Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:10][C:9](O[Si](C)(C)C)=[C:8](O[Si](C)(C)C)[CH2:7][C:6]=1[C:21]([O:23][CH3:24])=[O:22])=[O:4].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:4])[C:5]1[C:6](=[CH:7][C:8]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:9]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:10]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)C1=C(C(=O)OC)CC(O[Si](C)(C)C)=C(O[Si](C)(C)C)C1
Reactant: Nc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)c1cc(Nc2ccccc2)c(Nc2ccccc2)cc1C(=O)OC

Procedure:
A solution of 5.6 g (15 mmol) of 4,5-bis(trimethylsilyloxy)cyclohexa 1,4-diene- 1,2-dicarboxylic acid dimethyl ester and 5.5 ml (60 mmol) of aniline in 60 ml of glacial acetic acid is boiled under reflux for 4 hours. The reaction mixture is cooled, the solvent is evaporated off and the dark-brown residue is dissolved in dichloromethane and the solution is washed in succession with 20 ml of 1N HCl, 50 ml of saturated NaHCO3 and twice with 20 ml of water, dried With sodium sulfate and concentrated by evaporation. The crude product is recrystallized from ethanol, yielding the title compound in the form of yellow crystals, m.p. 178°, FAB-MS: 377 [M+ +H].
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([C:11](=O)/[CH:12]=[CH:13]/[N:14](C)C)[CH:8]=[CH:7][C:6]=1[S:18]([CH3:21])(=[O:20])=[O:19])(=O)C.[NH:22]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][N:31]=1)[C:27]#[N:28])N>CCO.CC(O)=O>[CH3:1][O:4][C:5]1[CH:10]=[C:9]([C:11]2[N:22]([C:24]3[CH:25]=[C:26]([C:27]#[N:28])[CH:29]=[CH:30][N:31]=3)[N:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:6]=1[S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: CC(=O)Oc1cc(C(=O)/C=C/N(C)C)ccc1S(C)(=O)=O
Reactant: N#Cc1ccnc(NN)c1
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(-c2ccnn2-c2cc(C#N)ccn2)ccc1S(C)(=O)=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 14.4 %

Procedure:
A mixture of 5-[(2E)-3-(dimethylamino)prop-2-enoyl]-2-(methylsulfonyl)phenyl acetate (1.5 g, 5.3 mmol) and 2-hydrazinylisonicotinonitrile (0.8 g, 6 mmol, PREPARATION 2) in EtOH (15 mL) and AcOH (3 mL) was stirred at 90° C. overnight. The reaction mixture was cooled, concentrated, and purified by prep-HPLC to afford the title compound (270 mg, 14%).
Reaction SMILES: I[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C1([Mg]Br)C=CC=CC=1.[CH:22](=[O:26])[CH:23]([CH3:25])[CH3:24]>C1COCC1>[N+:11]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH:22]([OH:26])[CH:23]([CH3:25])[CH3:24])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1I
Reactant: CC(C)C=O
Agent: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CC(C)C(O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 30 %

Procedure:
To a solution of 1-iodo-2,6-dinitrobenzene (Smith and Ho, 1990), which is incorporated herein by reference) (1.55 g, 5.27 mmol) in anhydrous THF (18 mL) at minus 50° C. under a nitrogen atmosphere, phenylmagnesium bromide (2 M in THF, 3.2 mL, 6.4 mmol) was added dropwise at a rate such that the temperature would not exceed minus 45° C. Upon completion of the addition, the mixture was stirred at minus 50° C. for five min, followed by addition of isobutyraldehyde (0.96 mL, 11 mmol). The mixture was gradually warmed up to room temperature, quenched with saturated NH4Cl solution (10 mL), and then diluted with water (50 mL). The mixture was extracted with CH2Cl2 (100 mL) three times. The combined organic phase was washed with brine (50 mL), dried over Na2SO4, concentrated in vacuo, and the residue was purified by silica gel column chromatography to yield (R/S)-1-(2,6-dinitrophenyl)-2-methyl-1-propanol (0.375 g, 30%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.82 (d, 2H, J=8.0 Hz, Ph-H), 7.59 (t, 1H, J=8.0 Hz, Ph-H), 4.83 (dd, 1H, J=9.2 and 7.6 Hz, Ph-CH), 2.87 (d, 1H, J=7.6 Hz, OH), 2.19 (m, 1H, CH), 1.12 (d, 3H, J=6.4 Hz, CH3), 0.76 (d, 3H, J=6.8 Hz, CH3).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[N:13][C:12]([CH3:15])=[CH:11][N:10]=2)[C:6](=[S:16])[NH:5][C:4](=[O:17])[CH:3]=1.[N:18]([O-])=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)(=O)C.O>[NH2:18][C:3]1[C:4](=[O:17])[NH:5][C:6](=[S:16])[N:7]([CH2:8][C:9]2[CH:14]=[N:13][C:12]([CH3:15])=[CH:11][N:10]=2)[C:2]=1[NH2:1]
Reactant: Cc1cnc(Cn2c(N)cc(=O)[nH]c2=S)cn1
Reactant: O=N[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cnc(Cn2c(N)c(N)c(=O)[nH]c2=S)cn1
Reaction time: 2 h
Yield: 56.8 %

Procedure:
To 6-amino-1-[(5-methylpyrazin-2-yl)methyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (0.50 g, 2.00 mmol, obtained from Example 14(b)) in 90% acetic acid (7 mL) was added, dropwise, a solution of sodium nitrite (0.14 g, 2.1 mmol) in water (1 mL). After 2 h, sodium dithionite (1.0 g, 5.0 mmol) was added and after another 2 h the mixture was concentrated in vacuo providing the title compound (0.30 g, 57% yield) as a yellow solid. This was used without further purification.
Reaction SMILES: [CH2:1]([OH:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>N1C=CC=CC=1>[CH2:1]([O:21][S:28]([C:25]1[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=1)(=[O:30])=[O:29])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 4 h

Procedure:
(5Z,8Z,11Z,14Z)-Icosa-5,8,11,14-tetraen-1-ol (0.58 g, 1.997 mmol) was dissolved in pyridine (8 mL) and to this solution p-toluenesulfonyl chloride (0.762 g, 3.99 mmol) was added at 0° C. (ice-bath) and the reaction mixture was stirred under nitrogen for 4 h as the temperature was slowly allowed to rise to room temperature. The solvent was then removed under reduced pressure and the crude was purified on silica gel column chromatography using 5%-10% ethyl/hexane giving the title product as a clear oil (0.551 g, 62%). 1H NMR (CDCl3): δ 7.79 (d, 2H, J=8.2 Hz), δ 7.34 (d, 2H, J=8.2 Hz), 5.35 (m, 8H), 4.02 (t, 2H, J=6.4 Hz), 2.79 (m, 6H), 2.44 (s, 3H), 2.03 (m, 4H), 1.64 (m, 2H), 1.43-1.25 (m, 8H), 1.04 (t, 3H, J=6.8 Hz). m/z (ESI) 467.27 (M++Na).
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.O1CCCCC1[O:31][CH2:32][CH2:33][N:34]1[CH:38]=[C:37]([Sn](CCCC)(CCCC)CCCC)[N:36]=[CH:35]1.O1CCCCC1OCCN1C([Sn](CCCC)(CCCC)CCCC)=CN=C1>>[CH:20]([N:15]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:38]5[N:34]([CH2:33][CH2:32][OH:31])[CH:35]=[N:36][CH:37]=5)[CH:24]=[CH:23][C:5]=4[C:6]=3[N:7]=2)=[N:18][C:17]([CH3:19])=[N:16]1)([CH3:22])[CH3:21]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(CCOC2CCCCO2)cn1
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(Br)ccc2-3)n(C(C)C)n1
Agent: CCCC[Sn](CCCC)(CCCC)c1cncn1CCOC1CCCCO1
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(-c4cncn4CCO)ccc2-3)n(C(C)C)n1

Procedure:
Similar to described in General Procedure G: 8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with a mixture of 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(tributylstannyl)-1H-imidazole and 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-5-(tributylstannyl)-1H-imidazole to give 441 after THP-removal with aqueous HCl purification by reverse phase HPLC (4.8 mg). LCMS: 437.1.
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)C.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([CH:27]=O)[C:24]3[C:19](=[CH:20][C:21]([C:25]#[N:26])=[CH:22][CH:23]=3)[CH2:18][O:17]2)=[CH:12][CH:11]=1.[C:29]([OH:32])(=[O:31])[CH3:30]>>[CH2:2]([O:31][C:29]([CH2:30][CH2:27][C:16]1([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)[C:24]2[C:19](=[CH:20][C:21]([C:25]#[N:26])=[CH:22][CH:23]=2)[CH2:18][O:17]1)=[O:32])[CH3:3]
Reactant: CC(=O)O
Reactant: CC(C)[N-]C(C)C
Reactant: N#Cc1ccc2c(c1)COC2(C=O)c1ccc(F)cc1
Agent: [Li+]
Product: CCOC(=O)CCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
Triethyl phosphonoacetate (5.1 mL, 22.8 mmol) was added to a solution of LDA (22.8 mmol) in THE (100 mL) at −30° C. under an atmosphere of nitrogen. The mixture was stirred at this temperature for 1 h, then a solution of 1-(4-fluorophenyl)-1-formyl-1,3-dihydro-5-isobenzofurancarbonitrile (5.8 g, 21.7 mmol) in THE (50 mL) was added. The mixture was allowed to warm to room temperature during 2.5 h, then poured into ice/H20. The pH was adjusted to about 5 by addition of acetic acid and the aqueous phase was extracted with iEt2O, dried and evaporated. The crude product (8.0 g) was hydrogenated in ethanol (150 mL) using Pt/C (1.7 g, 5%) as catalyst. After 16 h, the mixture was filtered through Celite and evaporated. Silica gel chromatography (heptane, EtOAc 5:1) afforded the product as an oil (4.2g. 57%). 1H NMR (CDCl3) δ 1.20 (3H, t, J=7.0 Hz); 2.25 (2H, m); 2.50 (2H, m); 4.05 (2H, q, J=7.0 Hz); 5.15 (1H, d, J=12.7 Hz); 5.19 (1H, d, J=12.7 Hz); 7.02 (2H, t, J=9.0 Hz); 7.40 (3H, m); 7.50 (1H, s); 7.60 (1 H, d, J=8.0 Hz).
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:21]([O:24][CH2:25][CH2:26]Br)(=[O:23])[CH3:22]>CN(C)C=O.O.CCOCC>[C:7]([NH:6][N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:22][C:21]([O:24][CH2:25][CH3:26])=[O:23])(=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)NNC(=O)c1ccccc1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)CN(NC(=O)c1ccccc1)C(C)(C)C
Yield: 9.4 %

Procedure:
N'-t-butyl-N-benzoylhydrazine (2.0 g), powdered potassium carbonate (5 g) and bromoethyl acetate (1.6 g) were stirred in dimethylformamide (20 ml) at 60° C. for 14 hours. The reaction mixture was diluted with water and ether, and the organic layer was separated. The organic layer was washed several times with water, dried over magnesium sulfate and rotavapped to afford an oil. Chromatographic purification gave the pure oil product (0.25 g).
Reaction SMILES: C([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9]C=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)(=O)C.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].C([O:31][C:32](=[O:34])[CH3:33])(=O)C.[OH2:35]>C(O)(=O)C>[CH:16]1[CH:15]=[C:14]2[C:13]3[CH:12]=[CH:11][C:33]([C:32]([OH:31])=[O:34])=[CH:9][C:8]=3[C:7](=[O:35])[C:6]2=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1ccc2c(c1)Cc1ccccc1-2
Reactant: O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(c1)C(=O)c1ccccc1-2
Reaction time: 3 h

Procedure:
A solution of 2-acetylfluorene (86 g.) in acetic acid (1075 ml.) at 60° was treated slowly with sodium dichromate (1020 g.), and then with acetic anhydride (285 ml.). The mixture was heated to reflux with stirring for 3 hours, cooled and poured into water (6 l.), and the precipitate was filtered and washed well with water. This solid was warmed with N-sodium hydroxide (520 ml.) and the mixture was filtered. The aqueous filtrate was washed three times with dichloromethane (3 × 60 ml.) and then heated on the steam-bath and cautiously acidified with hydrochloric acid. The yellow product was filtered, washed well with water and dried in vacuo to give fluorenone-2-carboxylic acid m.p. > 300°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([CH3:14])[CH2:11][C:12]#[CH:13])[CH:6]=[CH:7][CH:8]=1.O1[CH2:20][CH2:19]COO1.C=O.[CH2:23]([NH:25][CH2:26]C)[CH3:24].[OH-].[Na+]>O1CCOCC1.C(O)(=O)C>[CH2:23]([N:25]([CH2:19][CH3:20])[CH2:26][C:13]#[C:12][CH2:11][CH:10]([CH3:14])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:24]
Reactant: C#CCC(C)Cc1cccc(OC)c1
Reactant: C1COOOC1
Reactant: CCNCC
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCN(CC)CC#CCC(C)Cc1cccc(OC)c1

Procedure:
Heat 5-(m-methoxyphenyl)-4-methyl-pent-1-yne (8 g), trioxan (0.5 g), 30% formalin (5.5 cc), diethylamine (4 g), acetic acid (2.75 g), dioxan (25 cc) and cuprous chloride (0.12 g) together at 70° for 15 hours. Make cooled solution alkaline with 10% aqueous sodium hydroxide and extract with ether. Wash the ethereal solution with water and extract with 10% hydrochloric acid (3 × 20 cc). Combine the acid extracts, wash with ether and make alkaline with 10% aqueous sodium hydroxide and extract with ether. Wash the ethereal solution, dry, remove the solvent and distil the residue at 0.1 mm to obtain 1-diethylamino-5-methyl-6-(m-methoxyphenyl)-hex-2-yne.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[CH2:11][C@@H:10]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C([Li])CCC.[CH2:33]1[O:36][C@@H:34]1[CH3:35].B(F)(F)F.CCOCC>C1COCC1.CCCCCC>[CH2:24]([C:21]1[CH:20]=[N:19][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([C@H:10]3[CH2:11][C@H:9]3[CH2:8][O:7][CH2:6][C:5]3[CH:26]=[CH:27][C:2]([CH2:33][C@H:34]([OH:36])[CH3:35])=[CH:3][CH:4]=3)[CH2:13][CH2:14]2)=[N:23][CH:22]=1)[CH3:25]
Reactant: C[C@@H]1CO1
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(Br)cc3)CC2)nc1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(C[C@@H](C)O)cc3)CC2)nc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
The product of example 54 (step A) (100 mg, 0.2 mmol), was dissolved in THF (2.3 mL), and the solution was cooled to −78° C. under N2. n-Butyl lithium (0.1 mL of a 2.5 M solution in hexane, 0.25 mmol) was added dropwise at 78° C. The solution was stirred at −78° C. for 20 minutes. (R)-propylene oxide (16 mg, 0.028 mmol) and BF3.Et2O (33 mg, 0.23 mmol) were then added. The solution was stirred at −78° C. for 30 minutes, and then at RT for 1 h. The solution was partitioned between water and DCM. The aqueous layer was extracted with DCM. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified via silica gel column chromatography (2/1 hexanes/EtOAc) to provide the title compound. MS (ESI) m/z 410 [M+H]+. GPR119 Human EC50: 11 nM
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[C:10]2[NH:16][C:15](=[O:17])[CH2:14][C:11]2=[N:12][CH:13]=1.[C:18]([O:22]C)(=O)[CH:19]=[CH2:20].O>CS(C)=O.C(OCC)(=O)C>[Br:7][C:8]1[CH:9]=[C:10]2[NH:16][C:15](=[O:17])[C:14]3([CH2:20][CH2:19][C:18](=[O:22])[CH2:2][CH2:1]3)[C:11]2=[N:12][CH:13]=1
Reactant: O=C1Cc2ncc(Br)cc2N1
Reactant: CC(C)(C)[O-]
Reactant: C=CC(=O)OC
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C1CCC2(CC1)C(=O)Nc1cc(Br)cnc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 753 %

Procedure:
Potassium tert-butoxide (0.03 g, 0.27 mmol) was added to a suspension of 6-bromo-1H-pyrrolo[3,2-b]pyridin-2(3H)-one (preparation 16c, 0.87 g, 4.1 mmol) in dimethylsulphoxide (4 mL) and, after stirring for 10 minutes at room temperature, the mixture was heated to 40-45° C. and methyl acrylate (1.14 mL, 12.71 mmol) was added dropwise over 60 minutes. After the addition, the mixture was stirred for 2 hours and then further potassium tert-butoxide (1.4 g, 12.21 mmol) was added portionwise over 30 minutes keeping the temperature below 50° C. The mixture was then heated to 100° C. and stirred for 2 hours. Water (20 mL) was added and heating was continued at 85° C. for 2 hours and then the mixture was left to cool overnight. Ethyl acetate was added and the organic layer was washed with water, brine, dried (MgSO4) and evaporated to give the title compound (0.60 g, 50%) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])(C)(C)C.C(O[C:28](=[O:45])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[N:43]=[N:42][C:41]([CH3:44])=[N:40][CH:39]=2)[CH:33]=1)=O)(C)(C)C>>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:28](=[O:45])[CH2:29][C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]4[N:43]=[N:42][C:41]([CH3:44])=[N:40][CH:39]=4)[CH:33]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1ncc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)nn1
Product: Cc1ncc(-c2cccc(C3=Nc4cc(N(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)nn1

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (160 mg, 0.5 mmol) and 3-[3-(3-methyl-[1,2,4]triazin-6-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K46) (180 mg, 0.55 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (8 mg).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=3)=[C:7]([F:18])[CH:8]=2)[N:3]=1.[C:29]([O:33][C:34]([NH:36][C:37]1[N:42]=[CH:41][C:40](B(O)O)=[CH:39][N:38]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(O)C>[F:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=1)[N:3]=[C:2]([C:40]1[CH:41]=[N:42][C:37]([NH:36][C:34](=[O:35])[O:33][C:29]([CH3:31])([CH3:30])[CH3:32])=[N:38][CH:39]=1)[N:11]=[C:10]2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CS(=O)(=O)c1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3cc2F)c1
Reactant: CC(C)(C)OC(=O)Nc1ncc(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3cc(F)c(-c4cccc(S(C)(=O)=O)c4)cc3n2)cn1
Temperature: 75 °C
Reaction time: 3 h
Yield: 51.7 %

Procedure:
To a 50 mL round bottom flask, 4-(2-chloro-6-fluoro-7-(3-(methylsulfonyl)phenyl)quinazolin-4-yl)morpholine (0.1 g, 0.0002 mol), (2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)boronic acid (0.085 g, 0.0003 mol), cesium carbonate (0.192 g, 0.0005 mol), toluene (5 mL), ethanol (5 mL) and water (2 mL) were added. The reaction vessel was degassed with N2 for 5-10 minutes. To the same reaction mixture, Pd(PPh3)2Cl2 (0.008 g, 0.000012 mol) was added and again degassed with N2 for 5-10 minutes. The reaction mixture was stirred at 75° C. for 3 hours. The reaction mixture was cooled and diluted with chloroform. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under the reduced pressure to afford the crude product. The crude product was purified by column chromatography (60-120 silica gel, 50% ethyl acetate in n-hexane) to yield tert-butyl (5-(6-fluoro-7-(3-(methylsulfonyl)phenyl)-4-morpholinoquinazolin-2-yl)pyrimidin-2-yl)carbamate [0.06 g, 43%]. LC-MS (ESI): Calculated mass: 580.1; Observed mass [M+H]+: 581.3 (RT=1.52 min).
Reaction SMILES: [CH:1]([CH2:3][N:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])[C:5](=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)=O.[F:23][C:24]1[CH:37]=[CH:36][C:27]([C:28]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[O:29])=[CH:26][CH:25]=1.C([BH3-])#N.[Na+].CC(C)=O>CO.CCOCC>[F:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([CH:30]2[CH2:35][CH2:34][N:33]([CH2:1][CH2:3][N:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])[C:5](=[O:14])[C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=3)[CH2:32][CH2:31]2)=[O:29])=[CH:36][CH:37]=1
Reactant: COc1cccc(C(=O)N(CC=O)c2ccccc2OC)c1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: CC(C)=O
Product: COc1cccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccccc2OC)c1
Reaction time: 0.75 h
Yield: 46.1 %

Procedure:
N-Formylmethyl-3-methoxy-N-(2-methoxyphenyl)-benzamide (141 mg, 0.473 mmol), and 4-(4-fluorobenzoyl)piperidine (125 mg, 0.60 mmol) were dissolved in methanol (4.5 ml) to which was subsequently added molecular sieve 4A (300 mg) at room temperature. After 1 hour of stirring at the same temperature, sodium cyanoborohydride (12 mg, 0.191 mmol) was added to the above mixture, followed by 45 minutes of stirring and subsequent addition of acetone (2 ml). The reaction solution was diluted with ether (15 ml) and filtered through cerite, and the solvent was removed by evaporation. The thus obtained colorless oily residue was dissolved in ether (7 ml), mixed with saturated hydrogen chloride/ether solution (7 ml) and stirred for 5 minutes. After removing the ether layer, the reaction solution was mixed with water (7 ml) and potassium carbonate (1.5 g) and extracted with ether and dried on potassium carbonate, and then the solvent was removed by evaporation. Thereafter, the resulting colorless oily residue was purified by subjecting it to a silica gel column chromatography (ether:hexane=3:2) to obtain 107 mg (46.1%) of the title compound in the form of light yellow oil.
Reaction SMILES: Br[CH:2]([CH:6](Br)[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[Cl:13])[C:3]([O-:5])=[O:4].BrC(CBr)C([O-])=O>>[Cl:13][CH:8]1[CH:7]([C:6]#[C:2][C:3]([OH:5])=[O:4])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C([O-])C(Br)C(Br)C1CCCCC1Cl
Agent: O=C([O-])C(Br)CBr
Product: O=C(O)C#CC1CCCCC1Cl

Procedure:
When α,β-dibromo-β-(3-chloro-4cyclohexyl)propionate in the above example is replaced by the α,β-dibromopropionate of Example 26, then the corresponding propiolic acid is prepared.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[OH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:12][CH2:11]1
Reactant: OCC1CCNCC1
Reactant: Clc1ccccn1
Product: OCC1CCN(c2ccccn2)CC1
Yield: 80.9 %

Procedure:
The title compound (2.7 g, 80%) was prepared as a syrupy liquid from 2-chloropyridine (7.8 g) and 4-hydroxymethylpiperidine (2 g) by an analogous procedure to that described in preparation 1.
Reaction SMILES: O=[C:2]1[C:11]2[CH2:12][CH2:13]O[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[C:4]=2[NH:3]1.[CH3:20][C:21]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23]>C(O)COCCO.[Cl-].[Na+].O>[CH3:20][C:21]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:22]=1[N:23]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[C:4]=3[N:3]=[C:2]([NH:3][CH2:4][CH2:5][OH:15])[C:11]=2[CH2:12][CH2:13]1
Reactant: Cc1cccc(N)c1C
Reactant: O=c1[nH]c2c(OC(F)(F)F)cccc2c2c1CCO2
Agent: [Cl-]
Agent: [Na+]
Solvent: OCCOCCO
Solvent: O
Product: Cc1cccc(N2CCc3c(NCCO)nc4c(OC(F)(F)F)cccc4c32)c1C
Temperature: 250 °C
Yield: 113.5 %

Procedure:
4-Oxo-6-trifluoromethoxy-2,3,4,5-tetrahydrofuro[3,2-c]quinoline(5.0 g, 19 mmol) was dissolved in diethylene glycol(30 ml), and 2,3-dimethylaniline(5.6 ml, 46 mmol) was added under nitrogen. The reaction mixture was refluxed at 250° C. for 15 hours. The reaction mixture was diluted in brine(20 ml), and the aqueous layer was extracted with dichloromethane(15 ml) for 3 times. The organic layer was washed with water(15 ml) for 3 times, dried with by anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate as eleunt to obtain 4.5 g of desired compound as solid in 65% of yield.