Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(CC(Cl)=O)C=CC=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.[C:33]1([CH2:39][C:40]([N:42]=[C:43]=[S:44])=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1(C)C=CC=CC=1.C(O)C>[C:33]1([CH2:39][C:40]([N:42]=[C:43]=[S:44])=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:43]([NH:42][C:40](=[O:41])[CH2:39][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[S:44])=[CH:28][CH:27]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cc1ccccc1)N=C=S
Agent: O=C(Cl)Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
2-Phenylethanoyl isothiocyanate was prepared using commercially available 2-phenylethanoyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-phenylethanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (38 mg, yield 48%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Cl[CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH:10]=2)[O:3]1
Reactant: ClCc1ccncc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CC1(C)OB(c2cnn(Cc3ccncc3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 899.8 %

Procedure:
A mixture of 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (750 mg, 0.387 mmol), 4-Chloromethyl-pyridine (740 mg, 0.581 mmol) and cesium carbonate (3.77 g, 1.16 mmol) was dissolved in acetonitrile (15 mL) was stirred overnight at room temperature. Stirring continued for 5 hrs at 60° C. and the reaction mixture was cooled, diluted with water and extracted with ethyl acetate. The organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (100% Ethyl acetate-4% 2M NH3 in MeOH/CH2Cl2) provided the title compound (993 mg, 90%). 1H NMR (300 MHz, CDCl3): δ 8.59-8.57 (m, 2H), 7.87 (s, 1H), 7.76 (s, 1H), 7.07-7.05 (m, 2H), 5.35 (s, 2H), 1.33 (s, 12H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:28][C:15]3[N:16]=[C:17](SC)[N:18]=[C:19]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[C:29]1([C:35]2[CH:40]=[CH:39][C:38]([Sn](CCCC)(CCCC)CCCC)=[CH:37][N:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>COCCOC.C(OCC)(=O)C.CSC.[Cu]Br.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>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:28][C:15]3[N:16]=[C:17]([C:38]4[CH:37]=[N:36][C:35]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:40][CH:39]=4)[N:18]=[C:19]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:3])=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(-c2ccccc2)nc1
Reactant: CSc1nc(N2CCOCC2)c2cc(CN3CCN(S(C)(=O)=O)CC3)sc2n1
Agent: [Cu]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CSC
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4ccc(-c5ccccc5)nc4)nc3s2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-(4-methanesulfonyl-piperazin-1-ylmethyl)-2-methylsulfanyl-4-morpholin-4-yl-thieno[2,3-d]pyrimidine (90 mg) in 1,2-dimethoxyethane (10 mL) was added 2-phenyl-5-tributylstannanyl-pyridine (180 mg) and copper(I)bromide-dimethyl sulfide (84 mg) and the reaction mixture was stirred at room temperature for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (12 mg) was then added and the reaction mixture was heated at reflux for 16 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (20 mL) and washed with water (2×20 mL) and brine (2×20 mL). The organic phase was dried (MgSO4), reduced in vacuo and purified by column chromatography to give 387. NMR: (CDCl3): 2.65-2.69 (4H, m), 2.82 (3H, s, Me), 3.28-3.32 (4H, m), 3.84 (2H, s, CH2), 3.90-3.93 (4H, m), 4.00-4.02 (4H, m), 7.18 (1H, s, Ar), 7.45-7.53 (3H, m, Ar), 7.85 (1H, d, J 8.5, Ar), 8.09-8.12 (2H, m, Ar), 8.76 (1H, d, J 8.5, Ar) and 9.72 (1H, d, J 1.2, Ar). MS: (ESI+): MH+551.14
Reaction SMILES: [Br:1][C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][C:7]3([C:15]42[NH:19][C:18](=S)[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][CH:10]([O:13][CH3:14])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[NH3:24]>>[Br:1][C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][C:7]3([C:15]42[N:19]=[C:18]([NH2:24])[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][CH:10]([O:13][CH3:14])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1
Reactant: COC1CCC2(CC1)Cc1ccc(Br)cc1C21N=C(C)C(=S)N1
Reactant: N
Product: COC1CCC2(CC1)Cc1ccc(Br)cc1C21N=C(C)C(N)=N1
Temperature: 120 °C
Yield: 82.2 %

Procedure:
6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione (Example 19 Step 3, 0.936 g, 2.38 mmol) was taken up in ammonia (7M in MeOH, 10 mL, 70.00 mmol) and the resulting mixture was bubbled with argon and then heated in the microwave reactor at 120° C. for 1 h. The solvent was evaporated. Ammonia (7M in MeOH, 6 mL, 42 mmol) was added and the reaction was bubbled with argon and heated again using MW for 60 min at 120° C. The solvent was evaporated and ammonia (7M in MeOH, 10 mL, 70 mmol) was added. The reaction was bubbled with argon and then heated using MW for 2 h at 120° C. The solvent was evaporated and ammonia (7M in MeOH, 15 mL, 105 mmol) was added and the reaction was heated again for 2 h at 120° C. The solvent was evaporated and ammonia (7M in MeOH, 15 mL, 105 mmol) was added and the reaction was heated again for 2 h at 120° C. The solvent was evaporated and ammonia (7M in MeOH, 20 mL, 140 mmol) was added. The reaction was heated again using MW for 1 h at 120° C. The solvent was evaporated and the resulting residue was taken up in DCM (60 mL) and brine (×2) and poured into a phase separator. The organic phase was dried with MgSO4, filtered and evaporated to give the title compound (0.736 g, 82% yield) as a mixture of isomers: 1H NMR (500 MHz, CDCl3) δ ppm 1.09 (td, 1 H), 1.27-1.49 (m, 3 H), 1.62-1.74 (m, 2 H), 1.93-2.01 (m, 2 H), 2.37 (s, 3 H), 3.04-3.18 (m, 3 H), 3.34 (s, 3 H), 6.90 (d, 1 H), 7.20 (d, 1 H), 7.38 (dd, 1 H); MS (MM-ES+APCI)+m/z 376 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[CH:17]=O>N1CCCCC1.C(O)C>[CH3:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[CH:17]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: O=C1Cc2ccccc2N1
Reactant: Cc1ccsc1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1ccsc1C=C1C(=O)Nc2ccccc21
Temperature: 90 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
A reaction mixture of 134.0 mg of oxindole, 151.4 mg of the 3-methylthiophene-2-carboxaldehyde, and 3 drops of piperidine in 2 mL of ethanol was stirred at 90° C. for 3 h. After cooling, the precipitate was filtered, washed with cold ethanol, and dried to yield 157.8 mg (65%) of the title compound as a yellow solid.
Reaction SMILES: [OH-:1].[Na+].[C:3]([OH:22])(=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]CCCCCCCC.[OH2:23]>C(O)(C)C>[C:12]([OH:23])(=[O:1])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:22])=[O:21]
Reactant: O
Reactant: [OH-]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: [Na+]
Solvent: CC(C)O
Product: O=C(O)CCCCCCCCC(=O)O
Temperature: 70 °C
Reaction time: 5 h

Procedure:
10 g of Mg—Al hydroxide carbonate of the formula Mg6Al2(OH)16CO3 aq. (Pural MG 70, Sasol, Germany) are dispersed by stirring in 100 ml of deionized water at 70° C. for 15 minutes. Then a solution of 1.5 g of sebacic acid in 50 ml of deionized water is prepared with the addition of sodium hydroxide to a pH of approximately 9 and is added to the Mg—Al hydroxide carbonate suspension. Subsequently a solution of 2 g of stearic acid in a mixture of 50 ml of deionized water and 50 ml of isopropanol is prepared with the addition of sodium hydroxide to a pH of approximately 12 and heating to 70° C. and is added to the reaction mixture. The total mixture is stirred at 80° C. for 5 hours, and then the suspension is filtered, the solid product is washed repeatedly with deionized water and then the washed solid is dried in vacuo at 60° C.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:13]=[C:12](I)[CH:11]=[C:10]2[N+:15]([O-:17])=[O:16])[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1.[CH2:18]([Sn](CCCC)(CCCC)C#CC)[CH2:19][CH2:20]C>CN(C=O)C.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>[C@@H:1]1([N:9]2[CH:13]=[C:12]([C:18]#[C:19][CH3:20])[CH:11]=[C:10]2[N+:15]([O-:17])=[O:16])[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Reactant: O=[N+]([O-])c1cc(I)cn1[C@H]1C[C@H](O)[C@@H](CO)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CC#Cc1cc([N+](=O)[O-])n([C@H]2C[C@H](O)[C@@H](CO)O2)c1
Temperature: 100 °C
Yield: 59.4 %

Procedure:
1-(2-Deoxy-β-D-ribofuranosyl)-4-iodo-2-nitropyrrole (Compound 1) (280 mg, 0.79 mmol) and Pd(PPh3)2Cl2 (56 mg, 0.08 mmol) were dissolved in DMF (7.9 ml), followed by addition of tributyl(1-propynyl)tin (481 μl, 1.6 mmol). The reaction mixture was heated at 100° C. for 1.5 hours, concentrated and then purified on a silica gel column (CH2Cl2:MeOH, 50:1, v/v) and by HPLC (34%-35% CH3CN, 13 minutes) to give Compound 2 (125 mg, 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][C:8](=[O:15])[CH:7]=[N:6]2.[H-].[Na+].CS(O[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27][CH2:26]1)(=O)=O.COC1C=C2C(C=CC(=O)N2CCN2CCC(NC(=O)OC(C)(C)C)CC2)=CC=1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:33])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:27][CH2:26]1)[C:8](=[O:15])[CH:7]=[N:6]2
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Reactant: COc1cc2ncc(=O)[nH]c2cc1OC
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc2ncc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2cc1OC
Yield: 27.6 %

Procedure:
6,7-Dimethoxyquinoxalin-2(1H)-one (Intermediate 158, 540 mg, 2.60 mmol) was deprotonated with sodium hydride (60% in oil, 2.90 mmol) and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (3.9 mmol) as described for Intermediate 2. Chromatography on silica gel with 20-50% acetone in hexanes gave 310 mg (28%) of the product as an off-white solid.
Reaction SMILES: [CH2:1]([Mg:5]CC)[CH2:2][CH2:3][CH3:4].[CH3:8][Si:9]([CH3:16])([CH3:15])[NH:10][Si:11]([CH3:14])([CH3:13])[CH3:12]>CCCCCCC>[CH3:8][Si:9]([N-:10][Si:11]([CH3:14])([CH3:13])[CH3:12])([CH3:16])[CH3:15].[CH2:1]([Mg+:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Mg]CC
Reactant: C[Si](C)(C)N[Si](C)(C)C
Solvent: CCCCCCC
Product: CCCC[Mg+]
Product: C[Si](C)(C)[N-][Si](C)(C)C
Reaction time: 1 h

Procedure:
A Fischer-Porter test tube size aerosol compatibility vessel is fitted with a tee and valves to maintain a nitrogen atmosphere. A heptane solution of butyl ethyl magnesium (25 mL, 16 mMoles) and hexamethyl disilazane (3.3 mL) are injected by syringe into the tube. Gas is evolved when the two reactants are contacted. After 1 hour and 40 minutes at room temperature, the contents of the tube are transferred to a flask for solvent evaporation without exposing the contents to air. After about four hours at room temperature, with a N2 flow, crystals began to appear in the viscous residue. The following day, the residue appears to be completely solidified. A vacuum is applied for two hours to remove any volatiles.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][NH:10][CH2:11][C:4]=2[C:3]=1[CH3:12].C([O-])(=O)/C=C\C([O-])=O.[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>>[Cl:1][C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:24](=[O:25])[C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[F:21])[CH2:11][C:4]=2[C:3]=1[CH3:12]
Reactant: O=C(Cl)c1ccccc1F
Reactant: Cc1c(Cl)nnc2c1CNCC2
Agent: O=C([O-])/C=C\C(=O)[O-]
Product: Cc1c(Cl)nnc2c1CN(C(=O)c1ccccc1F)CC2

Procedure:
A suspension of 14.4 g of 6-carbethoxy-5,6,7,8-tetrahydro-4-methyl-3(2H)pyrido[4,3-c]-pyridazinone in 100 cc of concentrated hydrochloric acid is heated to the boil at reflux for 20 hours while stirring. The resulting 5,6,7,8-tetrahydro-4-methyl-3(2H)pyrido[4,3-c]pyridazinone is isolated (M.P. of the hydrochloride 344° to 348°) and is converted in a manner analogous to that described in Example 1(e) into 3-chloro-5,6,7,8-tetrahydro-4-methylpyrido[4,3-c]pyridazine (M.P. of the maleate: 170° to 173°), this is reacted with o-fluorobenzoyl chloride, whereby 3-chloro-6-(o-fluorobenzoyl)-5,6,7,8-tetrahydro-4-methylpyrido[4,3-c]pyridazine is obtained (M.P. 151°-153°).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11](Br)[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:14]([B-](F)(F)F)=[CH2:15].[K+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[Cl:1][C:2]1[CH:12]=[C:11]([CH:14]=[CH2:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1ccc(Br)cc1Cl
Reactant: C=C[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C=Cc1ccc(C(=O)OCC)c(Cl)c1
Temperature: 80 °C
Yield: 68.4 %

Procedure:
To a stirred solution of ethyl 2-chloro-4-bromobenzoate (2 g, 7.63 mmol) in dimethylsulfoxide (20 mL) was added potassium vinyltrifluoroborate (3.06 g, 22.9 mmol) and potassium carbonate (3.16 g, 22.9 mmol). The reaction mixture was degassed with argon for 30 min Bistriphenylphosphine(diphenylphosphinoferrocene)palladium dichloride (0.27 g, 0.38 mmol) was added and the reaction mixture was heated to 80° C. for 1 h. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (2×50 mL), washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain the compound as brown gummy material (1.1 g, 69%): 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J=8.4 Hz, 1H), 7.46 (s, 1H), 7.33 (d, J=8.4 Hz, 1H), 6.70 (dd, J=17.6, 11.2 Hz, 1H), 5.87 (d, J=17.6 Hz, 1H), 5.42 (d, J=10.8 Hz, 1H), 4.41 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H); ESIMS m/z 211.22 ([M+H]+); IR (thin film) 1729, 886 cm−1.
Reaction SMILES: [CH3:1][C:2](=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)[CH2:3]O.CN(C)C=O.S(Cl)([Cl:20])=O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[Cl:20][CH2:3][C:2]([CH3:1])=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1
Reactant: CC(=Cc1ccc(C)cc1)CO
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=Cc1ccc(C)cc1)CCl
Temperature: 13.5 °C
Reaction time: 1.5 h
Yield: 87.3 %

Procedure:
To a solution of 2-methyl-3-(4-methylphenyl)-2-propen-1-ol (750 g) in toluene (2367 ml) was added dimethylformamide (29.6 ml). To the solution was added dropwise thionyl chloride (431.1 ml) at 20° C. or below and the solution was stirred at 12 to 15° C. for 1.5 hr. Water was then added thereto under ice-cooling. The toluene layer was fractionated and a 10% aqueous solution of sodium carbonate was added thereto to adjust the pH to 5. The toluene layer was fractionated again, washed successively with 5% sodium hydrogencarbonate and 5% brine. The solvent was distilled off to give the title compound as an oil (776.8 g, yield 87.3%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9](OC)(=[O:14])[CH2:10][C:11]([CH3:13])=O>>[CH3:13][C:11]1[CH:10]=[C:9]([OH:14])[C:5]2[C:3](=[C:2]([CH3:1])[CH:8]=[CH:7][CH:6]=2)[N:4]=1
Reactant: COC(=O)CC(C)=O
Reactant: Cc1ccccc1N
Product: Cc1cc(O)c2cccc(C)c2n1
Yield: 37.5 %

Procedure:
Following a procedure similar to (454a), 2-methylaniline (21.4 g, 0.2 mol) was condensed with methyl acetoacetate (23.2 g, 0.2 mol) to provide the desired 2,8-dimethyl-4-hydroxyquinoline (456a) (13.0 g, 38%). MS (AP+): 173 (M+1).
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]1[S:11][CH:10]=[N:9][CH:8]=1.F[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24]>CCCCCCC.C1COCC1>[CH3:6][C:7]1[S:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[N+:23]([O-:25])=[O:24])=[N:9][CH:8]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: Cc1cncs1
Agent: [Li]CCCC
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: Cc1cnc(-c2ccc(C(F)(F)F)cc2[N+](=O)[O-])s1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 28.7 %

Procedure:
A solution of n-BuLi (2.5 mmol) in heptane (c=2.5 M) under nitrogen atmosphere was cooled to −78° C. To the solution was added drop-wise 5-methyl-thiazole (750 mg, 7.5 mmol) dissolved in anhydrous THF (10 ml). The reaction was stirred for 20 min at −78° C. followed by the addition of 1-fluoro-2-nitro-4-trifluoromethyl-benzene (1.56 g, 7.5 mmol) dissolved in anhydrous THF (10 ml). The reaction was stirred for 10 min at −78° C. and then allowed to reach ambient temperature. The reaction was quenched with aqueous sodium bicarbonate and the phases separated. The ether phase was washed with brine, dried with MgSO4 and filtered. The solvent was removed in vacuo and the residue purified by flash chromatography (Silica, Hexane/ethyl acetate) to afford the title compound (620 mg, 29%). LC/MS (Method I): tR=1.44 min, >90%, m/z (ESI+)=289 (MH+).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH3:26])[C:12](=[O:25])[CH2:13][N:14]1[C:18]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=2[S:16][C:15]1=[O:24].CN(C=O)C.Br[CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37].C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[Si:36]([O:35][CH2:34][CH2:33][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH3:26])[C:12](=[O:25])[CH2:13][N:14]1[C:18]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=2[S:16][C:15]1=[O:24])([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CN(Cc1nc2ccccc2[nH]1)C(=O)Cn1c(=O)sc2ccc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(Cc1nc2ccccc2n1CCO[Si](C)(C)C(C)(C)C)C(=O)Cn1c(=O)sc2ccc(Cl)cc21
Temperature: 95 °C
Reaction time: 24 h

Procedure:
To a mixture of N-(1H-benzimidazol-2-ylmethyl)-2-(5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)-N-methylacetamide (500 mg) and DMF (15 mL) were added (2-bromoethoxy)(tert-butyl)dimethylsilane (555 μL) and K2CO3 (358 mg), followed by heating and stirring at 95° C. for 24 hours. The reaction mixture was diluted with EtOAc, and washed with water and brine in this order. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. To the resulting solid was added EtOAc, followed by suspending. An equivalent amount of Hex was added thereto, followed by collecting by filtration and washing with a Hex-EtOAc mixed solvent to obtain N-{[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1H-benzimidazol-2-yl]methyl}-2-(5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)-N-methylacetamide (523 mg).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([OH:19])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)C.[NH3:21].CO>>[OH:19][C:6]1([CH2:5][C:4]([NH2:21])=[O:3])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1
Reactant: CCOC(=O)CC1(O)CCN(Cc2ccccc2)CC1
Reactant: N
Solvent: CO
Product: NC(=O)CC1(O)CCN(Cc2ccccc2)CC1

Procedure:
A solution of ethyl[4-hydroxy-1-(phenylmethyl)-4-piperidinyl]acetate (15 g, 54.15 mmol) [prepared according to Caroon, J. M.; et al. J. Med. Chem. 1981, 24, 1320.] in 7N NH3-MeOH (16 mL) was heated to 100° C. in a sealed tube for 3d. The solution was cooled and concentrated and the residue washed with DCM providing the title compound (4 g, 30%) as a white solid which was used directly without further purification: LCMS (ES) m/e 249 (M+H)+.
Reaction SMILES: C[C:2]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]([Br:6])([Br:5])[CH:3]1[CH3:7].[OH-].[K+].[K].[CH3:16]C1(Br)C(C(O)=O)C1(C)Br.BrC[C:28]1[CH:33]=[CH:32][CH:31]=C[C:29]=1[C:34](=[CH:39][O:40][CH3:41])[C:35]([O:37][CH3:38])=[O:36]>C(O)C.CN1CCCC1=O>[CH3:16][CH:11]([O:10][C:8]([CH:2]1[C:4]([Br:5])([Br:6])[CH:3]1[CH3:7])=[O:9])[C:12]1[CH:31]=[CH:32][CH:33]=[CH:28][C:29]=1[C:34](=[CH:39][O:40][CH3:41])[C:35]([O:37][CH3:38])=[O:36]
Reactant: CCOC(=O)C1(C)C(C)C1(Br)Br
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Reactant: CC1(Br)C(C(=O)O)C1(C)Br
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: CCO
Solvent: CN1CCCC1=O
Product: COC=C(C(=O)OC)c1ccccc1C(C)OC(=O)C1C(C)C1(Br)Br
Yield: 32 %

Procedure:
A solution of 11.0 g (36 mmol) of ethyl 1,2-dimethyl-3,3-dibromocyclopropanecarboxylate (prepared according to Intermediate 12a) and 2.2 g (40 mmol) of potassium hydroxide in 100 ml of ethanol was stirred for 6 hours at 60° C. and then evaporated down. The solution was covered with a layer of diethyl ether, after which the resulting precipitate was separated off and washed with diethyl ether. Subsequent reaction of the resulting potassium salt of dimethyldibromocyclopropanecarboxylic acid in 60 ml of N-methylpyrrolidone with 5.1 g (18 mmol) of methyl alpha- (2-bromomethylphenyl ) -beta-methoxyacrylate was carried out similarly to Example 1. After hydrolysis of the reaction mixture, the product was extracted with methyl tert-butyl ether and was isolated and purified similarly to Example 1. Yield: 32% colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21](I)[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:9][C:8]=1[Cl:25].C[Si](C)(C)[O:31][CH2:32][C:33]#[CH:34].C(N(CC)CC)C>CN(C=O)C.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.[Cu]I>[F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:34]#[C:33][CH2:32][OH:31])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:9][C:8]=1[Cl:25]
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4ccc(I)cc34)cc2Cl)c1
Reactant: C#CCO[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OCC#Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-iodoquinazolin-4-amine (1.52 g), trimethyl(prop-2-ynyloxy)silane (0.7 mL), triethyl amine (0.5 mL) in DMF (10 mL) was added Pd(PPh3)2Cl2 (106 mg), CuI (114 mg) and the mixture was heated at 40° C. overnight. The solvent was removed, then methanol (10 mL) and 4N HCl (2 mL) were added. The reaction mixture was stirred at room temperature for one hour and the solvent was removed. Another 10 mL methanol and triethyl amine (2 mL) were added and the reaction mixture was stirred at room temperature for one hour. The solvent was removed and the residue was purified by flash chromatography, eluting with EtOAc to give the desired product. LCMS ESI(+) m/z: 434 (M+1). Yield: 86%.