Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]1[C:5](=[O:39])[C:6](=O)[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][C@@H:32]3[CH3:37])[C:18]3[CH2:24][CH2:23][N:22]([C:25]4[N:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:21][C:19]=3[N:20]=2)=[CH:11][CH:10]=1)C.Cl.[CH2:41]([NH2:43])[CH3:42].C(O)C.C(N(CC)CC)C>>[CH2:41]([NH:43][CH:6]1[CH:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][C@@H:32]4[CH3:37])[C:18]4[CH2:24][CH2:23][N:22]([C:25]5[N:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[CH2:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)[C:4](=[O:3])[C:5]1=[O:39])[CH3:42]
Reactant: CCOc1c(Nc2ccc(-c3nc4c(c(N5CCOC[C@@H]5C)n3)CCN(c3ncccn3)C4)cc2)c(=O)c1=O
Reactant: CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCNC1C(=O)C(=O)C1Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(c2ncccn2)C3)cc1

Procedure:
Step 2—Synthesis of compound un: (S)-3-ethoxy-4-(4-(4-(3-methylmorpholino)-7-(pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenylamino)cyclobut-3-ene-1,2-dione (0.087 g, 0.00016 mol), Ethylamine Hydrochloride (0.0780 g, 0.000956 mol), and Ethanol (8.00 mL, 0.137 mol) were combined then added Triethylamine (0.230 mL, 0.00165 mol) and stirred overnight. The reaction mixture was concentrated, and chromatographed through silica gel (12 g, 0-5% MeOH in dichloromethane). 1H NMR (400 MHz, DMSO) δ 9.83 (s, 1H), 8.44 (d, J=4.7, 2H), 8.31 (d, J=8.7, 2H), 7.72 (s, 1H), 7.53 (d, J=8.5, 2H), 6.69 (t, J=4.7, 1H), 4.90 (d, J=18.7, 1H), 4.75 (d, J=18.6, 1H), 4.14 (t, J=9.3, 2H), 3.85 (dd, J=20.6, 7.2, 2H), 3.74-3.55 (m, 6H), 3.44 (t, J=11.9, 1H), 2.75 (s, 2H), 1.31-1.15 (m, 6H). LC/MS-m/z+527.3 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([N:14]=[C:15]=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:17][C:18]1[NH:22][N:21]=[C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[CH:19]=1.Cl>C(OCC)(=O)C>[C:8]1([NH:14][C:15]([N:22]2[C:18]([CH3:17])=[CH:19][C:20]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:31])([F:32])[F:33])=[N:21]2)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cc(Oc2ccccc2C(F)(F)F)n[nH]1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2ccccc2C(F)(F)F)nn1C(=O)Nc1ccccc1
Reaction time: 6 h
Yield: 89.9 %

Procedure:
Triethylamine (0.19 g, 1.4 mmol) and phenyl isocyanate (0.17 g, 1.4 mmol) were added to a solution of 5-methyl-3-(2-trifluoromethylphenyloxy)pyrazole (0.30 g, 1.2 mmol) in ethyl acetate (5 ml) at 0° C., and the mixture was allowed to have room temperature gradually and stirred for 6 hours. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (10 ml) and extracted with ethyl acetate (10 ml×2). An organic layer was washed with water (10 ml×2), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/15), to give an orange solid of N-phenyl-5-methyl-3-(2-trifluoromethylphenyloxy)pyrazole-1-carboxamide (0.39 g, yield: 87.5%). mp: 87-89° C., 1H-NMR (CDCl3, TMS, ppm): δ 2.65 (d, J=0.7 Hz, 3H), 5.78 (d, J=0.7 Hz, 1H), 7.14 (ddd, J=1.2, 2.3 and 7.3 Hz, 1H), 7.28-7.38 (m, 4H), 7.51-7.60 (m, 3H), 7.69-7.73 (m, 1H), 8.90 (br s, 1H).
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH2:25]([O:27][C:28]1[CH:38]=[CH:37][C:31]([CH2:32][C:33]2([NH2:36])[CH2:35][CH2:34]2)=[CH:30][CH:29]=1)[CH3:26].FC(F)(F)C([O-])=O>>[CH2:25]([O:27][C:28]1[CH:38]=[CH:37][C:31]([CH2:32][C:33]2([NH:36][CH2:21][CH:20]([C:12]3[C:13]4[O:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=4[C:9]([OH:8])=[CH:10][CH:11]=3)[OH:24])[CH2:35][CH2:34]2)=[CH:30][CH:29]=1)[CH3:26]
Reactant: CCOc1ccc(CC2(N)CC2)cc1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Agent: O=C([O-])C(F)(F)F
Product: CCOc1ccc(CC2(NCC(O)c3ccc(O)c4c3OCC(=O)N4)CC2)cc1

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 191 mg (1 mmol) 1-(4-ethoxy-benzyl)-cyclopropylamine. Yield: 17 mg (3%, trifluoroacetate); mass spectroscopy: [M+H]+=399.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]2[S:12][C:13]3[C:14](Cl)=[N:15][CH:16]=[CH:17][C:18]=3[N:19]=2)=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6].[Br:21][Si](C)(C)C.C(=O)(O)[O-].[Na+]>C(#N)CC>[Br:21][C:14]1[C:13]2[S:12][C:11]([C:3]3[C:2]([Cl:1])=[CH:9][C:8]([F:10])=[CH:7][C:4]=3[C:5]#[N:6])=[N:19][C:18]=2[CH:17]=[CH:16][N:15]=1
Reactant: N#Cc1cc(F)cc(Cl)c1-c1nc2ccnc(Cl)c2s1
Reactant: C[Si](C)(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC#N
Product: N#Cc1cc(F)cc(Cl)c1-c1nc2ccnc(Br)c2s1
Temperature: 50 °C
Yield: 100.2 %

Procedure:
To a suspension of 3-chloro-2-(4-chlorothiazolo[5,4-c]pyridin-2-yl)-5-fluorobenzonitrile (118 mg, 0.36 mmol) in propionitrile (3.5 mL) was added bromotrimethylsilane (0.15 mL, 1.1 mmol) and the reaction mixture was heated at 50° C. for 7 hours. The cooled mixture was treated with aqueous sodium bicarbonate and extracted three times with DCM. The combined organic washings were dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a yellow solid (133 mg, 100%). 1H NMR (300 MHz, CDCl3): δ 8.53 (d, J=5.6 Hz, 1H), 8.04 (d, J=5.6 Hz, 1H), 7.59 (dd, J=7.7, 2.5 Hz, 1H), 7.55 (dd, J=7.3, 2.5 Hz, 1H). LCMS (Method D): RT=3.88, m/z: 368 [M+H+].
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].Br[CH2:10][CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:1]([CH:3]([CH2:10][CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)C(C#N)CC(OCC)OCC
Yield: 29.2 %

Procedure:
A mixture of ethyl 2-cyanoacetate (1000 g, 8.84 mol), 2-bromo-1,1-diethoxyethane (400 g, 2.03 mol), KI (33.4 g, 0.201 mol) and K2CO3 (280 g, 2.03 mol) was heated to reflux for 12 hrs. The reaction mixture was diluted with CH2Cl2 (1000 mL) and the resulting precipitate was filtered off and the filtrate was washed with brine and dried over anhydrous Na2SO4. The solvent was removed in vacuo and the residue distilled to give the title compound (136 g, 29.2% yield) as a light yellow oil that was used as is in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16])=[CH:4][C:3]=1[S:23]([NH:26][CH2:27][O:28][C:29](=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])(=[O:25])=[O:24].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:45][Cl:46]>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16])=[CH:4][C:3]=1[S:23]([NH:26][CH2:27][O:28][C:29](=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:45][Cl:46])=[O:35])(=[O:25])=[O:24]
Reactant: O=C(O)CCCCC(=O)OCNS(=O)(=O)c1cc(C(=O)OCC(Cl)(Cl)Cl)c(NCc2ccco2)cc1Cl
Reactant: ClCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: O=C(CCCCC(=O)OCNS(=O)(=O)c1cc(C(=O)OCC(Cl)(Cl)Cl)c(NCc2ccco2)cc1Cl)OCCl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The 6-(2-chloro-4-[(2-furanylmethyl)amino]-5-(2,2,2-trichloroethoxycarbonyl)phenylsulfonamidomethoxy)(6-oxo)hexanoic acid (0.060 mole) is dispersed with stirring in a methanol-water mixture (100 mL), and an aqueous solution of cesium carbonate (2 molar) is added dropwise until the solution pH is 6.6. The volatiles are removed by spin evaporation in vacuo. The resulting cesium salt is dried by addition of toluene and removal of the volatiles under reduced pressure. This is repeated several times. The dry cesium salt is dissolved in dimethylformamide (100 mL), and bromochloromethane (Aldrich) (0.060 mole) is slowly added to the solution. The reaction is stirred at ambient temperature in the dark for 12 hours. The mixture is filtered to remove cesium bromide, and the volatiles are removed by spin evaporation in vacuo. The reaction mixture is diluted with dichloromethane (200 mL) and extracted with sodium bicarbonate solution, washed with water, and then with a saturated sodium chloride solution. The organic layer may be dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give chloromethyl 6-(2-chloro-4-[(2-furanylmethyl)amino]-5-(2,2,2-trichloroethoxycarbonyl)phenylsulfonamidomethoxy)(6-oxo)hexanoate.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])(=O)C.[Na+].[Br:30]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.C(O)(=O)C>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:30])[N:6]2[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: BrBr
Reactant: Nc1nc(Nc2ccccc2)nc2c1ncn2Cc1ccccc1
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1nc(Nc2ccccc2)nc2c1nc(Br)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
6-Amino-2-anilino-9-benzylpurine (87 mg, 0.31 mmol) was dissolved in a mixture of methylene chloride (50 ml) and acetic acid (10 ml). To the solution were added sodium acetate (105 mg, 1.28 mmol) and bromine (0.5 ml), and the mixture was stirred at room temperature for 3 hour. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, washed with aqueous saturated sodium hydrogen carbonate, dried on sodium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (93 mg, yield 92%).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([C:8]([NH2:10])=[NH:9])=[CH:5][C:4]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:15]=1.[CH3:22]N.O>CO>[NH:9]=[C:8]([NH:10][CH3:22])[C:6]1[S:7][C:3]([S:2][CH3:1])=[C:4]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)[CH:5]=1
Reactant: CN
Reactant: CSc1sc(C(=N)N)cc1-c1nc(-c2ccccc2)cs1
Solvent: CO
Solvent: O
Product: CNC(=N)c1cc(-c2nc(-c3ccccc3)cs2)c(SC)s1
Yield: 72 %

Procedure:
5-Methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamidine (20 mg, 0.06 mmol) as prepared in Example 10 step (b) was dissolved in MeOH, and to this solution methylamine (0.6 mL, 2M solution in tetrahydrofuran) was added. This solution was refluxed for 6 h, at which time the solvents were removed under vacuum to give a solid. This solid was dissolved in a small amount of MeOH. H2O was added dropwise to the methanolic solution until a precipitate was formed. This solid was isolated, washed with a small amount of water and dried under vacuum to give 15 mg (72%) of {imino[5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))(2-thienyl)]methyl}methylamine. 1H-NMR (DMSO-d6; 300 MHz) δ 2.77 (s, 3H), 3.00 (s, 3H), 7.36-7.42 (m, 1H), 7.47-7.52 (m, 2H), 8.07-8.10 (m, 2H), 8.23 (s, 1H), 8.55 (s, 1H). Mass spectrum (ESI, m/z): Calcd. for C16H15N3S3, 346.5 (M+H), found 346.2.
Reaction SMILES: [H-].[Na+].O1CCC[CH2:4]1.[CH3:8][C@H:9]1[CH2:14][N:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C@H:12]([CH3:23])[CH2:11][N:10]1[C@H:24]([C:32]1[CH:44]=[CH:43][C:35]([C:36]([N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])=[O:37])=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=1.CI>CCCCC>[CH3:8][C@H:9]1[CH2:14][N:13]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[C@H:12]([CH3:23])[CH2:11][N:10]1[C@H:24]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])=[O:37])=[CH:43][CH:44]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:4])[CH:26]=1
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2cccc(O)c2)N2C[C@@H](C)N(Cc3ccc(F)cc3)C[C@@H]2C)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCCCC
Product: CCN(CC)C(=O)c1ccc([C@H](c2cccc(OC)c2)N2C[C@@H](C)N(Cc3ccc(F)cc3)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Sodium hydride (60% dispersion in oil, 400 mg (240 mg NaH, 10 mmol)) was washed with pentane (2×7 mL), then tetrahydrofuran (10 mL) added as supernatant. 4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide (Example 1, 1.007 g, 2.0 mmol) was dissolved in the stirred suspension, and when effervescence had subsided, methyl iodide (249 μL, 568 mg, 4 mmol) was added. The reaction mixture was sealed under nitrogen and stirred for 6 h at ambient temperature. The reaction mixture was evaporated to dryness, and the residue partitioned between ethyl acetate (15 mL) and water (5 mL). The organic layer was separated, the aqueous portion extracted with ethyl acetate (2×10 mL) and the combined organic extracts dried over anhydrous sodium sulfate. The organic solution was evaporated to a pale yellow gum, which on trituration and sonication with pentane yielded 4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide as a flocculent white solid (0.798 g, 77% after drying at room temperature and 5 mm Hg). Calc. for C32H40FN3O2 0.25 H2O: C, 73.60; H, 7.82; N, 8.05; F, 3.64. Found C, 73.58; H, 7.70; N, 8.04; F, 3.84%. 1H NMR (CDCl3, 300 MHz); δ 1.09 (d, J=6.2 Hz, 6H, superimposed on br m, 3H); 1.21 (br m, 3H); 1.99 (m, 2H); 2.57 (br m, 2H); 2.66 (m, 3H); 3.15 (d, J=13.3 Hz, 1H); 3.27 (br m, 2H); 3.54 (br m, 2H); 3.78 (s, 3H); 3.84 (d, J=13 Hz, 1H); 5.10 (s, 1H); 6.76 (s, 1H); 6.70 (d, J=8.1 Hz, 2H); 6.96 (t, J=8.2 Hz, 2H); 7.26 (m, 5H); 7.46 (d, J=7.8 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)=O.C(N(CC)CC)C.Cl.Cl.[CH2:23]([NH:30][NH2:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)C>[CH2:23]([N:30]1[C:5]2[C:4](=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][CH:6]=2)[C:2]([CH3:1])=[N:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1F
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nn(Cc2ccccc2)c2ccc([N+](=O)[O-])cc12

Procedure:
2-Fluoro-5-nitroacetophenone (H. Sato et al, Bioorganic and Medicinal Chemistry Letters, 5(3), 233-236, 1995) (0.24 g) was treated with triethylamine (0.73 ml) and benzyl hydrazine dihydrochloride (0.255 g) in ethanol (20 ml) at reflux under N2 for 8 days. The mixture was cooled and the solid 1-benzyl-3-methyl-5-nitroindazole (0.16 g) was collected by filtration; m/z (M+1)+ 268.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:12][S:11][C:10]=2[CH:21]=1.[CH3:22][NH:23][CH2:24][CH2:25][OH:26]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:23]([CH3:22])[CH2:24][CH2:25][OH:26])=[CH:21][C:10]=3[S:11][CH:12]=2)=[CH:15][CH:16]=1
Reactant: Fc1ccc(-c2csc3cc(OCCCBr)ccc23)cc1
Reactant: CNCCO
Product: CN(CCO)CCCOc1ccc2c(-c3ccc(F)cc3)csc2c1

Procedure:
In analogy to example 3.1, 6-(3-Bromo-propoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and 2-(methylamino)ethanol were converted to yield 2-({3-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-methyl-amino)-ethanol as colorless oil, MS: 360 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]([N+:23]([O-])=[O:24])([CH3:22])[CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C>C(O)C.[Zn]>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[N+:23]([C:12]([CH3:22])([CH3:11])[CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O-:24]
Reactant: O=Cc1ccc(F)cc1F
Reactant: CC(C)(COCc1ccccc1)[N+](=O)[O-]
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(COCc1ccccc1)[N+]([O-])=Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 7 h
Yield: 48 %

Procedure:
A suspension of 2,4-difluorobenzaldehyde (443.7 mg, 3.12 mmol), 2-methyl-2-nitro-1-benzyloxypropane (639.4 mg, 3.06 mmol) and zinc (326.4 mg, 4.99 mmol) in ethanol (6 ml) was cooled to 0° C. in ice-water bath. Acetic acid (0.57 ml, 9.9 mmol) was added dropwise to the mixture. The mixture was gradually warmed to room temperature and stirred for 7 hours. The mixture was filtered through Celite® bed and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=10/1-4/1) to give the title compound (468.8 mg; 48%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=O.[CH3:18][S:19]([CH2:22][C:23](=O)[CH3:24])(=[O:21])=[O:20].[Na]>CC(O)C>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:23]([CH3:24])[C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[C:9]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccc(Cl)cc1
Reactant: CC(=O)CS(C)(=O)=O
Agent: [Na]
Solvent: CC(C)O
Product: Cc1nc2ccc(Br)cc2c(-c2ccc(Cl)cc2)c1S(C)(=O)=O
Yield: 18.9 %

Procedure:
(2-Amino-5-bromo-phenyl)-(4-chloro-phenyl)-methanone (compound of example A.2) (4 g, 12.9 mmol), methanesulfonylacetone (2.63 g, 19.3 mmol) and sodium tetrachloroaureate(III) dihydrate (0.26 g, 0.64 mmol) were heated at reflux in 2-propanol (50 ml) for 4 days. The resulting mixture was evaporated to dryness and the residue extracted with dichloromethane (2×), 1 N NaOH (2×) and sat. NaCl (1×). The crude product was purified by chromatography on silica gel in dichloromethane. The product was crystallized from dichloromethane/heptane by evaporation of dichloromethane. One obtained a light yellow solid (1 g, 19%). MS: m/z=410 (M).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:11](=[O:13])[CH3:12])=[N:6][C:7]=1[CH:8]=O.[CH3:14][C:15]([S@@:18]([NH2:20])=[O:19])([CH3:17])[CH3:16]>C(Cl)Cl.S([O-])([O-])(=O)=O.[Cu+2]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:11](=[O:13])[CH3:12])=[N:6][C:7]=1[CH:8]=[N:20][S@:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: CC(=O)Nc1ccc(Br)c(C=O)n1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Br)c(C=N[S@@](=O)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Copper(II) sulfate (anhydrous 2.8 g, 17.2 mmol) was added to a solution of N-(5-bromo-6-formylpyridin-2-yl)acetamide (crude material, assume 8.6 mmol) and (S)-2-methylpropane-2-sulfinamide (1.2 g, 9.4 mmol) in DCM (30 ml). The suspension was stirred overnight at room temperature. The reaction was filtered and washed with DCM (3×20 ml). The filtrate was concentrated. The crude product was purified by flash column (30% EtOAc/Hexanes). MS (m/z) 346.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13]O.S(Cl)([Cl:17])=O>C(Cl)Cl>[Cl:17][CH2:13][C:3]1[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[N:5][O:6][C:2]=1[CH3:1]
Reactant: Cc1onc(-c2ccccn2)c1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1onc(-c2ccccn2)c1CCl
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To a solution of (5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-methanol (3.0 g, 16 mmol) in DCM (30 mL) at 0° C. was added thionyl chloride (3.75 g, 32 mmol) and the resulting mixture stirred for 1 h and then evaporated. After 1 h the reaction mixture was quenched with a solution of sodium hydrogen carbonate (1N, 15 mL) and extracted with ethyl acetate. The combined extracts were washed with water, dried over sodium sulfate, filtered and concentrated to give the title compound (3.2 g, 96%) as a light brown solid. MS: m/e=209.1 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[S:15][C:14]2[C:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[N:12][C:11]([Cl:22])=[N:10][C:9]=2[CH:8]=1)C.[OH-].[Na+].Cl>CO>[Cl:22][C:11]1[N:12]=[C:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:14]2[S:15][C:7]([CH2:6][CH2:5][C:4]([OH:23])=[O:3])=[CH:8][C:9]=2[N:10]=1
Reactant: CCOC(=O)CCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
To a mixture of 3-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)propionic acid ethyl ester (1 g) in methanol (30 mL) was added 1 N aqueous sodium hydroxide solution (10 mL). The reaction mixture was stirred at room temperature for 1 h and then acidified to pH 6 using 2 M aqueous hydrochloric acid. The product was then filtered and washed with water to give 3-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-propionic acid as a greenish-yellow solid (612 mg).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([O:23][CH:24]([CH3:26])[CH3:25])[CH:22]=2)[O:19][C:18]([CH3:28])([CH3:27])[CH2:17][C:16]3([CH3:30])[CH3:29])=[CH:7][CH:6]=1.[OH-].[Na+]>CO>[CH:24]([O:23][C:21]1[CH:22]=[C:13]([C:12]#[C:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:31])=[O:2])=[CH:10][CH:9]=2)[CH:14]=[C:15]2[C:20]=1[O:19][C:18]([CH3:27])([CH3:28])[CH2:17][C:16]2([CH3:30])[CH3:29])([CH3:26])[CH3:25]
Reactant: COC(=O)Cc1ccc(C#Cc2cc(OC(C)C)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Oc1cc(C#Cc2ccc(CC(=O)O)cc2)cc2c1OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.8 %

Procedure:
A solution of [4-(8-isopropoxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl)phenyl]-acetic acid methyl ester (Intermediate 24, 0.02 g, 0.05 mmol) in methanol (1 mL) was treated with a 2M solution of sodium hydroxide (1 mL, 2 mmol) and the resulting reaction mixture was stirred at ambient temperature for 3 h. The volatiles were evaporated in vacuo to a residue that was neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil. Flash column chromatography over silica gel (230-400 mesh) using 5% methanol in ethyl acetate as the eluent followed by preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase afforded the title product (0.015 g, 78%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+]>CO.CCOCC>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[CH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(C=Cc2ccnc3ccccc23)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: OCc1ccc(C=Cc2ccnc3ccccc23)cc1
Reaction time: 0.33 h

Procedure:
A 50 mL solution of (1) in MeOH was cooled to 0° C. and NaBH4 (2 molar excess) was added. Stirring continued for 20 minutes at a temperature of about 0° to 20° C. The reaction mixture was diluted with Et2O, filtered through a thin layer of SiO2 and evaporated to provide a 1.59 g (≈100%) yield of (2).