, 52.42, 60.54, 108.92, 118.07, 120.78, 121.86, 122.91, 127.68, 133.99, 138.89, 144.02, 147.35, 149.21, 149.76, 154.55, 168.73. ES-MS m/z 570 (M+H). Anal. Calcd. for C31H34N3F3O4.0.28CH2Cl2: C, 63.31; H, 5.87; N, 7.08. Found: C, 63.01; H, 5.88; N, 7.47.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:7]=[CH:6][S:5][CH:4]1[C:8]#[N:9].S(Cl)(Cl)(=O)=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]#[N:9]
Reactant: COC1C=CSC1C#N
Solvent: ClC(Cl)Cl
Solvent: O=S(=O)(Cl)Cl
Product: COc1ccsc1C#N
Yield: 91 %

Procedure:
14.1 parts of 3-methoxy-2-cyanodihydrothiophene in 80 parts by volume of chloroform are reacted with 6.75 parts of sulfuryl chloride in 20 parts by volume of chloroform for 0.5 hour at 0° C. The end product is isolated from the reaction mixture by the method described in Example 14(c). 12.6 parts (91% of theory) of 3-methoxy-2-cyanothiophene of boiling point 73° C./0.16 mbar are obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:32][CH:33]1[CH2:35][CH2:34]1>O1CCCC1>[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2NC1=O
Reactant: BrCC1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2N(CC2CC2)C1=O
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
To a solution of 0.6 g (2.2 mmol) (S)-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester in 10 ml of tetrahydrofuran at −75° C. 2.2 ml (2.2 mmol) of lithium bis(trimethylsilyl)amide solution (1M in tetrahydrofurane) was added. After stirring for 30 min at −75° C. the mixture was allowed to reach room temperature and 0.35 g (2.6 mmol) of bromomethyl-cyclopropane was added. The mixture was stirred for 2.5 hours at room temperature and concentrated in vacuo. The residue was distributed between 1M NaHSO4 solution and ethyl acetate. The combined organic layers were re-extracted with water and dried (MgSO4) to yield 0.285 g (40%) of ((S)-1-cyclopropylmethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[S:6][CH:7]=1.CCN(CC)CC.CS(Cl)(=O)=O.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C(Cl)Cl>[O:31]1[CH2:32][CH2:33][N:28]([CH2:2][C:3]2[N:4]=[C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[S:6][CH:7]=2)[CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)Nc1nc(CO)cs1
Reactant: C1COCCN1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(CN2CCOCC2)cs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
tert-Butyl 4-(hydroxymethyl)thiazol-2-ylcarbamate (57; 2.0 g, 8.7 mmol) was taken up in 25 mL of CH2Cl2 along with Et3N (1.82 mL, 13.05 mmol) and cooled to 0° C. Methanesulfonyl chloride (0.85 mL, 10.88 mmol) was added and the resulting reaction mixture was stirred at 0° C. for 60 min. Morpholine (48; 3.0 mL, 35 mmol) was then added and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was taken up in EtOAc and washed with dilute aqueous NaHCO3, brine, dried (Na2SO4) and concentrated under reduced pressure. This material was purified by filtering through a short column of silica gel. The filtrate was concentrated to afford 1.88 g of tert-butyl 4-(morpholinomethyl)thiazol-2-ylcarbamate 58. The Boc group was removed by treating tert-butyl 4-(morpholinomethyl)thiazol-2-ylcarbamate 58 with 20 mL of 25% TFA in CH2Cl2 for 18 h at room temperature. After all the solvent had been removed by concentrating and drying under high vacuum, the resulting residue was treated with a mixture of pentane/EtOAc to afford 2.17 g 4-(morpholinomethyl)thiazol-2-amine 59 as a white solid.
Reaction SMILES: [OH:1][C:2]1([C:20]([F:23])([F:22])[F:21])[C:14]2[CH:13]=[C:12]([C:15]([O:17]C)=[O:16])[CH:11]=[C:10]([CH3:19])[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.O1CCCC1.[OH-].[Na+]>CO>[OH:1][C:2]1([C:20]([F:21])([F:22])[F:23])[C:14]2[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=[C:10]([CH3:19])[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: COC(=O)c1cc(C)c2c(c1)C(O)(C(F)(F)F)c1ccccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(=O)O)cc2c1-c1ccccc1C2(O)C(F)(F)F
Temperature: 25 °C
Yield: 110.1 %

Procedure:
A mixture of methyl 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylate (1.000 g), tetrahydrofuran (4 ml), methanol (6 ml) and 4N aqueous sodium hydroxide solution (1.6 ml) was stirred with heating under reflux for 3 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. Water (30 ml) was added to the obtained residue, and the mixture was adjusted to pH 1 with 6N hydrochloric acid (2 ml), and extracted with ethyl acetate (30 ml). The organic layer was successively washed with water and saturated brine. After addition of anhydrous magnesium sulfate and activated carbon (0.2 g), the mixture was stirred at room temperature for 10 min. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (1.053 g). The residue was directly used for the next reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH:3]([N:7]1[CH:11]=[C:10]([C:12]2[C:13]3[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]=3[N:15]=[CH:16][N:17]=2)[CH:9]=[N:8]1)[CH2:4][C:5]#N.[H-].C([Al+]CC(C)C)C(C)C.C[OH:42].Cl>C(Cl)Cl.O>[F:1][C:2]([F:29])([F:30])[CH:3]([N:7]1[CH:11]=[C:10]([C:12]2[C:13]3[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[C:14]=3[N:15]=[CH:16][N:17]=2)[CH:9]=[N:8]1)[CH2:4][CH:5]=[O:42]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)C(F)(F)F)c3)ncnc21
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC=O)C(F)(F)F)c3)ncnc21
Temperature: -47.5 °C
Reaction time: 3 h
Yield: 46.8 %

Procedure:
To a −70° C. solution of 4,4,4-trifluoro-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo-[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile (1.06 g, 0.00243 mol) (see, Example 93, Step 1) in DCM (10 mL, 0.2 mol) was added 1.0 M diisobutylaluminum hydride in DCM (4.8 mL). The resulting mixture was stirred for 3 h and allowed to warm during this time interval from −70 to −25° C., after which the reaction was cooled back at −70° C. Methanol (1.5 mL, 0.037 mol) was added, followed by 2.0 M HCl in water (15 mL). Insoluble material was then filtered from the reaction mixture. The organic filtrate was washed sequentially with: 2.0 M HCl in water, water and saturated aqueous NaCl. The washed organic phase was dried over sodium sulfate and was concentrated using a rotory evaporator to give 0.58 g of the crude product as a pale yellow foam/solid. The crude product was chromatographed with 0-80% ethyl acetate/hexanes to give the purified product (0.5 g) as a pale orange oil (47% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH:26]([CH3:28])[CH3:27])=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])=[CH:13][C:12]([Cl:25])=[CH:11][CH:10]=2)=[O:5])C.[I-].[Li+]>N1C=CC=CC=1>[Cl:25][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:26]([CH3:28])[CH3:27])[C:6]([C:4]([OH:5])=[O:3])=[C:15]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24]
Reactant: CCOC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1Cc1ccccc1OC
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: COc1ccccc1Cc1c(C(=O)O)c(C(C)C)nc2ccc(Cl)cc12

Procedure:
The title compound was prepared in analogy to example 20 step D from 6-chloro-2-isopropyl-4-(2-methoxy-benzyl)-quinoline-3-carboxylic acid ethyl ester (80 mg, 0.2 mmol) and lithium iodide (134.5 mg, 1.01 mmol) in pyridine. Off white solid (24 mg, 32%). LC-MS (ESI): 368 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([Br:10])=[CH:5][C:6]=1[N+:7]([O-])=O.[C:11](OC(=O)C)(=[O:13])[CH3:12]>[Fe]>[Br:1][C:2]1[S:3][C:4]([Br:10])=[CH:5][C:6]=1[NH:7][C:11](=[O:13])[CH3:12]
Reactant: O=[N+]([O-])c1cc(Br)sc1Br
Reactant: CC(=O)OC(C)=O
Agent: [Fe]
Product: CC(=O)Nc1cc(Br)sc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
To an ice cold solution of 2,5-dibromo-3-nitrothiophene (5.0 g, 17.4 mmol, DellErba, C.; Spinelli, D. Tetrahedron, 1965, 21, 1061-1066) in acetic acid-acetic anhydride (1:1, 50 mL) was added iron powder (5.8 g, 104.5 mmol) slowly for 15 min. and stirred at rt for 4 h. After completion of the reaction, the reaction mixture was poured into ice cold water (500 mL) and stirred for 15 min. The precipitated solid was filtered, washed with water and dried. The crude product was chromatographed over silica gel column using hexane-EtOAc (95:5) as eluent to give the product as a white color solid (3.0 g, 58%), mp 114-116° C. 1H NMR (400 MHz, CDCl3): δ 7.78 (1H, s), 7.21 (1H, s), 2.20 (3H, s).
Reaction SMILES: OS(O)(=O)=O.[NH2:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]#[N:15])=[C:9]([CH3:16])[N:8]=1.[N+:17]([O-])([OH:19])=[O:18]>>[NH2:6][C:7]1[C:12]([N+:17]([O-:19])=[O:18])=[C:11]([CH3:13])[C:10]([C:14]#[N:15])=[C:9]([CH3:16])[N:8]=1
Reactant: Cc1cc(N)nc(C)c1C#N
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1nc(N)c([N+](=O)[O-])c(C)c1C#N
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 55.2 %

Procedure:
To 10 mL of H2SO4 (97%) kept in an ice-bath was added portionwise 2.45 g (16.6 mmol) of 2-amino-4,6-dimethyl-5-pyridinecarbonitrile (16) and it was stirred for 30 min. The resulting solution was heated at 55° C. and 1.2 mL (18.8 mmol) of HNO3 (d=1.41, 69-70%) was added dropwise. The solution was heated at 55°-60° C. for 3 h after addition of HNO3. It was cooled to room temperature and poured into 60 mL of ice-water. The yellow precipitate was filtered, washed with water, and dried to leave a yellow solid (1.76 g, 55%). 1H NMR (CDCl3), 2.612 (s, 3), 2.716 (s, 3), 6.51 (mb, 2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:12](=[CH:13][C:14]3[C:15]([CH3:23])=[N:16][CH:17]=[N:18][C:19]=3[C:20]=2[F:22])[N:11]([S:24]([C:27]2([CH2:30][CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:29][CH2:28]2)(=[O:26])=[O:25])C1=O.C[Si](C)(C)[O-].[K+]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:21]1[C:20]([F:22])=[C:19]2[C:14]([C:15]([CH3:23])=[N:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[NH:11][S:24]([C:27]1([CH2:30][CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[CH2:28][CH2:29]1)(=[O:25])=[O:26]
Reactant: Cc1ncnc2c(F)c3c(cc12)n(S(=O)(=O)C1(CCO[Si](C)(C)C(C)(C)C)CC1)c(=O)n3-c1ccc(I)cc1F
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ncnc2c(F)c(Nc3ccc(I)cc3F)c(NS(=O)(=O)C3(CCO[Si](C)(C)C(C)(C)C)CC3)cc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-(2-fluoro-4-iodophenyl)-1-(1-(2-(tert-butyldimethylsilyloxy)ethyl)cyclopropylsulfonyl)-4-fluoro-8-methyl-1H-imidazo[4,5-g]quinazolin-2(3H)-one (66 mg, 0.1 mmol) in THF (5 ml) is added potassium trimethylsilanolate (65 mg, 0.5 mmol). The resulting solution is stirred at room temperature for 24 h. The reaction is quenched with saturated aqueous NH4Cl solution (10 ml) and extracted with EtOAc (2×10 ml). The combined organic solution is washed with brine (10 ml), dried over MgSO4 and concentrated. Silica gel chromatography yields the desired product.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[C:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[O:22]=[C:20]1[NH:19][C:18](=[O:23])[C:17](=[CH:16][C:13]2[CH:12]=[CH:11][C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][N:2]([CH3:1])[C:31]([NH:30][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:32])[CH:5]=3)=[CH:15][CH:14]=2)[S:21]1
Reactant: CNCc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Reactant: O=C=Nc1ccccc1
Product: CN(Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)C(=O)Nc1ccccc1
Yield: 112.7 %

Procedure:
In a manner similar to that of Example 9(a) by reacting 300 mg (0.9 mmol) of 5-(3′-methylaminomethylbiphenyl-4-ylmethylene)thiazolidine-2,4-dione with 190 μl (1.8 mmol) of phenyl isocyanate, 450 mg (98%) of the expected product are obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][N:12]3[C:17]=2[C:16]([NH:18][C:19]2[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=2)[N:24]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=2)[N:23]=[CH:22]4)=[N:15][CH:14]=[N:13]3)[CH2:4][CH2:3]1.[O:36]1[CH2:40][CH2:39]OC1=O>C(Cl)Cl>[F:35][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=1)[CH2:28][N:24]1[C:25]2[C:21](=[CH:20][C:19]([NH:18][C:16]3[C:17]4=[C:9]([CH2:8][N:5]5[CH2:4][CH2:3][CH:2]([NH:1][CH2:39][CH2:40][OH:36])[CH2:7][CH2:6]5)[CH:10]=[CH:11][N:12]4[N:13]=[CH:14][N:15]=3)=[CH:27][CH:26]=2)[CH:22]=[N:23]1
Reactant: O=C1OCCO1
Reactant: NC1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Solvent: ClCCl
Product: OCCNC1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Temperature: 100 °C

Procedure:
A mixture of [5-(4-amino-piperidin-1-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-[1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine (188 mg, 0.4 mmole) and [1,3]dioxolan-2-one (352 mg, 10 equiv) in a sealed tube was heated at 100° C. for 3.5 h. The title compound was isolated by radial chromatography (2 mm silica gel plate, gradient elution with DCM containing 0 to 3% MeOH) afforded the title compound as a solid (43 mg, 21%); MS: 515 (M+H+); HPLC Ret Time: 1.29 min (YMC Xterra ODS S7 3.0×50 mm column, 2 min gradient, 5 ml/min).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][CH:24]([CH2:26][OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1>>[OH:27][CH2:26][CH:24]1[CH2:25][N:22]([C:3]2[C:2]([C:32]3[CH:33]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC(CO)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC(CO)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 128 using 5-bromo-6-(3-(hydroxymethyl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 135.1) and pyrimidin-5-ylboronic acid. HPLC (Condition 4) tR=4.6 min, UPLC-MS (Condition 3) tR=0.90 min, m/z=446.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.53-2.68 (m, 1H) 3.38-3.53 (m, 4H) 3.63-3.77 (m, 2H) 4.68 (t, J=1.00 Hz, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.83 (d, J=8.99 Hz, 2H) 8.05 (d, J=1.96 Hz, 1H) 8.77 (d, J=1.00 Hz, 1H) 8.89 (s, 2H) 9.15-9.31 (m, 1H) 10.18 (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(OCCBr)cc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(OCCN2CCOCC2)cc1
Temperature: 80 °C
Yield: 84 %

Procedure:
Into a 30 mL vial, [A] 1-(2-Bromo-ethoxy)-4-nitro-benzene (5.00 g, 0.0203 mol), Morpholine (3.54 mL, 0.0406 mol), Acetonitrile (15.0 mL, 0.287 mol) and Potassium carbonate (5.62 g, 0.0406 mol) were added. The reaction was heated at 80° C. for 4 hours. The reaction was partitioned with water (250 mL). The solid was filtered and washed with water. The resulting solid was dried under vacuum overnight to give 4-[2-(4-Nitrophenoxy)-ethyl]-morpholine as an off-white solid (4.30 g, 84%). NMR 1H (DSMO-d6)-8.20 (d, 1H, J=9.34 Hz), 7.17 (d, 2H, J=9.34 Hz), 4.24 (t, 2H, J=5.65 Hz), 3.57 (t, 4H, J=4.60 Hz), 2.72 (t, 2H, J=4.68 Hz), 2.47 (t, 4H, J=4.52 Hz),
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])[CH:5]=[N:6][C:7]=1[CH3:8].[H-].[Na+].[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31](Br)[CH3:32])[N:26]=1>CN(C)C=O>[Br:24][C:25]1[N:26]=[C:27]([CH:31]([N:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20](=[O:21])[C:11]([C:9]([C:4]3[CH:5]=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)=[O:10])=[CH:12]2)[CH3:32])[CH:28]=[CH:29][CH:30]=1
Reactant: Cc1cc(C(=O)c2c[nH]c3ccccc3c2=O)cnc1C
Reactant: CC(Br)c1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cn(C(C)c3cccc(Br)n3)c3ccccc3c2=O)cnc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 55 mg (0.20 mmol) of 3-(5,6-dimethyl-pyridine-3-carbonyl)-1H-quinolin-4-one, 10 mg (0.26 mmol) of 60% sodium hydride, 68 mg (0.26 mmol) of 2-bromo-6-(1-bromo-ethyl)-pyridine and 0.7 mL of N,N-dimethylformamide. Yield: 24 mg of a white solid: LC-MSD, m/z for C24H20BrN3O2 [M+H]+=462.0, 464.0; HPLC retention time: 1.4 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH:13]=[CH2:14])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][SiH:18]([CH3:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[Pt](=O)=O>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][Si:18]([CH3:25])([CH3:17])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[SiH](C)c1ccccc1
Reactant: C=C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: O=[Pt]=O
Product: CC(C)(C)OC(=O)N1[C@@H](CC[Si](C)(C)c2ccccc2)COC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
(S)-2,2-Dimethyl-4-vinyl-oxazolidine-3-carboxylic acid tert-butyl ester (750 mg; CAS 133625-87-3) was dissolved in dimethylphenylsilane (25 ml), platinum(IV)-oxide (187 mg) was added and the mixture was stirred overnight at room temperature. The catalyst was filtered off and the filtrate was evaporated in vacuo. The crude product was purified by column chromatography (SiO2; heptane/ethyl acetate=4:1) to give (S)-4-[2-(dimethyl-phenyl-silanyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.14 g, 95%) as colourless oil, which was used directly for the next step.