Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10](O)[CH:11]([CH3:13])[CH3:12])=[C:7]([CH3:15])[C:6]=2[CH:16]=1.S(Cl)([Cl:19])=O.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:19][CH:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:16][C:6]=2[C:7]=1[CH3:15])[CH:11]([CH3:13])[CH3:12]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(C(O)C(C)C)oc2ccc(F)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(C(Cl)C(C)C)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(5-fluoro-3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-ol (1.128 g) obtained in Example A192(2) in tetrahydrofuran (10 mL) was added thionyl chloride (0.45 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hr. To the reaction mixture was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give a crude 2-(1-chloro-2-methylpropyl)-5-fluoro-3-methyl-1-benzofuran (1.10 g). To the obtained 2-(1-chloro-2-methylpropyl)-5-fluoro-3-methyl-1-benzofuran (485 mg) were added ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (500 mg) obtained in Example 1(2), sodium iodide (599 mg), sodium carbonate (424 mg) and N,N-dimethylformamide (5 mL) and the mixture was stirred at 80° C. for 13 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100:0-50:50, v/v) to give a colorless amorphous compound (123 mg). The obtained amorphous compound (123 mg) was dissolved in ethanol (2.0 mL) and tetrahydrofuran (2.0 mL), 1N aqueous sodium hydroxide solution (1.0 mL) was added to the solution, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, water (4 mL) was added to the residue, and the mixture was neutralized with 1N hydrochloric acid (1.0 mL) under ice-cooling and the mixture was stirred for 20 min. The resulting precipitate was collected by filtration, and dried to give the title compound (97 mg, 11%) as a yellow amorphous compound.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[S:2].[F:13][C:14]([F:25])([F:24])[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([NH2:23])[CH:17]=1>O1CCCC1>[SH:2][C:1]1[NH:23][C:18]2[CH:17]=[C:16]([O:15][C:14]([F:24])([F:25])[F:13])[CH:21]=[CH:20][C:19]=2[N:22]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(OC(F)(F)F)cc1N
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc2nc(S)[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.5 %

Procedure:
1,1′-thiocarbonyldiimidazole (1.13 g, 6.25 mmol) is added by portions to a solution of 4-(trifluoromethoxy)-ortho-phenylenediamine (1 g, 5.2 mmol) in 5 ml of tetrahydrofuran and the mixture is stirred at room temperature for 16 hours. The reaction mixture is then concentrated under reduced pressure and the residue is dissolved in 100 ml of ethyl acetate and washed with water (2×30 ml). The organic phase is then dried over MgSO4, filtered and concentrated. The residue is triturated in diisopropylether and pentane and dried under vacuum to yield 1.26 g of 2-mercapto-5-trifluoromethoxy-benzimidazole as a yellow powder. Quantitative yield. Analytical LC/MS (method B): retention time=3.69 min. m/z=235.67 (positive ion mode).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.CN(C=O)C.[Na+].[CH2:13]([O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O-:27])(=O)=[O:25])=[CH:20][CH:19]=1)[C:14]#[C:15][CH3:16]>C(Cl)Cl>[CH2:13]([O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([Cl:4])(=[O:27])=[O:25])=[CH:20][CH:19]=1)[C:14]#[C:15][CH3:16]
Reactant: CC#CCOc1ccc(S(=O)(=O)[O-])cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a stirred solution of oxalyl chloride (47.8 ml, 0.545 mol) at 0° C. in 240 mL of CH2Cl2 was added a DMF (43.0 ml) solution of 4-but-2-ynyloxy-benzenesulfonic acid sodium salt in a drop wise manner. The reaction mixture was stirred at 0° C. for 30 min and then let warm to room temperature and stirred for 18 h. The reaction was then poured into ice and extracted with hexanes. The organics were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to provide 42.0 g (95%) of the desired product as yellow solid.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20](O)(=[O:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH2:29]>C(OCC)(=O)C.CCCCCC>[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH2:29]
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Reactant: C=CCCCCCCCC(=O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=CCCCCCCCC(=O)OCCCCCCCCC=CCCCCCCCC
Yield: 96 %

Procedure:
Compound E was prepared from Oleyl alcohol and 9-decenoic acid following the general procedure previously discussed and shown in FIG. 10. Pure compound E was a colorless oil obtained by column chromatography with Ethyl acetate/Hexane=1:40.
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13](=[O:15])[CH3:14])=[CH:8][C:7]=1[CH3:16].CC(C)=O.[I-:27].[K+]>C(OCC)C>[I:27][CH2:2][CH2:3][C@H:4]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13](=[O:15])[CH3:14])=[CH:8][C:7]=1[CH3:16]
Reactant: [I-]
Reactant: CC(=O)Oc1ccc(O[C@H](CCCl)c2ccccc2)c(C)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC(=O)Oc1ccc(O[C@H](CCI)c2ccccc2)c(C)c1
Yield: 70 %

Procedure:
A mixture of (R)-3-chloro-1-phenyl-1-(2-methyl-4-acetoxyphenoxy)propane (0.200 gm, 0.63 mMol) and 15 mL acetone saturated with potassium iodide was stirred at reflux under argon overnight. The reaction mixture was poured into 50 mL diethyl ether and the resulting suspension was filtered. The filtrated was washed with saturated aqueous sodium hydrogen sulfite followed by water. The remaining organic phase was dried over magnesium sulfate and concentrated under reduced pressure to provide 0.18 gm (70%) of the desired compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[I:12]I>S([O-])([O-])(=O)=O.[Ag+2].C(O)C>[NH2:1][C:2]1[C:7]([I:12])=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1ncc(C(F)(F)F)cc1I
Temperature: 25 °C
Yield: 48.1 %

Procedure:
2 g (12.34 mmol) of 2-amino-5-trifluoromethylpyridine, 3.85 g (12.34 mmol) of silver sulfate and 80 mL of ethanol are introduced into a 500 mL two-necked flask equipped with a magnetic stirrer. 3.13 g (12.34 mmol) of iodine powder are then added portionwise to the reaction medium stirred at room temperature. The reaction mixture is then stirred at room temperature for 48 hours. The resulting yellow suspension is filtered, the precipitate is rinsed with ethanol and the filtrate is evaporated under reduced pressure. The residue is taken up in 100 mL of dichloromethane. This solution is washed successively with 20 mL of aqueous 5% sodium hydroxide solution, 20 mL of water and 20 mL of saturated aqueous sodium chloride solution and then dried over sodium sulfate and concentrated under reduced pressure. The resulting solid is purified by chromatography on a column of silica, eluting with a mixture of n-heptane and ethyl acetate. 1.71 g of product are obtained in the form of a pink powder.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[N:8]=[CH:7][C:6]2[CH2:9][N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:11][C:5]=2[CH:4]=1.FC(F)(F)C(O)=O>>[F:32][C:2]([F:1])([F:31])[C:3]1[N:8]=[CH:7][C:6]2[CH2:9][NH:10][CH2:11][C:5]=2[CH:4]=1
Reactant: FC(F)(F)c1cc2c(cn1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1cc2c(cn1)CNC2

Procedure:
Prepared in analogy to Example A2 (c) from 6-Trifluoromethyl-2-trityl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine and trifluoroacetic acid. Off white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:14])[CH:3]=1.S(Cl)([Cl:17])=O>ClCCCl>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([Cl:17])=[O:7])=[C:4]([F:14])[CH:3]=1
Reactant: Nc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: Nc1cc(F)c(C(=O)Cl)cc1[N+](=O)[O-]
Yield: 99 %

Procedure:
Prepared analogously to example 53a from 4-amino-5-nitro-2-fluoro-benzoic acid and thionyl chloride in 1,2-dichloroethane. Yield: 99%
Reaction SMILES: C[O:2][C:3](=[O:21])[CH:4]=[CH:5][C:6]1[C:7]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[N:8][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1.[Li+].[OH-]>C1COCC1.O>[CH2:19]([N:16]([CH2:17][CH3:18])[C:7]1[C:6]([CH:5]=[CH:4][C:3]([OH:21])=[O:2])=[CH:11][CH:10]=[C:9]([C:12]([F:15])([F:13])[F:14])[N:8]=1)[CH3:20]
Reactant: CCN(CC)c1nc(C(F)(F)F)ccc1C=CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)c1nc(C(F)(F)F)ccc1C=CC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.7 %

Procedure:
To a suspension of 3-(2-diethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid methyl ester (40 mg, 0.132 mmol) in THF (1 ml) was added a solution of 0.5 N-LiOH (0.3 ml), and the mixture was stirred for 3 hours at room temperature. The resulting residue was dissolved in H2O and then washed three times with EtOAc, acidified with 1N HCl to pH 1˜2. The solution was extracted three times with methylene chloride and then dried over anhyd. Na2SO4 and concentrated in vacuo to give 3-(2-diethylamino-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (33 mg, 87%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20](O)=[O:21])[CH2:9]2)=[CH:4][C:3]=1[F:23].S(Cl)([Cl:26])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([Cl:26])=[O:21])[CH2:9]2)=[CH:4][C:3]=1[F:23]
Reactant: O=C(O)C1=NN(c2ccccc2Cl)C(c2ccc(Br)c(F)c2)C1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C1=NN(c2ccccc2Cl)C(c2ccc(Br)c(F)c2)C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
5-(4-Bromo-3-fluoro-phenyl)-1-(2-chloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid (820.0 mg, 2.1 mmol) prepared in Step 4 was added to thionyl chloride (7.0 mL). The reaction mixture was stirred at 100° C. for 2 hours and then concentrated under reduced pressure. The resulting residue was concentrated under reduced pressure three times, along with using toluene, to give 5-(4-bromo-3-fluoro-phenyl)-1-(2-chloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carbonyl chloride as a dark brown liquid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:14][CH:15]1[CH2:19][CH2:18][CH2:17][O:16]1)C.[NH2:22][C:23]([NH2:25])=[S:24].C([O-])([O-])=O.[K+].[K+].Cl>COCCO.O>[O:16]1[CH2:17][CH2:18][CH2:19][CH:15]1[CH2:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]1[NH:25][C:23](=[S:24])[NH:22][C:4](=[O:3])[CH:5]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)CC(=O)c1ccccc1OCC1CCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCO
Solvent: O
Product: O=c1cc(-c2ccccc2OCC2CCCO2)[nH]c(=S)[nH]1
Yield: 64 %

Procedure:
To a solution of 3-oxo-3-[2-(tetrahydro-furan-2-ylmethoxy)-phenyl]-propionic acid ethyl ester (0.9 g, 3.08 mmol) in 2-methoxyethanol (5 mL) was added thiourea (0.31 g, 4.08 mmol) and K2CO3 (0.56 g, 4 mmol). The reaction mixture refluxed 5-6 h. After cooling, a mixture poured into water (10 mL), adjusted to pH 3 with 10% HCl and extracted with ethyl acetate (2×10 mL). Organic layers were combined, washed with water (10 mL), then dried over anhydrous sodium sulfate, concentrated and triturated with diethyl ether to obtained 0.6 g (64%) 6-[2-(tetrahydro-furan-2-ylmethoxy)-phenyl]-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one as a beige solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:41])[C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=3)=[C:12]([NH:27][C:28]3[C:29]4[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[N:34][C:30]=4[N:31]=[CH:32][N:33]=3)[CH:11]=2)=[N:6][CH:7]=1.[C:42](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O>ClCCl.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:41])[C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]([CH3:42])[CH2:24][CH2:25][CH3:26])=[CH:21][CH:22]=3)=[C:12]([NH:27][C:28]3[C:29]4[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[N:34][C:30]=4[N:31]=[CH:32][N:33]=3)[CH:11]=2)=[N:6][CH:7]=1
Reactant: CCCNc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cn3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCCN(C)c1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cn3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the product from Example 290 and sodium triacetoxyborohydride in 9/1 dichloromethane/methanol was added excess formaldehyde (37% in water). The mixture was stirred at room temperature for 2 hours and evaporated. The residue was purified by reverse phase preparative HPLC with the AA method to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm: 0.88 (t, J=7.35 Hz, 3 H) 1.34 (d, J=6.99 Hz, 6 H) 1.54 (m, 2 H) 2.93 (s, 3 H) 3.25 (m, 3 H) 6.75 (d, J=9.19 Hz, 2 H) 6.85 (d, J=7.72 Hz, 1 H) 7.27 (d, J=8.82 Hz, 2 H) 7.63 (d, J=8.46 Hz, 1 H) 7.87 (d, J=8.46 Hz, 1 H) 8.04 (d, J=2.57 Hz, 1 H) 8.07 (d, J=2.21 Hz, 1 H) 8.17 (m, 1 H) 8.49 (d, J=2.21 Hz, 1 H) 8.58 (s, 1 H) 8.88 (d, J=8.82 Hz, 1 H) 10.13 (s, 1 H) 10.91 (s, 1 H); MS (ESI+) m/z 642/644 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=3)[N:11]([C:20]([Cl:22])=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:33][CH2:34][CH3:35])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:38][S:39]([CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)(=[O:41])=[O:40]>>[ClH:22].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:47]3[CH2:46][CH2:45][N:44]([CH2:43][CH2:42][S:39]([CH3:38])(=[O:40])=[O:41])[CH2:49][CH2:48]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:33][CH2:34][CH3:35])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Br)cc2)[C@@H](c2ccc(Br)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Br)cc2)[C@@H](c2ccc(Br)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
[(4S,5R)-4,5-Bis-(4-bromo-phenyl)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone hydrochloride was prepared from (4S,5R)-4,5-bis-(4-bromo-phenyl)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12b) and 1-(2-methanesulfonylethyl)piperazine dihydrochloride (example 17) in an analogous manner as described in example 25. LR-MS: 773.3 [(M+H)+]
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.C[Si]([P:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(C)C>C1(C)C=CC=CC=1.CC#N.CC#N.Cl[Pd]Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[P:13]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[Si](C)(C)P(c1ccccc1)c1ccccc1
Reactant: Brc1ccccc1I
Agent: Cl[Pd]Cl
Solvent: Cc1ccccc1
Solvent: CC#N
Product: Brc1ccccc1P(c1ccccc1)c1ccccc1

Procedure:
According to the method described in a literature (S. E. Tunney and J. K. Stille, J. Org. Chem., 1987, 52, 748), (2-bromophenyl)diphenylphosphine was obtained by reacting 2-bromoiodobenzene and (trimethylsilyl)diphenylphosphine in toluene in the presence of dichlorobis(acetonitrile)palladium. Into a four-necked flask was weighed 10.00 g (29.3 mmol) of (2-bromophenyl)diphenylphosphine obtained in the above. The atmosphere of the reaction vessel fitted with a thermometer, a condenser tube, and a dropping funnel with a pressure-equalizing tube was completely replaced with nitrogen, and 100 mL of anhydrous tetrahydrofuran (hereinafter referred to as THF) was added thereto. Thereto was added dropwise 18.3 mL of n-butyllithium-hexane (1.6 M) solution at −78° C. over a period of 30 minutes, followed by 1 hour of stirring at the same temperature. The resulting mixed solution was added dropwise to a 25 mL THF solution of 4.83 g (29.3 mmol) of diethyl chlorophosphite (manufactured by Aldrich) at −78° C. over a period of 30 minutes. After the dropwise addition, a cooling bath was removed and the whole was further stirred at room temperature for 1 hour. After the reaction, THF was removed by evaporation, the residue was dissolved in 50 mL of diethyl ether, and insoluble matter was removed by filtration. The solvent was removed by evaporation and the residue was purified by active alumina column chromatography (eluent: hexane/ethyl acetate=2/1) to obtain the title compound (10.30 g, a pale yellow oily substance). Yield 92%.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5](=[O:11])[CH2:6][C:7](OC)=[NH:8])[CH3:3].[CH:12]1([NH2:15])[CH2:14][CH2:13]1>C(O)C>[ClH:1].[CH2:2]([O:4][C:5](=[O:11])[CH2:6][C:7]([NH:15][CH:12]1[CH2:14][CH2:13]1)=[NH:8])[CH3:3]
Reactant: CCOC(=O)CC(=N)OC
Reactant: NC1CC1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC(=N)NC1CC1
Reaction time: 8 h

Procedure:
To 13.3 g of 3-methoxy-3-imino propanoic acid ethyl ester hydrochloride in absolute ethanol was added 4.18 g of cyclopropylamine. The modest exotherm was controlled using a cold water bath and the reaction was stirred overnight. The ethanol was removed with rotary-evaporation to give a viscous oil. This oil was triturated with ethyl ether (1000 ml) to give a colorless solid. Yield=13.44 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7](Cl)=[O:8].Cl.[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[C:25]([C:27]3[CH:36]=[C:35]4[C:30]([CH2:31][CH2:32][NH:33][CH2:34]4)=[CH:29][CH:28]=3)[N:24]=[C:23]([NH2:37])[N:22]=2)[CH2:17][CH2:16]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7]([N:33]1[CH2:32][CH2:31][C:30]2[C:35](=[CH:36][C:27]([C:25]3[CH:26]=[C:21]([N:18]4[CH2:17][CH2:16][N:15]([CH3:14])[CH2:20][CH2:19]4)[N:22]=[C:23]([NH2:37])[N:24]=3)=[CH:28][CH:29]=2)[CH2:34]1)=[O:8]
Reactant: O=C(Cl)COc1cccc(Cl)c1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)COc3cccc(Cl)c3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 2 starting from (3-chlorophenoxy)acetyl chloride (Lancaster, Cat. #L18427) and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=493.2/495.1.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][C:3]=1[C:21]#[C:22][CH2:23][CH2:24][CH2:25]O.[CH2:27]([NH:29][CH2:30][CH2:31][OH:32])[CH3:28]>>[CH2:27]([N:29]([CH2:25][CH2:24][CH2:23][C:22]#[C:21][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[F:1])[N:8]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH2:7][CH2:6]2)[CH2:30][CH2:31][OH:32])[CH3:28]
Reactant: CCNCCO
Reactant: Cc1ccc(S(=O)(=O)N2CCc3cc(C#CCCCO)c(F)cc32)cc1
Product: CCN(CCO)CCCC#Cc1cc2c(cc1F)N(S(=O)(=O)c1ccc(C)cc1)CC2

Procedure:
In analogy to example 16.13, 5-[6-Fluoro-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indol-5-yl]-pent-4-yn-1-ol and 2-(ethylamino)ethanol instead of 2-(methylamino)ethanol were converted to yield 2-(Ethyl-{5-[6-fluoro-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indol-5-yl]-pent-4-ynyl}-amino)-ethanol as a light yellow oil, MS: 445 (MH+).
Reaction SMILES: Br[CH:2]([C:4]1[S:8][C:7]([S:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[C:6]([N+:18]([O-:20])=[O:19])[CH:5]=1)[CH3:3].[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[S:9][C:7]1[S:8][C:4]([CH:2]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[CH3:3])=[CH:5][C:6]=1[N+:18]([O-:20])=[O:19]
Reactant: CC(Br)c1cc([N+](=O)[O-])c(Sc2ccc(Cl)cc2Cl)s1
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc(CNC(C)c2cc([N+](=O)[O-])c(Sc3ccc(Cl)cc3Cl)s2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 11.2 %

Procedure:
5-(1-bromoethyl)-2-(2,4-dichlorophenyl)sulfanyl-3-nitro-thiophene (0.8 g, 1.9 mmol), 4-methoxybenzylamine (0.4 mL, 2.85 mmol) and potassium carbonate (0.524 g, 3.8 mmol) were mixed in N,N-dimethylformide (15 mL). The resulting reaction mixture was stirred at ambient temperature for 3 hours. After this time, water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was combined and was washed with brine. The organic layer was separated, dried (Na2SO4), concentrated and purified by preparative TLC using a 4:1 mixture of hexane and ethyl acetate as eluent to afford the title compound (100 mg, 11% yield). 1H NMR (400 MHz, CDCl3) δ: 7.71 (2H, m), 7.64 (2H, m), 7.51 (1H, m), 7.40 (1H, m), 7.11 (1H, m), 6.85 (1H, m), 3.93 (1H, q), 3.83 (3H, s), 3.58 (2H, m), 1.34 (3H, d). MS m/z: 468.9 [M+H]+.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[C:13]1([C:19]2[S:23][C:22]([C:24](O)=[O:25])=[CH:21][CH:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH:12][C:24]([C:22]3[S:23][C:19]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[CH:20][CH:21]=3)=[O:25])[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1ccc(-c2ccccc2)s1
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc(-c2ccccc2)s1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 5-phenylthiophene-2-carboxylic acid (Maybridge) according to methods A and C; yield 67 mg, 0.18 mmol (82%): 1H NMR (300 MHz, methanol-d4) δ 1.97 (d, J=14 Hz, 2H), 2.20 (s, 1H), 2.33 (d, J=14 Hz, 2H), 2.48 (s, 2H), 3.57 (s, 2H), 3.67 (d, J=2 Hz, 4H), 4.39 (s, 1H), 7.32-7.47 (m, 4H), 7.66-7.72 (m, 2H), 7.83 (d, J=4 Hz, 1H); MS (DCI/NH3) m/z 339 (M+H)+; Anal. C20H22N2OS.HCl: C, H, N.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19](O)=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[CH3:29][NH:30][CH3:31]>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:13]4[S:18][C:17]([C:19]([N:30]([CH3:31])[CH3:29])=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Reactant: CNC
Agent: Cl
Product: CN(C)C(=O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to N,N-dimethylamine HCl via General Procedure B. The product was purified via reverse phase HPLC to give 19.7 mg of 263. MS (Q1) 408.8 (M)+.
Reaction SMILES: [CH3:1][Sn:2]([CH3:9])([CH3:8])[C:3]1[O:4][CH:5]=[CH:6][CH:7]=1.[CH3:10][O:11][CH2:12]C1C=COC=1>>[CH3:10][O:11][CH2:12][C:7]1[CH:6]=[CH:5][O:4][C:3]=1[Sn:2]([CH3:9])([CH3:8])[CH3:1]
Reactant: COCc1ccoc1
Reactant: C[Sn](C)(C)c1ccco1
Product: COCc1ccoc1[Sn](C)(C)C

Procedure:
3-Methoxymethyl-2-trimethylstannylfuran was prepared in the same manner as 2-trimethylstannylfuran with 3-methoxymethylfuran as starting material. bp 93°-97° C. at 15 Torr.