Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH:6]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=O)=O.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>C(#N)C>[C:18]1([NH:17][CH:6]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(OS(C)(=O)=O)c1cccs1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(Nc1ccccc1)c1cccs1
Temperature: 100 °C
Yield: 76.7 %

Procedure:
Ethyl 2-(methylsulfonyloxy)-2-(thiophen-2-yl)acetate (I87) (5.7 g, 21.6 mmol), aniline (2.16 mL, 23.7 mmol) and DIPEA (4.52 mL, 25.9 mmol) are dissolved in acetonitrile (20 mL) to give a yellow solution which is heated under microwave irradiation into a sealed vial at 100° C. for 15 minutes. Conversion complete by UPLC/MS-UV. Solvent is evaporated and the residue is dissolved in DCM and washed with water and brine, dried (Na2SO4), filtered and evaporated to dryness. The resulting crude is purified by flash chromatography (Petroleum ether/EtOAc=85/15) to get desired compound as a yellow solid (4.33 g, 77% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([CH2:13]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:10]2)=[CH:5][CH:4]=1.Br.[CH3:26][O:27][C:28]([C:30]1[CH2:31][NH:32][CH2:33][CH2:34][CH:35]=1)=[O:29].C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH3:26][O:27][C:28]([C:30]1[CH2:31][N:32]([CH2:13][CH:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:10]2)[CH2:33][CH2:34][CH:35]=1)=[O:29]
Reactant: COc1ccc2c(c1)CC(COS(=O)(=O)c1ccc(C)cc1)CC2
Reactant: COC(=O)C1=CCCNC1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1=CCCN(CC2CCc3ccc(OC)cc3C2)C1
Reaction time: 18 h

Procedure:
To a solution of 5.19 g (15 mmol) of p-toluene-sulphonic acid (7-methoxy-1,2,3,4-tetrahydro-naphth-2-ylmethyl) ester in 75 ml of dimethylformamide there are added first 3.66 g (16.5 mmol) of 1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrobromide (guvacoline hydrobromide) and then 6.78 g (52.5 mmol) of N-ethyl-N,N-diisopropylamine. The mixture is stirred at 60° for 18 hours and then concentrated by evaporation under a high vacuum. Water is added to the residue and extraction is carried out with diethyl ether. The organic phases are washed with water and extracted with 2N hydrochloric acid. The hydrochloric acid extracts are rendered alkaline at reduced temperature with sodium hydroxide solution (30%) and are extracted with dichloromethane, whereupon the combined organic phases are dried over sodium sulphate and concentrated by evaporation under reduced pressure. 1-[(7-methoxy-1,2,3,4-tetrahydro-naphth-2-yl)methyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester is obtained in the form of a light-yellow oil.
Reaction SMILES: CO[C:3](=[O:20])[C:4]([CH3:19])([CH3:18])[C@:5]([NH2:17])([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[F:16])[CH3:6].[CH3:21][NH:22][C:23]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=S>>[C:28]([O:27][C:26](=[O:32])[NH:25][C:23]1[N:22]([CH3:21])[C:3](=[O:20])[C:4]([CH3:18])([CH3:19])[C@:5]([C:7]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=2[F:16])([CH3:6])[N:17]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CNC(=S)NC(=O)OC(C)(C)C
Reactant: COC(=O)C(C)(C)[C@](C)(N)c1cc([N+](=O)[O-])ccc1F
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc([N+](=O)[O-])ccc2F)N=C1NC(=O)OC(C)(C)C

Procedure:
Starting from (S)-3-amino-3-(2-fluoro-5-nitro-phenyl)-2,2-dimethyl-butyric acid methyl ester and tert-butyl [(methylamino)carbonothioyl]carbamate, the product [(S)-4-(2-fluoro-5-nitro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester was obtained as pale yellow oil. MS (ESI): m/z=407.3 [M−H]−.
Reaction SMILES: [CH3:1][P:2]([CH3:10])([CH:4]([OH:9])[C:5]([O:7][CH3:8])=[O:6])=[O:3].[CH3:11][O:12][CH2:13][N:14]=[C:15]=[O:16]>O1CCOCC1.C(N(CC)CC)C>[CH3:1][P:2]([CH3:10])([CH:4]([O:9][C:15](=[O:16])[NH:14][CH2:13][O:12][CH3:11])[C:5]([O:7][CH3:8])=[O:6])=[O:3]
Reactant: COCN=C=O
Reactant: COC(=O)C(O)P(C)(C)=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COCNC(=O)OC(C(=O)OC)P(C)(C)=O
Reaction time: 24 h
Yield: 103.2 %

Procedure:
0.2 g of triethylamine is first added to a solution of 12.5 g (0.075 mol) of methyl 2-(dimethylphosphinoyl)-2-hydroxy-acetate in 50 ml of absolute dioxane, and 6.6 g (0.075 mol) of methoxymethyl isocyanate in 20 ml of absolute dioxane are then added dropwise. The mixture is stirred at 25° for 24 hours, the solvent is stripped off and the residue is recrystallized from diisopropyl ether/ethyl acetate. 19.6 g (98%) of the desired product of melting point 101° are obtained.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:17]=[C:16]4[N:18]([CH2:21][C:22]5[CH:23]=[C:24]6[C:29](=[CH:30][CH:31]=5)[N:28]=[CH:27][CH:26]=[CH:25]6)[N:19]=[N:20][C:15]4=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[N:5](C(OC(C)(C)C)=O)[N:4]=1)[CH3:2].C(O)(C(F)(F)F)=O.[OH-].[Na+]>ClCCl>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:17]=[C:16]4[N:18]([CH2:21][C:22]5[CH:23]=[C:24]6[C:29](=[CH:30][CH:31]=5)[N:28]=[CH:27][CH:26]=[CH:25]6)[N:19]=[N:20][C:15]4=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[NH:5][N:4]=1)[CH3:2]
Reactant: CCc1nn(C(=O)OC(C)(C)C)c2cc(-c3ccc4nnn(Cc5ccc6ncccc6c5)c4n3)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1n[nH]c2cc(-c3ccc4nnn(Cc5ccc6ncccc6c5)c4n3)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
To a solution of Example 181 (0.050 g, 0.099 mmol) in dichloromethane (1 ml) cooled to 0° C., TFA (0.5 ml) was added and warmed to RT. After 2 h, the reaction mixture was poured in ice water and pH was adjusted to ca. 11 with 10% NaOH solution and extracted with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated to afford the title compound as a yellow solid (0.023 g, 61%). M.P.: 211-213° C. MS (m/z): 406.08 (M+).
Reaction SMILES: [CH:1]1([C:7]2[CH:35]=[CH:34][C:10]([C:11]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:24][CH2:23][CH:22]([CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]4)=[N:18][CH:19]=3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][C:37]([CH3:41])=[CH:38][CH2:39]Br>>[CH:1]1([C:7]2[CH:35]=[CH:34][C:10]([C:11]([N:13]([CH2:39][CH:38]=[C:37]([CH3:41])[CH3:36])[C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:24][CH2:23][CH:22]([CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:31])[CH3:32])[CH2:21]4)=[N:18][CH:19]=3)=[O:12])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2ccc(NC(=O)c3ccc(C4CCCCC4)cc3)cn2)C1
Reactant: CC(C)=CCBr
Product: CC(C)=CCN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N2CCC(CNC(=O)OC(C)(C)C)C2)nc1

Procedure:
tert-Butyl {1-[5-(4-cyclohexylbenzoylamino)pyridin-2-yl]pyrrolidin-3-yl}methylcarbamate was reacted with 3-methyl-2-butenyl bromide by method F-a. This resulted in the product with the molecular weight of 546.76 (C33H46N4O3); MS (ESI): 547 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[C:13]([Cl:19])[N:12]=2)[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:21][C:22]1[N:23]=[CH:24][N:25](COCC[Si](C)(C)C)[C:26]=1[C:27](O)=[O:28].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:21][C:22]1[N:23]=[CH:24][NH:25][C:26]=1[C:27]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[C:13]([Cl:19])[N:12]=2)[C:4]=1[F:20])=[O:28]
Reactant: N#Cc1cc(Cl)nc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)nc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 86.7 %

Procedure:
2-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-6-chloro-4-pyridinecarbonitrile (0.056 g, 0.181 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.05 g, 0.181 mmol) and DIPEA (0.063 mL, 0.361 mmol) were combined in THF (2 mL) and treated with HATU (0.076 g, 0.199 mmol) at 25° C. for 6 h with stirring. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The residue was dissolved in DCM (2.5 mL) and treated with TFA (2.5 mL) at 25° C. for 16 h. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The resultant solid was triturated with boiling IPA, cooled in an ice bath and filtered to give 4-chloro-N-({4-chloro-3-[(6-chloro-4-cyano-2-pyridinyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (0.069 g, 0.157 mmol, 87% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.18 (br. s., 1H), 8.28 (br. s., 1H), 7.99 (s, 1H), 7.95 (s, 1H), 7.78 (s, 1H), 7.49 (d, J=8.38 Hz, 1H), 7.30-7.41 (m, 1H), 4.46-4.61 (m, 2H). LC-MS (ES−) m/z 438.02, 440.05, 442.05 [M−1]. LC-MS (ES+) m/z 439.93, 441.90, 443.94 [M+H]
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1B(O)O)(=[O:4])=[O:3].Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[CH:23][C:24]([NH2:29])=[N:25][C:26]=2[C:27]#[N:28])=[C:17]([F:30])[CH:16]=1>>[NH2:29][C:24]1[N:25]=[C:26]([C:27]#[N:28])[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:2]([CH3:1])(=[O:4])=[O:3])=[CH:16][C:17]=2[F:30])=[N:22][CH:23]=1
Reactant: CS(=O)(=O)c1ccccc1B(O)O
Reactant: N#Cc1nc(N)cnc1-c1ccc(Br)cc1F
Product: CS(=O)(=O)c1ccccc1-c1ccc(-c2ncc(N)nc2C#N)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 using 2-(methylsulfonyl)phenylboronic acid and 5-(4-bromo-2-fluorophenyl)-6-cyanopyrazin-2-amine. MS (ESI): mass calcd. for C18H13FN4O2S, 368.07; m/z found, 369.0 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.26 (s, 1H), 8.13 (dd, J=8.0, 1.4, 1H), 7.84-7.77 (m, 1H), 7.76-7.70 (m, 1H), 7.69-7.62 (m, 1H), 7.51 (dd, J=7.6, 1.4, 1H), 7.46 (dd, J=11.0, 1.6, 1H), 7.42-7.35 (m, 3H), 2.97 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3]([NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:4][C:5]([C:8]2[C:13]([Cl:14])=[CH:12][N:11]=[C:10]([F:15])[CH:9]=2)=[CH:6][N:7]=1.[CH3:24]B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>COCCOC>[Cl:14][C:13]1[C:8]([C:5]2[N:4]=[C:3]([NH:16][CH2:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:2]([CH3:24])=[N:7][CH:6]=2)=[CH:9][C:10]([F:15])=[N:11][CH:12]=1
Reactant: CB(O)O
Reactant: Fc1cc(-c2cnc(Cl)c(NCC3CCOCC3)n2)c(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: Cc1ncc(-c2cc(F)ncc2Cl)nc1NCC1CCOCC1
Temperature: 105 °C
Reaction time: 0.33 h
Yield: 191.6 %

Procedure:
3-chloro-6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (0.0275 g, 0.077 mmol), methylboronic acid (0.014 g, 0.231 mmol), and sodium carbonate (0.100 ml, 0.200 mmol, 2M aq solution) were dissolved in DME (1.0 ml). The solution was then degassed by sparging with argon for 5 min. It was then treated with PdCl2(dppf).CH2Cl2 adduct (0.013 g, 0.015 mmol). The reaction mixture was then heated in the microwave at 105° C. for 20 min. More of the above reagents in the same amounts were added to the reaction mixture and heating in the microwave was continued at 115° C. for 20 min. The reaction mixture was allowed to cool to ambient temperature. It was then filtered through a pad of Celite. The filtrate was concentrated in vacuo to yield 0.0497 g of a mixture of 6-(5-chloro-2-fluoropyridin-4-yl)-3-methyl-N-((tetrahydro-2H-pyran-4-yl)pyrazine-2-amine and 6-(2-fluoro-5-methylpyridin-4-yl)-3-methyl-N-((tetrahydro-2H-pyran-4-yl_methyl)pyrazine-2-amine.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[C:14]3[N:15]=[C:16]([NH2:18])[S:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.[F:26][C:27]([F:35])([F:34])[CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.O>CN(C=O)C>[F:26][C:27]([F:35])([F:34])[CH:28]1[CH2:33][CH2:32][N:31]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]3[C:14]4[N:15]=[C:16]([NH2:18])[S:17][C:13]=4[CH:12]=[CH:11][CH:10]=3)[CH:3]=2)[CH2:30][CH2:29]1
Reactant: FC(F)(F)C1CCNCC1
Reactant: Nc1nc2c(Oc3cc(Cl)ncn3)cccc2s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc2c(Oc3cc(N4CCC(C(F)(F)F)CC4)ncn3)cccc2s1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(6-chloro-pyrimidin-4-yloxy)-benzothiazol-2-ylamine, (Example 133(a)), (300 mg, 1.1 mmol) in dry DMF (3.0 mL) stirred at room temperature was added K2CO3 (590 mg, 4.3 mmol) and 4-(trifluoromethyl)piperidine hydrochloride (410 mg, 2.1 mmol, Matrix Scientific). The reaction mixture was stirred at 80° C. for 4 h. The resulting mixture was allowed to cool to room temperature and treated with water (20 mL). The resulting precipitate was collected by filtration, washed with water (2×), MeOH (1×), and EtOAc (3×), then dried in vacuum. The title compound was obtained as a white amorphous solid. MS (ESI, pos. ion) m/z: 396 (M+1). Anal. Calcd for C17H16F3N5OS: C, 51.64; H, 4.08; N, 17.71; F, 14.41. Found: C, 51.62; H, 4.09; N, 17.61; F, 14.33.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:20][C:21]([CH3:44])([CH3:43])[C:22](=[O:42])[O:23][CH2:24][O:25][P:26]([CH2:38][C:39](O)=[O:40])([CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:27]>CN(C)C=O>[CH3:20][C:21]([CH3:44])([CH3:43])[C:22](=[O:42])[O:23][CH2:24][O:25][P:26]([CH2:38][C:39]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:40])([CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:27]
Reactant: CC(C)(C)C(=O)OCOP(=O)(CCCCc1ccccc1)CC(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OCOP(=O)(CCCCc1ccccc1)CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
L-Phenylalanine (1.65 g, 10 mmol), triethylamine (2.8 ml, 20 mmol) and [[(2,2-dimethyl-1-oxopropoxy)methoxy]-(4-phenylbutyl)phosphinyl]acetic acid, N-hydroxy succinimide ester (4.67 g, 10 mmol) are dissolved in 50 ml of dry dimethylformamide and stirred overnight under argon at room temperature. The reaction mixture is partitioned between dichloromethane and 5% KHSO4, and the organic layer is washed with water and brine and then dried and evaporated to yield the desired product.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[F:34][C:35]([F:46])([F:45])[C:36]([NH:38][C:39]1[CH:43]=[CH:42][S:41][C:40]=1[I:44])=[O:37].[C:47]([O:51][C:52]([N:54]1[CH2:59][CH:58]=[C:57]([CH2:60]O)[CH2:56][CH2:55]1)=[O:53])([CH3:50])([CH3:49])[CH3:48]>O1CCCC1>[C:47]([O:51][C:52]([N:54]1[CH2:55][CH:56]=[C:57]([CH2:60][N:38]([C:39]2[CH:43]=[CH:42][S:41][C:40]=2[I:44])[C:36](=[O:37])[C:35]([F:34])([F:45])[F:46])[CH2:58][CH2:59]1)=[O:53])([CH3:50])([CH3:48])[CH3:49]
Reactant: CC(C)(C)OC(=O)N1CC=C(CO)CC1
Reactant: O=C(Nc1ccsc1I)C(F)(F)F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(CN(C(=O)C(F)(F)F)c2ccsc2I)CC1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 62.9 %

Procedure:
Triphenylphosphine (2.29 g) was dissolved in tetrahydrofuran (50 ml) and the solution was cooled to −10° C. under argon. Diisopropylazodicarboxylate (1.70 ml) was added dropwise over 10 min and the resulting mixture was stirred at −10° C. for 20 min (formation of a white precipitate). 2,2,2-Trifluoro-N-(2-iodo-thiophen-3-yl)-acetamide (2.25 g) dissolved in a minimum volume of tetrahydrofuran was added, followed by 4-Hydroxymethyl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (J. Org. Chem. 2001, 66, 5545-5551, 1.49 g) dissolved in a minimum volume of tetrahydrofuran. The reaction mixture was allowed to warm to room temperature and stirred for 12 hours. The solution was then concentrated in vacuo and the residue subjected to silica gel chromatography (cyclohexane:ethyl acetate 93:7) to afford 4-{[(2-Iodo-thiophen-3-yl)-(2,2,2-trifluoro-acetyl)-amino]-methyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a colourless oil (2.27 g). 1H NMR (400 MHz, CDCl3) 1.5 (s, 9H), 2.15 (m, 2H), 3.43 (m, 1H), 3.52 (m 1H), 3.75 (d, J=19 Hz, 1H), 3.77 (m, 2H), 4.76 (d, J=17 Hz, 1H), 5.41 (s, 1H), 6.68 (br d, J=5.5 Hz, 1H), 7.42 (d, J=5.5 Hz, 1H); MS (ES+) 417 (M+H+—CO2-isobutene), 458 (M+H+-isobutene).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].[I-].[Na+].[CH3:31][NH:32][CH3:33]>O1CCCC1.C(OCC)(=O)C>[CH3:31][N:32]([CH3:33])[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28]
Reactant: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCCl
Reactant: CNC
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCN(C)C
Temperature: 135 °C
Yield: 46 %

Procedure:
A mixture of 0.67 g (1 equivalent) of 7-(2-chloroethoxy)-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile, 0.097 g (0.4 equivalent) of sodium iodide and 15 ml of 2M dimethylamine in tetrahydrofuran was heated at 135° C. for 14 hours in a sealed tube. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, the organic layer was dried over magnesium sulfate and concentrated to give 0.50 g. The crude product was purified by chromatography (Silica Gel: ethyl acetate, ethyl acetate/methyl alcohol/triethylamine 6:4:0.1) to give 0.312 g (46%) of pure product. MP 218-219° C. mass spectrum (electrospray m/e): M+H=402.9.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].[C:16]([C:21]1[N:26]=[N:25][C:24]([S:27][CH3:28])=[N:23][C:22]=1Cl)([O:18][CH2:19][CH3:20])=[O:17].C(N(CC)CC)C>O1CCCC1>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:22]3[N:23]=[C:24]([S:27][CH3:28])[N:25]=[N:26][C:21]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:3]=2)[NH:7][CH:6]=1
Reactant: CCOC(=O)c1nnc(SC)nc1Cl
Reactant: CN(C)CCc1c[nH]c2ccc(N)cc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1nnc(SC)nc1Nc1ccc2[nH]cc(CCN(C)C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
5-Amino-3-(2-dimethylaminoethyl)indole and 6-carbethoxy-5-chloro-3-methylthio-1,2,4-triazine [Pesson, M. et al., Eur. J. Med. Chem., 269 (1972)] were used. Triethylamine was used as base, tetrahydrofuran was used as solvent, and the reaction was stirred at room temperature for 1 hour. Chromatography afforded the title compound (53%) as an orange solid: mp, 197.0°-199.0° C. with effervescence; 13C NMR (DMSO-d6) δ173.2, 165.5, 150.5, 133.9, 132.5, 127.7, 127.1, 123.9, 116.8, 113.0, 112.2, 111.5, 62.0, 60.0, 45.2, 23.1, 14.0, 13.2; LRMS (m/z, relative intensity) 400 (M30 , 11 ), 386 (5), 195 (11), 163(13), 58 (100). Anal. calcd. for C19H24N6O2S.0.3 H2O: C, 56.22 ; H, 6.11; N, 20.70. Found: C, 55.50; H, 5.89; N, 20.33.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][Cl:26])=[CH:17][CH:16]=2)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([Mg]Cl)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][Cl:26])=[CH:17][CH:16]=2)([OH:14])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: O=C(c1ccc(OCCCCCl)cc1)c1ccc(OCc2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(Cc1ccccc1)(c1ccc(OCCCCCl)cc1)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Combine 4-benzyloxy-4'-(4-chlorobutyloxy)benzophenone (3.95 g, 10.0 mmol) and tetrahydrofuran (50 mL). Add a solution benzylmagnesium chloride (6.0 mL, 2M in tetrahydrofuran, 12 mmol). After 1 hour, cool to 0° C. and add a saturated aqueous solution of ammonium chloride and stir for 1 hour to give a solid. Filter the solid and rinse three times with tetrahydrofuran. Combine the filtrate and rinses and separate the layers. Extract the organic layer with a saturated sodium chloride solution. Dry the organic layer over MgSO4, filter, and dry in vacuo to give a 1-(4-benzyloxyphenyl)-1-(4-(4-chlorobutyloxy) phenyl)-2-phenyl ethanol: Rf =0.36 (silica gel, 30% ethyl acetate/hexane).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([Br:10])=[CH:4][C:3]=2[O:2]1.[C:11]12(O)[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.S(=O)(=O)(O)O>C(Cl)Cl>[C:11]12([C:7]3[CH:6]=[C:5]([Br:10])[CH:4]=[C:3]4[O:2][CH2:1][O:9][C:8]=34)[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2
Reactant: Brc1ccc2c(c1)OCO2
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Brc1cc2c(c(C34CC5CC(CC(C5)C3)C4)c1)OCO2
Reaction time: 72 h
Yield: 52.9 %

Procedure:
To a mixture of 3,4-methylenedioxy-1-bromobenzene (5.00 g, 24.87 mmol) and 1-adamantanol (3.79 g, 24.87 mmol) in CH2Cl2 (50 mL) under an atmosphere of argon was added sulfuric acid (2.0 mL) at room temperature. After stirring for 3 days the resulting mixture was diluted with CH2Cl2 and washed with water. The aqueous layer was extracted with CH2Cl2 and the combined organics were washed successively with water, brine and dried (MgSO4). The mixture was filter, evaporated and the residue purified on silica gel (hexane) to give 4.41 g of 3-(1-adamantyl)-4,5-methylenedioxy-1-bromobenzene (53%) as a white solid, mp 135.5–136.0° C.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:18])[C:13]([O:15]CC)=[O:14])=[CH:8][CH:7]=1)[CH:2]=[C:3]([CH3:5])[CH3:4].[OH-].[Na+].O>C(O)C>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([CH3:18])[C:13]([OH:15])=[O:14])=[CH:10][CH:11]=1)[CH:2]=[C:3]([CH3:5])[CH3:4]
Reactant: CCOC(=O)C(C)c1ccc(CC=C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)=CCc1ccc(C(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
24.6 g of ethyl α-(p-prenylphenyl)propionate was dissolved in 250 ml of ethanol, and a solution composed of 6.0 g of sodium hydroxide and 10 ml of water was added. The mixture was stirred overnight at room temperature, and concentrated. Water was added, and the mixtue was washed with diethyl ether. The resulting aqueous layer was acidified with 1 N hydrochloric acid, and extracted with diethyl ether. The extract was washed with an aqueous solution of sodium chloride, dried, concentrated and distilled to give 19.5 g of α-(p-prenylphenyl)propionic acid having the following boiling point and NMR spectrum.