Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]2[C:5]([CH2:6][C:7]3[C:15]4[CH:14]=[CH:13][C:12]([O:16][CH3:17])=[CH:11][C:10]=4[NH:9][C:8]=32)=[CH:4][CH:3]=1.[OH-].[Na+].I[CH3:23]>C1C=CC=CC=1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[F:1][C:2]1[CH:19]=[C:18]2[C:5]([CH2:6][C:7]3[C:15]4[CH:14]=[CH:13][C:12]([O:16][CH3:17])=[CH:11][C:10]=4[N:9]([CH3:23])[C:8]=32)=[CH:4][CH:3]=1.[F:1][C:2]1[CH:19]=[C:18]2[C:5]([CH2:6][C:7]3[C:15]4[CH:14]=[CH:13][C:12]([O:16][CH3:17])=[CH:11][C:10]=4[NH:9][C:8]=32)=[CH:4][CH:3]=1
Reactant: CI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: COc1ccc2c3c([nH]c2c1)-c1cc(F)ccc1C3
Agent: [I-]
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc2c3c(n(C)c2c1)-c1cc(F)ccc1C3
Temperature: 40 °C
Reaction time: 17 h

Procedure:
To a solution of 55 (as a 3:1 mixture of regioisomers, 1.26 g, 4.98 mmol) in benzene (25 mL) was added aqueous sodium hydroxide (50% by mass, 3 mL), tetrabutylammonium iodide (152.1 mg, 0.41 mmol), and iodomethane (2.48 mL, 39.8 mmol). The reaction mixture was stirred vigorously at 40° C. for 17 hours and then cooled to room temperature over 3.5 hours. The mixture was diluted with benzene (20 mL) and H2O (20 mL), and the aqueous layer was extracted 2×20 mL ethyl acetate. Organic layers were combined, washed 1×25 mL H2O, dried over anhydrous magnesium sulfate and concentrated. Crude product was purified by flash column chromatography (40:1 hexanes-ethyl acetate) to give 56 as one regioisomer in 71% yield (713 mg, 2.67 mmol, % yield based on amount of 55 in starting material mixture). 1H NMR (600 MHz, CDCl3): δ 7.49 (d, 1H, J=9 Hz), 7.37-7.39 (dd, 1H, J=7.8 Hz, 4.8 Hz), 7.21-7.23 (dd, 1H, J=9.3 Hz, 1.8 Hz), 6.82-6.86 (m, 3H), 3.92 (s, 3H), 3.91 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 162.2 (d, J=240 Hz), 156.4, 142.8, 142.7 (d, J=3 Hz), 142.6 (d, J=3 Hz), 137.1 (d, J=9.5 Hz), 125.8 (d, J=9.2 Hz), 122.4, 119.8, 118.4, 109.9 (d, J=22.5 Hz), 109.3, 104.3 (d, J=24.8 Hz), 93.7, 55.7, 30.9, 29.5; 19F NMR (CD3CD, 376 MHz): δ −116.0 (q, J=14.1, 9.4 Hz); FTIR: cm−1 1611, 1592, 1530, 1460, 1380, 1258, 1221, 1161. EI-HRMS: Calcd. for C17H14FNO+ [M]+: 267.1059, found 267.1062.
Reaction SMILES: [CH2:1]([C:3]1[CH2:7][CH:6]=[C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:4]=1)[CH3:2].C([Li])CCC.CN1CCN(C)C1=O.[C:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>CCCCCC.C1COCC1>[C:8]([C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[C:7](=[C:25]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CCC1=CC(C(C)(C)C)=CC1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CN1CCN(C)C1=O
Product: CCC1=CC(C(C)(C)C)=CC1=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 55.9 %

Procedure:
A 300-ml three-necked flask equipped with a magnetic stirrer and a three-way cock in a nitrogen atmosphere was charged with 5.11 g (23.9 mmol) of 1-ethyl-3-tert-butylcyclopentadiene (GC purity: 75%) and 150 ml of THF. In a dry ice/methanol bath, 16 ml of a 1.56 M hexane solution of n-butyllithium (25.2 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 20 hours, and 3.1 ml (28.8 mmol) of 1,3-dimethyl-2-imidazolidinone was added and 5.3 g (28.8 mmol) of benzophenone was further added. The mixture was stirred under reflux for 48 hours, and the resultant reaction solution was poured into 100 ml of 2N hydrochloric acid. The organic phase was separated, and the aqueous phase was extracted with 50 ml of hexane two times. The organic phases were combined and washed with a saturated aqueous sodium hydrogencarbonate solution, water and a saturated aqueous sodium chloride solution. The product was dried over magnesium sulfate and the solvent was distilled off. The distillate was purified by column chromatography to give 4.2 g of an orange solid. The yield was 56%. The compound was identified by 1H-NMR spectroscopy. The results are as follows.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[CH3:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([C:32](O)=[O:33])=[N:30][CH:31]=1>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:32]([C:29]3[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[CH:31][N:30]=3)=[O:33])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: COc1ccc(C(=O)O)nc1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Product: COc1ccc(C(=O)Nc2ccc(F)c([C@]3(C)CCOC(N)=N3)c2)nc1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F1 (R1=Me) and 5-methoxy-pyridine-2-carboxylic acid followed by deprotection using procedure H yielded the title compound.
Reaction SMILES: [CH2:1]([O:11][C:12]1[C:16]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:15][S:14][C:13]=1[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][CH:29]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].O.NN.CCCCCC>C(O)C.[Pt]>[CH2:1]([O:11][C:12]1[C:16]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:15][S:14][C:13]=1[C:28]1[CH:29]=[CH:30][C:31]([NH2:34])=[CH:32][CH:33]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1csc(-c2ccc([N+](=O)[O-])cc2)c1OCCCCCCCCCC
Agent: [Pt]
Agent: NN
Solvent: CCCCCC
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCOc1csc(-c2ccc(N)cc2)c1OCCCCCCCCCC
Yield: 91 %

Procedure:
A solution of 1-(3,4-didecyloxythien-2-yl)-4-nitrobenzene (0.995 g, 1.92 mmol) in 95% ethanol (30 mL) containing platinum on sulfide carbon (30 mg) was added hydrazine hydrate (0.5 mL). The mixture was refluxed for 5 to 10 hours. After cooling, the mixture was filtered and the solvent was evaporated to give a solid. Addition of hexane followed by filtration gave 1-(3,4-didecyloxythien-2-yl)-4-aminobenzene which was subsequently recrystallized from ethanol containing few drops of acetone, 0.855 g. yield=91%, mp=64.5-65.5° C. IR (KBr; cm-1) 3427, 3335, 3116, 2920, 2850, 1624, 1520, 1467, 1372, 1144 and 826. 1H NMR (CDCl3 ; δ in ppm): 0.880 (t, J=7.4 Hz, 6H), 1.381 (m, 28H), 1.700 (m, 4H), 3.947 (m, 4H), 5.992 (s, 1H), 6.674 (d, J=9.5 Hz, 2H) and 7.522 (d, J=9.5 Hz, 2H). 13C NMR (CDCl3 ; δ in ppm): 14.11, 22.69, 25.98, 26.12, 29.17, 29.34, 29.60, 30.09, 30.24, 32.05, 69.75, 72.77, 92.47, 114.96, 123.97, 125.96, 128.06, 141.57, 145.45 and 150.75. MS(EI) m/z (rel int): 487 [(M)+, 40%], 346 [(M+ --C10H21), 8.4%], 207 [(M+ --C20H40), 11%], 178 [(M+ --C21H41O), 8.4%], 150 [(M+ --C22H41O2), 7%] and 136 [(M+ --C23H45NO), 11%]. Anal. Calcd for C30H49NSO2 : C, 73.87; H, 10.13; N, 2.87; S, 6.57. Found: C, 73.99; H, 10.66; N, 2.41; S, 6.32.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[N:11]=[C:10]([CH2:12]O)[CH:9]=[CH:8][C:6]=2[N:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:39]N1C(=O)CCC1=O.C1C(=O)N(Br)C(=O)C1.C1C(=O)N(Br)C(=O)C1>ClCCl>[Br:39][CH2:12][C:10]1[CH:9]=[CH:8][C:6]2[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:5]=2[N:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1nc(N2CCOCC2)c2nc(CBr)ccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
(2-Chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methanol 6 (2.0 g, 0.0071 mol) and 40 mL dichloromethane were cooled to 0° C. and triphenylphosphine (2.2 g, 0.0085 mol) was added. The solution was recooled to 0° C. and N-Bromosuccinimide NBS (1.5 g, 0.0085 mol) was added in one portion. The heterogeneous mixture became homogeneous yellow upon NBS addition. After 30 mins, the progress was checked by tlc. The reaction mixture again became heterogeneous yellow mixture and was stirred overnight at room temperature. A check by LC/MS showed the reaction was complete. The reaction mixture was concentrated to dryness, taken up in MeOH, and filtered to yield 2.13 gm (87%) of 4-(6-(bromomethyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine 7 as a yellow solid. More product 7 precipitated from the mother liquor, filtered, and dried to give a second batch (133 mg) of product 7. Analyzed and confirmed by LC/MS.
Reaction SMILES: [C:1]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:23][C:24]([C:26]2[N:27]=[N:28][NH:29][CH:30]=2)=[O:25])[CH2:9][C@@:10]([CH3:22])([CH2:14][O:15][CH:16]2CCCC[O:17]2)[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.Cl.O1CCOCC1.CC#N.C(Cl)Cl.[C:50](Cl)(=O)[CH:51](C)[CH3:52].CCN(C(C)C)C(C)C>>[C:1]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:23][C:24]([C:26]2[NH:27][N:28]=[N:29][CH:30]=2)=[O:25])[CH2:9][C@:10]([CH2:14][O:15][C:16](=[O:17])[CH:51]([CH3:52])[CH3:50])([CH3:22])[C:11]([OH:13])=[O:12])=[CH:5][CH:6]=1
Reactant: C[C@@](COC1CCCCO1)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1c[nH]nn1)C(=O)O
Reactant: CC(C)C(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)C(=O)OC[C@](C)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1)C(=O)O
Reaction time: 0.17 h
Yield: 4.1 %

Procedure:
(2S,4R)-5-Biphenyl-4-yl-2-methyl-2-(tetrahydropyran-2-yloxymethyl)-4-[(1H-1,2,3-triazole-4-carbonyl)amino]pentanoic acid (126 mg, 255 μmol) was combined with 4 M HCl in dioxane (191 μL, 765 μmol) in MeCN (0.7 mL, 10 mmol). The mixture was then concentrated under reduced pressure and the residue was purified by reverse phase chromatography. DCM (1 mL, 20 mmol) and isobutyryl chloride (32.6 mg, 306 μmol) were added, followed by DIPEA (133 μL, 765 μmol). The resulting mixture was stirred for 10 minutes. The solvent was evaporated and the residue was dissolved in AcOH and purified by preparative HPLC to yield the title compound (5 mg). MS m/z [M+H]+ calc'd for C26H30N4O5, 479.22. found 479.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=3[O:10][CH:9]=2)=[CH:4][CH:3]=1.[Mg].[C:19](=[O:21])=[O:20].Cl>O1CCCC1>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]2[O:10][CH:9]=[C:8]([C:5]3[CH:4]=[C:3]([CH:2]=[CH:7][CH:6]=3)[C:19]([OH:21])=[O:20])[C:12]=2[CH:13]=1
Reactant: Cc1ccc2occ(-c3ccc(Br)cc3)c2c1
Reactant: O=C=O
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc2occ(-c3cccc(C(=O)O)c3)c2c1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
The product of step B in 150 ml. of tetrahydrofuran is added to 5 g. of magnesium turnings in 25 ml. of tetrahydrofuran at a rate sufficient to sustain refluxing. Refluxing is continued for an additional three hours, then the mixture is stirred overnight at about 20° C. To this reaction mixture is added gaseous carbon dioxide over a period of one hour. The mixture is maintained at reflux during the second half hour. The reaction mixture is cooled and cautiously added to 50 ml. of 6N hydrochloric acid. The reaction mixture is evaporated to provide a residue which is recrystallized from acetic acid to provide tan crystals of 3-(5-methyl-3-benzofuranyl)benzoic acid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH:22][CH2:23][CH2:24][NH2:25]>>[OH:22][CH2:23][CH2:24][NH:25][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: NCCO
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Product: COc1ccc(N(C)c2nc(NCCO)nc3ccccc23)cc1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (15 mg, 0.050 mmol) and 2-hydroxylethylamine (20 μL) by a procedure similar to Example 10 and was isolated as white solid (12 mg, 80%). 1H NMR (CDCl3): 7.43 (ddd, J=8.4, 1,5 and 0.9 Hz, 1H), 7.35 (ddd, J=7.8, 3.3 and 1.5 Hz, 1H), 7.12-7.06 (m, 2H), 6.92-6.90 (m, 2H), 6.84 (dd, J=8.4 and 1.5 Hz, 1H), 6.66 (ddd, J=7.2, 6.3 and 1.5 Hz, 1H), 3.91-3.89 (m, 2H), 3.83 (s, 3H), 3.69-3.65 (m, 2H), 3.48 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[N:4]([CH3:15])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([C:26](=[O:28])[CH3:27])=[CH:23][C:22]=2[CH:29]=1>>[C:26]([C:24]1[O:25][C:21]2[CH:20]=[CH:19][C:18]([NH:17][C:2]3[C:3](=[O:16])[N:4]([CH3:15])[S:5](=[O:14])(=[O:13])[C:6]=3[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:29][C:22]=2[CH:23]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)c1cc2cc(N)ccc2o1
Reactant: CN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: CC(=O)c1cc2cc(NC3=C(c4ccccc4)S(=O)(=O)N(C)C3=O)ccc2o1

Procedure:
The title compound was prepared from 4-chloro-2-methyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 1-(5-amino-1-benzofuran-2-yl)ethanone in a similar manner as described for e.g. Examples 9 and 13. 1H NMR (400 MHz, CD3CN): δ 7.89 (bs, 1H), 7.38-7.37 (m, 1H), 7.25 (d, 1H), 7.16-7.10 (m, 4H), 7.09-7.03 (m, 3H), 3.22 (s, 3H), 2.50 (s, 3H); Mass Spectrum: M+H+ 397.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([CH:19]=[O:20])=[C:17]2[C:12]([C:13](=[O:32])[C:14]([CH3:31])=[C:15]([CH:21]3[CH2:26][CH2:25][N:24]([C:27](=[O:30])[CH2:28][CH3:29])[CH2:23][CH2:22]3)[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(=CC)C.O.O.P([O-])(O)(O)=[O:41].[Na+].Cl([O-])=O.[Na+].Cl>O.C(O)(C)(C)C>[CH2:1]([O:8][C:9]1[C:18]([C:19]([OH:41])=[O:20])=[C:17]2[C:12]([C:13](=[O:32])[C:14]([CH3:31])=[C:15]([CH:21]3[CH2:26][CH2:25][N:24]([C:27](=[O:30])[CH2:28][CH3:29])[CH2:23][CH2:22]3)[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)N1CCC(c2oc3c(C=O)c(OCc4ccccc4)ccc3c(=O)c2C)CC1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCC(=O)N1CCC(c2oc3c(C(=O)O)c(OCc4ccccc4)ccc3c(=O)c2C)CC1
Reaction time: 19 h
Yield: 98.4 %

Procedure:
To a mixture composed of 7-(benzyloxy)-3-methyl-4-oxo-2-(1-propanoylpiperidin-4-yl)-4H-chromene-8-carbaldehyde (400 mg, 0.92 mmol) obtained in Example 34-2, tert-butyl alcohol (8 mL), water (8 mL), 2-methyl-2-butene (8 mL), and sodium dihydrogen phosphate dihydrate (864 mg, 5.54 mmol), 80% sodium chlorite (313 mg, 2.77 mmol) was added under cooling with ice, and then the mixture was brought back to room temperature and stirred for 19 hours. A 0.2 N aqueous hydrochloric acid solution (20 mL) was added to the reaction solution, and then the organic solvent was distilled off under reduced pressure. The resulting solid was collected by filtration to obtain 407 mg of the title compound (yield: 95%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][C:13]1[CH:14]=[CH:15][C:10]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:11][CH:12]=1
Reactant: OB(O)c1cccs1
Reactant: Cc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(-c2cccs2)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.8 %

Procedure:
A mixture of 2-thiopheneboronic acid (0.483 g, 3.78 mmol), 2-bromo-5-methylpyridine (0.5 g, 2.91 mmol), a solution of Na2CO3 (1M in H2O, 7.8 mL, 7.8 mmol) and a catalytic amount of Pd(PPh3)4 in DME (10 mL) was heated at the reflux temperature for 3 h., then allowed to cool to room temperature and poured onto ice. The resulting mixture was stirred for 10 min and extracted with CH2Cl2 (2×25 mL), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash chromatography (70% EtOAc/hex) to give 2-(5-methyl-2-pyridyl)thiophene (0.499 g, 98%): GC-MS m/z (rel abundance) 176 (MH+, 100%); 1H NMR (CDCl3) δ 1.39 (s, 3H), 7.15 (m, 1H), 7.39 (m, 1H), 7.61-7.43 (m, 3H), 8.41 (s, 1H).
Reaction SMILES: C=O.[BH3-][C:4]#N.[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]([CH2:38][NH:39][CH:40]([CH3:42])[CH3:41])[C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:27][N:26]=[C:25]4[NH:35][CH:36]=[CH:37][C:24]=34)[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1.C([O-])(O)=O.[Na+]>CO>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]([CH2:38][N:39]([CH:40]([CH3:42])[CH3:41])[CH3:4])[C:15]([N:17]2[CH2:18][CH2:19][N:20]([C:23]3[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:27][N:26]=[C:25]4[NH:35][CH:36]=[CH:37][C:24]=34)[CH2:21][CH2:22]2)=[O:16])=[CH:10][CH:9]=1
Reactant: CC(C)NC[C@@H](C(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)N(C)C[C@@H](C(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 26.2 %

Procedure:
Formaldehyde (0.0712 mL, 0.957 mmol) and NaCNBH3 (0.0120 g, 0.191 mmol) were added to (S)-2-(4-chlorophenyl)-3-(isopropylamino)-1-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)propan-1-one (0.055 g, 0.096 mmol, see Example 13) in MeOH (0.5 mL). The mixture was stirred at room temperature for 20 minutes. Saturated NaHCO3 (5 mL) was added, the aqueous layer was extracted with DCM (20 mL), and the combined organic phases were dried over sodium sulfate. After removal of the solvent, the residue was purified by chromatography (20:1:0.1 DCM:ethyl acetate:ammonium hydroxide) to give (S)-2-(4-chlorophenyl)-3-(isopropyl(methyl)amino)-1-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)propan-1-one (0.013 g, 23%) as a solid. MS ESI (+) m/z 516 detected.
Reaction SMILES: CC1C=CC=C(C)C=1NN.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([Te:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=O)=[CH:15][CH:14]=1>C1(C)C=CC=C(C)C=1>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([Te:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[CH:26][CH:25]=1
Reactant: COc1ccc([Te](=O)c2ccc(OC)cc2)cc1
Agent: Cc1cccc(C)c1NN
Solvent: Cc1cccc(C)c1
Product: COc1ccc([Te]c2ccc(OC)cc2)cc1
Yield: 74 %

Procedure:
2,6-Dimethylphenylhydrazine (68 mg, 0.50 mmol) was reacted with bis-(p-methoxyphenyl)-telluroxide for 0.2 h. to yield m-xylene (70%, p.l.c. (benzene-petroleum ether 1:1) afforded bis-(p-methoxyphenyl)-telluride (126 mg, 74%) and what appears to be 2,6-dimethylphenyl-4-methoxyphenyl-telluride as a colourless oil, m/e 342 (M+, 100%), 234, 212, 197, 105, 104, 79, 77, and 77.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[OH:20])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:21]1(=[O:27])[O:26][C:24](=[O:25])[CH2:23][CH2:22]1.Cl>CCCCCC.O1CCCC1>[C:24]([CH2:23][CH2:22][C:21]([O:20][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[CH:19][C:10]=1[CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:27])([OH:26])=[O:25]
Reactant: O=C1CCC(=O)O1
Reactant: Oc1c(Cc2ccccc2)ccc2ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)Oc1c(Cc2ccccc2)ccc2ccccc12
Yield: 68.7 %

Procedure:
Sodium hydride (60% in mineral oil; 1.32 g, 0.33 mol) was washed free of mineral oil by stirring in hexane and decanting the solvent. Tetrahydrofuran (75 mL) was added and the suspension was stirred at 0°. A solution of 2-phenylmethyl1-naphthol (7.00 g, 0.030 mol) in tetrahydrofuran (100 mL) was added dropwise. After the mixture was stirred for two hours, a solution of succinic anhydride (3.30 g, 0.033 mol) in tetrahydrofuran (80 mL) was added dropwise. After stirring for one hour at 0°, 1 N hydrochloric acid was added slowly until the mixture was acidic. The tetrahydrofuran was removed on a rotary evaporator and the residue was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, water and brine and was dried over MgSO4. Concentration provided a yellow solid, which was recrystallized (1-chlorobutane) to provide the title compound (6.89 g, 69%) as white crystals: mp 139.5°-140.5°; NMR (CDCl3) 7.79 (m, 2H), 7.66 (d, J=7 Hz, IH), 7.47 (m, 2H), 7.3-7.2 (m, 6H), 4.02 (s, 2H), 3.01 (t, J=6 Hz, 2H), 2.81 (t, J=6 Hz, 2H); IR (mull) 3200-2400, 1745, 1714; Calcd. for C21H18O4 : C-75.43 H-5.43; Found C-75.13 H-5.42.
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[CH2:16]([N:18]1[C:24]2[CH:25]=[C:26]([F:30])[C:27]([NH2:29])=[CH:28][C:23]=2[O:22][CH2:21][CH2:20][CH2:19]1)[CH3:17].Cl[C:32]1[N:37]=[C:36]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[CH:41][C:40]=2[O:51][CH3:52])[C:35]([Cl:53])=[CH:34][N:33]=1.C(=O)([O-])[O-]>C(O)(C)C.C(Cl)Cl>[Cl:53][C:35]1[C:36]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([N:45]3[CH2:46][CH2:47][O:48][CH2:49][CH2:50]3)=[CH:41][C:40]=2[O:51][CH3:52])=[N:37][C:32]([NH:29][C:27]2[C:26]([F:30])=[CH:25][C:24]3[N:18]([CH2:16][CH3:17])[CH2:19][CH2:20][CH2:21][O:22][C:23]=3[CH:28]=2)=[N:33][CH:34]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCCOc2cc(N)c(F)cc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Solvent: ClCCl
Product: CCN1CCCOc2cc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OC)n3)c(F)cc21
Reaction time: 1 h

Procedure:
10-Camphorsulfonic acid (70.5 mg, 0.303 mmol) was added to 9-Ethyl-2-fluoro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamine (58 mg, 0.28 mmol) and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (98 mg, 0.28 mmol) in Isopropyl alcohol (2 mL). The mixture was irradiated in a CEM microwave (140° C., 30 min) MP-Carbonate (2.69 mmol/g loading; 0.21 g, 0.57 mmol) and DCM (2 mL) were added and the mixture stirred for 1 h, then filtered onto a 5 g SiO2 cartridge, which which was air dried. The sample was chromatographed (ISCO, 2×12 g SiO2, 0-50% EtOAc:Hex) to afford 5-Chloro-N*2*-(9-ethyl-2-fluoro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-yl)-N*4*-(2-methoxy-4-morpholin-4-yl-phenyl)-pyrimidine-2,4-diamine as a lavender film (43 mg, 29%). LCMS 529 (M+H), 1H-NMR (CDCl3): 8.23 (d, 1H, J=8.7 Hz), 8.00 (s, 1H), 7.77 (d, 1H, J=8.7 Hz), 7.58 (s, 1H), 6.75 (s, 1H), 6.60 (d, 1H, J=13.2 Hz), 6.55 (m, 2H), 4.08 (t, 2H, J=5.6 Hz), 3.91 (s, 3H), 3.88 (t, 4H, J=4.6 Hz), 3.17 (m, 8H), 1.98 (m, 2H), 1.21 (t, 3H, J=7.0 Hz); 19F-NMR: −135.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14](=[O:32])[N:15]2[CH2:18][CH2:19][CH2:20][C:21]2([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[C:39]1([S:45][CH2:46][CH2:47]Br)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O.C(OCC)(=O)C>[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14](=[O:32])[N:15]2[CH2:18][CH2:19][CH2:20][C:21]2([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][N:24]([CH2:47][CH2:46][S:45][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:23][CH2:22]2)=[CH:10][CH:9]=1
Reactant: BrCCSc1ccccc1
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCN(CCSc2ccccc2)CC1
Temperature: 57.5 °C
Reaction time: 4.5 h
Yield: 68.1 %

Procedure:
To 2.5 mL of an N,N-dimethylformamide solution containing 0.10 g of ethyl 4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylate, 74 mg of potassium carbonate and 64 mg of 1-phenylthio-2-bromoethane were added at room temperature, and stirred at 55-60° C. for 4.5 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added. The organic layer was separated, was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=20:1], to give 93 mg of ethyl 4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)-1-(2-(phenylthio)ethyl)piperidine-4-carboxylate as a yellow oil.