Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([CH:11]=[O:12])=[CH:5][C:4]=1[CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][C:15]([O:17][CH3:18])=[O:16].[CH2:24]([Mg]I)[CH3:25]>O1CCCC1.C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11](=[O:12])[CH2:24][CH3:25])=[CH:5][C:4]=1[CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: CCCCCC(CC(=O)OC)c1cc(C=O)c(OC)cc1OC
Reactant: CC[Mg]I
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCC(CC(=O)OC)c1cc(C(=O)CC)c(OC)cc1OC
Reaction time: 0.67 h

Procedure:
A solution of 644 mg (2.0 mmol) of methyl 3-(2,4-dimethoxy-5-formylphenyl)octanoate [prepared as described in Preparation 32(ii)] in 10 ml of tetrahydrofuran was added dropwise over a period of 5 minutes to a solution of 1.2 ml (2.2 mmol) of a 1.8 M solution of ethylmagnesium iodide in diethyl ether diluted with 20 ml of tetrahydrofuran, whilst ice-cooling, and the resulting mixture was stirred at the same temperature for 40 minutes. The reaction was then terminated by the addition of a saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with a mixture of ethyl acetate and hexane. The extract was washed several times with water and once with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, giving the title compound as a crude product. This product was dissolved in 40 ml of methylene chloride, and 3.48 g of manganese dioxide were added to the resulting solution. The resulting mixture was stirred for 1 hour, after which a further 3.48 g of manganese dioxide were added. The mixture was then stirred for 12 hours, and then a further 1.72 g of manganese dioxide [8.68 g (99.8 mmol) in total] were added to the mixture, which was then stirred for 8 hours. At the end of this time, the reaction mixture was filtered using a Celite (trade mark) filter aid, and the filtrate was concentrated by evaporation under reduced pressure. The concentrate was triturated with hexane to give approximately pure crystals of the title compound. The compound was firther purified by column chromatography through 10 g of silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 5:1 to 3:1 by volume as the eluent, to give 416 mg (yield 59%) of the desired propionyl derivative, melting at 75.5-77.5° C. (from hexane).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12]O)[N:9]=1)(=[O:3])[CH3:2].S(Cl)([Cl:16])=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][Cl:16])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(CCCO)cs1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1nc(CCCCl)cs1
Temperature: 60 °C

Procedure:
To a suspension of 2-acetylamino-4-(3-hydroxypropyl)thiazole (1.5 g) in chloroform (2 ml) was added thionyl chloride (1.1 ml) and the mixture was warmed at 60° C. After the reaction was finished, the reaction mixture was poured into ice water and neutralized with an aqueous solution of sodium hydrogen carbonate. The mixture was extracted with chloroform and the extract was dried over magnesium sulfate and concentrated to give 2-acetylamino-4-(3-chloropropyl)thiazole (1.50 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:28]([CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[N:27]=[C:26]([C:35]#[C:36][C:37]([O:39]CC)=[O:38])[CH:25]=3)=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[Li+].[OH-]>CO.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:28]([CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[N:27]=[C:26]([C:35]#[C:36][C:37]([OH:39])=[O:38])[CH:25]=3)=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C#Cc1cc(-c2ccc(OCc3cc(OC)ccc3-c3ccc(Cl)cc3)cc2)n(C2CCCCC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(Cl)cc2)c(COc2ccc(-c3cc(C#CC(=O)O)nn3C3CCCCC3)cc2)c1

Procedure:
Ester 7.6 (55 mg, 0.097 mmol) was stirred with 1N LiOH (1 ml) in 4 ml of MeOH/THF (1:3) at rt for 24 h, concentrated, and partitioned between Et2O and H2O. The organic phase was extracted with 0.1 N NaOH (2×), and the combined aqueous extracts were acidified with conc. HCl, and extracted with EtOAc (3×). The combined organic extracts were washed with H2O, brine, and dried (Na2SO4). The crude mixture was purified by semi-preparative HPLC (gradient elution: 70 to 100% CH3CN/H2O+0.1% TFA) to give 7.7, 52 mg (100%). HRMS (ESI) calc'd for C32H30ClN2O4 514.1894, found 541.1913 (MH+); 1H NMR (300 MHz, CDCl3) δ 7.39–7.17 (m, 8H), 7.00–6.94 (m, 3H), 6.51 (s, 1H), 4.95 (s, 2H), 4.14–4.05 (m, 1H), 3.88 (s, 3H), 2.08–1.96 (m, 2H), 1.90–1.86 (m, 4H), 1.26 (br s, 4H).
Reaction SMILES: [CH:1]1([C:4]#[CH:5])[CH2:3][CH2:2]1.I[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.C(N(CC)CC)C>O1CCCC1.[Cu]I>[CH:1]1([C:4]#[C:5][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: C#CC1CC1
Reactant: COc1ccc(I)cc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C#CC2CC2)cc1
Reaction time: 4 h
Yield: 66.9 %

Procedure:
Cyclopropylethyne (15 g, 0.22 mol) was slowly added to a mixture of 4-iodoanisole (30. g, 0.13 mol), copper (I) iodide (1.2 g, 0.0063 mol), and triethylamine (30. g, 0.30 mol) in tetrahydrofuran (THF, 400 mL). After being stirred for 4 hours, the resulting precipitate was filtered and washed with THF. The combined filtrate was evaporated to dryness and the residue was purified by column chromatography to afford 1-cyclopropylethynyl-4-methoxy-benzene as a yellow oil (15 g, 0.087 mol, 67%). 1H NMR (CDCl3): δ 7.31 (d, J=8.8 Hz, 2H), 6.80 (d, J=8.8 Hz, 2H), 3.79 (s, 3H), 1.43 (m, 1H), 0.85 (m, 2H), 0.78 (m, 2H).
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4].Cl[C:13]1[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=1.Cl>C(COC)OC>[Cl:19][C:18]1[C:13]([CH2:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])=[N:14][CH:15]=[C:16]([C:20]([F:22])([F:21])[F:23])[CH:17]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: CC(=O)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(Cc1ncc(C(F)(F)F)cc1Cl)c1ccccc1
Reaction time: 0.75 h

Procedure:
To a suspension of 2.6 g (0.065 mol) of sodium hydride 60% in dimethoxyethane at room temperature is added 3.4 mL (0.029 mol) of acetophenone. After 45 min., 5.55 mL (0.038 mol) of 2,3-dichloro-5-(trifluoromethyl)pyridine is added. After 25 min., the reaction mixture is poured over 100 mL of hydrochloric acid 1N, extracted twice with 100 mL of ethyl acetate.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[CH:13]=[N:14][N:15]([CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])[CH:16]=1)=[CH:7][CH:6]=2.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]3[CH2:34][CH2:35][N:36](C(OC(C)(C)C)=O)[CH2:37][C:32]3=[N:31][CH:30]=2)=[CH:25][C:24]=1[O:45][CH3:46]>>[CH3:46][O:45][C:24]1[CH:25]=[C:26]([C:29]2[N:33]3[CH2:34][CH2:35][NH:36][CH2:37][C:32]3=[N:31][CH:30]=2)[CH:27]=[CH:28][C:23]=1[NH:22][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[CH:13]=[N:14][N:15]([CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])[CH:16]=1)=[CH:7][CH:6]=2
Reactant: COc1cc(-c2cnc3n2CCN(C(=O)OC(C)(C)C)C3)ccc1N
Reactant: CC(C)(O)Cn1cc(-c2ccc3cnc(Cl)cc3c2)cn1
Product: COc1cc(-c2cnc3n2CCNC3)ccc1Nc1cc2cc(-c3cnn(CC(C)(C)O)c3)ccc2cn1

Procedure:
The title compound was prepared according to the method described for Example 110 using 1-(1-(4-(3-chloroisoquinolin-6-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Preparation 22) and tert-butyl 3-(4-amino-3-methoxyphenyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (Preparation 89).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]2[C:6]([C:7](=[O:23])[C:8](=[O:22])[C:9]3[S:19][CH2:18][C:12]4([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]4)[O:11][C:10]=32)=[CH:5][CH:4]=1.[F:24][C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][C@@H:31]2[CH2:33][O:32]2)=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][C@@H:31]([OH:32])[CH2:33][N:15]2[CH2:16][CH2:17][C:12]3([O:11][C:10]4[C:20]5[C:6]([C:7](=[O:23])[C:8](=[O:22])[C:9]=4[S:19][CH2:18]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:21]=5)[CH2:13][CH2:14]2)=[CH:27][CH:26]=1
Reactant: Fc1ccc(OC[C@@H]2CO2)cc1
Reactant: COc1ccc2c(c1)C1=C(SCC3(CCNCC3)O1)C(=O)C2=O
Product: COc1ccc2c(c1)C1=C(SCC3(CCN(C[C@H](O)COc4ccc(F)cc4)CC3)O1)C(=O)C2=O

Procedure:
Compound 211 was synthesized using 9-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-[(4-fluorophenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=80-81° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.88 (d, J=8.8 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.09 (m, 3H), 6.95 (m, 2H), 4.85 (s, 1H), 3.98 (brm, 6H), 3.07 (s, 2H), 2.80 (m, 2H), 2.41 (m, 4H), 1.99 (m, 2H), 1.80 (m, 2H); LCMS: 500 [M+H].
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([Cl:21])[C:6]2[N:7]([C:9]([CH2:19]Cl)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][C:23]1=[O:27]>>[Cl:2][C:3]1[CH:4]=[C:5]([Cl:21])[C:6]2[N:7]([C:9]([CH2:19][N:22]3[CH2:26][CH2:25][CH2:24][C:23]3=[O:27])=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1
Reactant: Cc1ccc(-c2nc3c(Cl)cc(Cl)cn3c2CCl)cc1
Reactant: O=C1CCCN1
Agent: Cl
Product: Cc1ccc(-c2nc3c(Cl)cc(Cl)cn3c2CN2CCCC2=O)cc1

Procedure:
The title compound was prepared according to Method B and the experimentals described for compound 91 from 6,8-dichloro-3-(chloromethyl)-2-p-tolylimidazo[1,2-a]pyridine hydrochloride and pyrrolidin-2-one. m/e+ 374 for C19H18Cl2N3O [M+H]+; 1H-NMR (300 MHz, CDCl3) δ 8.49 (d, J=1.5 Hz, 1H), 7.63 (d, J=8.1 Hz, 2H), 7.33 (m, 3H), 4.93 (s, 2H), 3.11 (t, J=6.9 Hz, 2H), 2.43 (m, 5H), 1.92 (m, 2H) ppm.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([CH:18]=O)[CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CC(O)=O>[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][NH:10][C@@H:8]2[CH2:9][C@H:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:14][CH2:13]1
Reactant: CN1CCC(C=O)CC1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CN1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.1 %

Procedure:
A mixture of [trans-2-phenylcyclopropyl]amine (540 mg, 4.05 mmol), 1-methyl-4-piperidinecarbaldehyde (506 mg, 3.98 mmol) and AcOH (l μL, 0.017 mmol) in chloroform (15 mL) was stirred at room temperature for 18 hours. Sodium triacetoxyborohydride (947 mg, 4.47 mmol) was added and stirring continued for 18 hours. Upon completion, saturated NaHCO3 was added to the reaction mixture and the mixture was extracted with THF—CHCl3 (2×50mL). The organics were combined, dried over Na2SO4 and concentrated. The residue was adsorbed onto silica and purified via column chromatography on the ISCO Companion (gradient 0-100% 80:20:2 [CHCl3/MeOH/NH4OH]/CHCl3; 40 g column) to obtain pure final compound (166 mg, 13% yield) as an off white solid: LC-MS (ES) m/z=245 (M+H)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.17-7.27 (m, 2H), 7.06-7.15 (m, 1H), 6.97-7.06 (m, 2H), 2.64-2.77 (m, 2H), 2.41-2.49 (m, 2H), 2.27 (br. s., 1H), 2.18 (ddd, J=3.28, 4.23, 7.14 Hz, 1H), 2.08-2.15 (m, 3H), 1.70-1.83 (m, 2H), 1.57-1.70 (m, 2H), 1.30 (ddd, J=4.29, 7.26, 10.93 Hz, 1H), 1.01-1.16 (m, 2H), 0.86-0.98 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:16][C:17]2([OH:21])[CH2:20][CH2:19][CH2:18]2)[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6](Cl)[C:5]=2[N:15]=1.[NH3:22]>CO>[NH2:1][C:2]1[N:3]([CH2:16][C:17]2([OH:21])[CH2:20][CH2:19][CH2:18]2)[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:22])[C:5]=2[N:15]=1
Reactant: Nc1nc2c(Cl)nc3ccccc3c2n1CC1(O)CCC1
Reactant: N
Solvent: CO
Product: Nc1nc2ccccc2c2c1nc(N)n2CC1(O)CCC1
Temperature: 150 °C

Procedure:
1-[(2-Amino-4-chloro-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanol (1.14 g, 3.77 mmol) and ammonia (15 mL of a 7 N solution in methanol) were added to a pressure vessel, which was sealed and heated at 150° C. for five days. Additional ammonia in methanol (50 mL) was added after two days. When the reaction was complete, the volatiles were removed under reduced pressure, and the residue was triturated sequentially with methanol and saturated aqueous sodium bicarbonate and isolated by filtration. The resulting yellow solid was purified by automated flash chromatography on silica gel (40+M cartridge, eluting with 0% to 75% CMA in chloroform) followed by recrystallization from methanol. The crystals were dried overnight in a vacuum oven at 90° C. to provide 0.240 g of 1-[(2,4-diamino-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanol as pale yellow crystals, mp 295° C. (decomposition).
Reaction SMILES: C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:32][CH2:33][CH2:34][C:35]([OH:37])=O)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31].[NH2:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][C:46]2[S:61][C:49]3[N:50]([CH2:57][CH:58]([CH3:60])[CH3:59])[C:51](=[O:56])[N:52]([CH3:55])[C:53](=[O:54])[C:48]=3[CH:47]=2)=[CH:41][CH:40]=1>ClCCl>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:32][CH2:33][CH2:34][C:35]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([CH2:45][C:46]3[S:61][C:49]4[N:50]([CH2:57][CH:58]([CH3:59])[CH3:60])[C:51](=[O:56])[N:52]([CH3:55])[C:53](=[O:54])[C:48]=4[CH:47]=3)=[CH:41][CH:40]=2)=[O:37])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: COc1ccc(CCCC(=O)O)cc1OC
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2cc(Cc3ccc(N)cc3)sc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1ccc(CCCC(=O)Nc2ccc(Cc3cc4c(=O)n(C)c(=O)n(CC(C)C)c4s3)cc2)cc1OC
Reaction time: 8 h
Yield: 26.4 %

Procedure:
To a solution of N-ethyl-N′-[3-(dimethylamino)propyl]carbodiimide (37 mg), 1-hydroxybenzotriazole (26 mg) and 4-(3,4-dimethyloxyphenyl)butanoic acid (36 mg) in dichloromethane (6 ml) was added 6-(4-aminophenylmethyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4-(1H, 3H)-dione (45 mg) in dichloromethane (2 ml). The reaction mixture was stirred overnight and then washed with half saturated sodium hydrogen carbonate and extracted into ethyl acetate. The organic layer was dried over magnesium sulfate, evaporated and the residue was purified by normal phase HPLC (isohexane:ethyl acetate 50-0:50-100) to give the title compound (19 mg) as a foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[CH:10][N:11]([CH3:23])[C:12]=2[C:13]2[S:22][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH2:21])[C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:24][N:25](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[NH2:21][C:20]1[C:15]2[CH:14]=[C:13]([C:12]3[N:11]([CH3:23])[CH:10]=[N:9][C:8]=3[C:4]3[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=3)[C:24]#[N:25])[S:22][C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: CN(C)C=O
Reactant: Cn1cnc(-c2cccc(Br)c2)c1-c1cc2c(N)ncnc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cn1cnc(-c2cccc(C#N)c2)c1-c1cc2c(N)ncnc2s1
Temperature: 80 °C
Yield: 16 %

Procedure:
6-[4-(3-Bromophenyl)-1-methyl-1H-imidazol-5-yl]thieno[2,3-d]pyrimidin-4-amine (Example 50) (192 mg) was stirred with zinc cyanide (118 mg) and tetrakis(triphenylphosphine)palladium (116 mg) in DMF (7 mL), degassed, then heated under an inert atmosphere at 80° C. for 20 hours. The solvent was evaporated and the residue was purified by flash chromatography on silica using 0-100% EtOAc in DCM then 0-20% MeOH in DCM as eluent. Further purification by preparative RPBPLC using an MeCN/water/formic acid gradient gave the title compound as a solid (28 mg, 16%);
Reaction SMILES: I[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]3[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=3)[C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:21][NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=1)=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C>[CH3:21][NH:22][C:23]([NH:25][C:26]1[CH:27]=[C:28]([C:2]2[N:6]3[N:7]=[CH:8][C:9]([C:11]4[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=4)[C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:5]3=[N:4][CH:3]=2)[CH:29]=[CH:30][CH:31]=1)=[O:24]
Reactant: CNC(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COC(=O)c1cccc(-c2cnn3c(I)cnc3c2)c1
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)Nc1cccc(-c2cnc3cc(-c4cccc(C(=O)OC)c4)cnn23)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (2.8 mg, 0.0040 mmol) was added to a mixture of methyl 3-(3-iodoimidazo[1,2-b]pyridazin-7-yl)benzoate (0.050 g, 0.13 mmol), N-methyl-N′-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea (44 mg, 0.16 mmol) and sodium carbonate (28 mg, 0.26 mmol) in 1,4-dioxane (1 mL) and water (0.1 mL) and then the reaction vessel containing the mixture was evacuated and refilled with nitrogen 3 times. The reaction was stirred at 100° C. overnight. To this mixture was added aqueous acetonitrile and then filtered, washed with aqueous AcCN, and dried to provide the product. LCMS (M+H)+: m/z=402.1
Reaction SMILES: [CH3:1][Si:2]([CH3:23])([CH3:22])[C:3]1[C:16]2[S:15](=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[Si:18]([CH3:21])([CH3:20])[CH3:19])[S:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(Cl)(=O)C>CC(C)=O>[CH3:1][Si:2]([CH3:23])([CH3:22])[C:3]1[C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[Si:18]([CH3:21])([CH3:20])[CH3:19])[S:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)c1cccc2c1S(=O)c1c(cccc1[Si](C)(C)C)S2
Solvent: CC(=O)Cl
Solvent: CC(C)=O
Product: C[Si](C)(C)c1cccc2c1Sc1c(cccc1[Si](C)(C)C)S2
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a stirred solution of 4,6-bis(trimethylsilyl)thianthrene-5-oxide (1.67 g, 4.44 mmole) and acetyl chloride (3.80 mL, 53.2 mmole) in acetone (75 mL), KI (17.00 g, 102.0 mmole) was added. After stirring at room temperature for 2 hrs, solvent was removed in vacuo and the residue was extracted with ether. The extract washed with water and 1 M Na2S2O3 solution, dried with MgSO4, and the solvent was removed in vacuo to afford yellow oil (1.50 g, 86%). The product was eventually crystallized and used without further purification. mp 90˜91° C. (lit. 95˜96° C.). 1H NMR (300 MHz, CDCl3) δ: 7.47 (dd, 2H, J=7.5, 1.5 Hz), 7.42 (dd, 2H, J=7.5, 1.2 Hz), 7.20 (dd, 2H, J=7.5, 7.5 Hz), 0.46 (s, 18H). 13C NMR (125 MHz, CDCl3) δ: 142.4, 139.8, 134.3, 134.0, 129.6, 126.8, 0.52. HR-MS (ESI): calcd. for C18H24S2Si2+Na 383.0750 [(M+Na)+]. Found 383.0747.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([CH3:17])=[C:6]([CH2:8]P(=O)(OCC)OCC)[N:7]=1)[CH3:2].[H-].[Na+].[CH3:20][O:21][CH2:22][O:23][C:24]1[C:28]([CH:29]=O)=[CH:27][N:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:25]=1.O>O1CCCC1>[CH2:1]([C:3]1[S:4][C:5]([CH3:17])=[C:6](/[CH:8]=[CH:29]/[C:28]2[C:24]([O:23][CH2:22][O:21][CH3:20])=[N:25][N:26]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:27]=2)[N:7]=1)[CH3:2]
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Reactant: CCOP(=O)(Cc1nc(CC)sc1C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCOC)c(C)s1
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
To a solution of diethyl [(2-ethyl-5-methyl-1,3-thiazol-4-yl)methyl]phosphonate (4.16 g) in tetrahydrofuran (100 mL) was added sodium hydride (60% in oil, 0.66 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (3.48 g) was added to the reaction mixture, and the mixture was heated under reflux for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (5:95-25:75, v/v) to give 2-ethyl-4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-5-methyl-1,3-thiazole as a yellow oil (3.56 g, yield 68%). NMR (CDCl3) δ: 1.38 (3H, t, J=7.6 Hz), 2.45 (3H, s), 2.98 (2H, q, J=7.6 Hz), 3.63 (3H, s), 5.55 (2H, s), 7.09 (1H, d, J=15.8 Hz), 7.14-7.33 (2H, m), 7.35-7.46 (2H, m), 7.55-7.65 (1H, m), 7.82 (1H, s).
Reaction SMILES: Br[CH2:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][C:4]=1[N+:18]([O-:20])=[O:19].C1(=O)[NH:25]C(=O)C2=CC=CC=C12.[K]>CN(C=O)C.C(OCC)(=O)C.C1(=O)NC(=O)C2=CC=CC=C12.[K]>[NH2:25][CH2:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][C:4]=1[N+:18]([O-:20])=[O:19]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CBr)c([N+](=O)[O-])c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccc(CN)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.9 %

Procedure:
A mixture of compound 65b (1.08 g, 3.11 mmol) and potassium phthalimide (0.634 g) in DMF (10 mL) was stirred at rt overnight. Additional potassium phthalimide (0.063 g) was added and stirring was continued for 4 h. The reaction was diluted with ethyl acetate, washed with water and brine, dried, and concentrated. The residue was dissolved in ethanol (20 mL) and hydrazine (0.34 mL) was added. The reaction mixture was refluxed for 1 h, and then cooled and filtered. The filtrate was concentrated to give compound 65c (1.04 g). ESI-MS m/e 282 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4]1)[CH3:2].Cl.[CH2:12]([O:14][C:15](=[O:19])[CH2:16][CH2:17][NH2:18])[CH3:13].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:3]1[CH:7]=[CH:6][C:5]([C:8]([NH:18][CH2:17][CH2:16][C:15]([O:14][CH2:12][CH3:13])=[O:19])=[O:10])=[CH:4]1)[CH3:2]
Reactant: CCn1ccc(C(=O)O)c1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)c1ccn(CC)c1

Procedure:
Into a suspension of 3.33 g (23.9 mmol) of 1-ethyl-3-pyrrolecarboxylic acid, 4.41 g (28.7 mmol) of β-alanine ethyl ester hydrochloride and 5.50 g (28.7 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride in 40 ml of methylene chloride, 4.0 ml (28.7 mmol) of triethylamine were added dropwise under ice cooling and stirring. The reaction mixture was stirred at room temperature for 2.5 hours.