Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][N:18]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([O:14]C)=[O:13])=[CH:8]2.[OH-].[Na+]>O1CCCC1.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][N:18]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8]2
Reactant: COC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cn3)cc(OC)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C(=O)O)[nH]c12
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 81.5 %

Procedure:
To a solution of methyl 7-methoxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylate (2.78 g) in a mixture of tetrahydrofuran (25 mL) and ethanol (20 mL) was added 1M aqueous sodium hydroxide solution (11 mL), and the mixture was stirred at 50° C. for 40 min. The mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1M hydrochloric acid (11 mL) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residual oil was solidified with diethyl ether to give the title compound (2.18 g, 81%) as a pale orange solid. MS 363 (MH+).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:15]=[CH:16][C:17]([F:21])=[C:18]([CH:20]=3)[NH2:19])[C:8]([CH2:12][CH3:13])=[N:9]2)=[CH:4][N:3]=1.[C:22]([NH2:25])(=[O:24])[CH3:23].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(P(C(C)(C)C)C1N(C2C(C3C=CC=CC=3)=NN(C3C=CC=CC=3)C=2C2C=CC=CC=2)N=CC=1)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:19][C:18]1[CH:20]=[C:14]([C:7]2[C:8]([CH2:12][CH3:13])=[N:9][C:10]3[C:5]([CH:6]=2)=[CH:4][N:3]=[C:2]([NH:25][C:22](=[O:24])[CH3:23])[CH:11]=3)[CH:15]=[CH:16][C:17]=1[F:21]
Reactant: CCc1nc2cc(Cl)ncc2cc1-c1ccc(F)c(N)c1
Reactant: CC(N)=O
Agent: [Pd]
Agent: CC(C)(C)P(c1ccnn1-c1c(-c2ccccc2)nn(-c2ccccc2)c1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2cc(NC(C)=O)ncc2cc1-c1ccc(F)c(N)c1
Temperature: 80 °C
Yield: 36.9 %

Procedure:
Sparge a solution of 5-(7-chloro-2-ethyl-1,6-naphthyridin-3-yl)-2-fluoroaniline (0.63 g, 2.088 mmol) in dioxane (20 mL) with argon, add acetamide (0.987 g, 16.70 mmol), K3PO4 (1.773 g, 8.35 mmol), Pd2(dba)3 (0.096 g, 0.104 mmol) and BippyPhos (0.106 g, 0.209 mmol) and heat at 80° C. for 16 h. Cool to RT, remove the solids via filtration through diatomaceous earth, rinse well with EtOAc and H2O, and separate the layers of the filtrate. Extract the aqueous layer with EtOAc (1×), wash the combined organics with brine, dry over Na2SO4, concentrate to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford the title compound (250 mg, 37%) as an off-white solid. MS(ESI) m/z: 325.1 (M+H+).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10](=[O:17])[C:11]#[C:12][C:13](O)([CH3:15])[CH3:14])[CH:7]=[CH:6][C:5]=12.C(NCC)C.C([OH:25])C>>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[O:17][C:13]([CH3:14])([CH3:15])[C:12](=[O:25])[CH:11]=3)[CH:7]=[CH:6][C:5]=12
Reactant: CCO
Reactant: CC(C)(O)C#CC(=O)c1ccc2nonc2c1
Solvent: CCNCC
Product: CC1(C)OC(c2ccc3nonc3c2)=CC1=O
Reaction time: 2 h
Yield: 83 %

Procedure:
To a stirred solution of 1-(benzo[c][1,2,5]oxadiazol-5-yl)-4-hydroxy-4-methylpent-2-yn-1-one (0.3 g, 1.304 mmol) in ethanol (15 mL), a solution of diethyl amine (0.095 g, 1.304 mmol) in EtOH (5 mL) was added dropwise at RT. The reaction mixture was then stirred for 2 h. The ethanol was then removed, and the mixture was diluted with EtOAc (10 mL). The combined organic layers were washed with water (5 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford 5-(benzo[c][1,2,5]oxadiazol-5-yl)-2,2-dimethylfuran-3(2H)-one (0.25 g, 83%) as a black oil.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:21]=[C:20]([C:22]([OH:24])=O)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].Cl.[OH:26][C:27]1[C:36]([N:37]([CH3:39])[CH3:38])=[CH:35][CH:34]=[C:33]2[C:28]=1[CH2:29][CH2:30][NH:31][CH2:32]2>>[C:1]([NH:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:21]=[C:20]([C:22]([N:31]3[CH2:30][CH2:29][C:28]4[C:33](=[CH:34][CH:35]=[C:36]([N:37]([CH3:39])[CH3:38])[C:27]=4[OH:26])[CH2:32]3)=[O:24])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Reactant: CN(C)c1ccc2c(c1O)CCNC2
Agent: Cl
Product: CC(=O)NCc1ccc(-c2nc(C(=O)N3CCc4c(ccc(N(C)C)c4O)C3)c3ccccc3n2)cc1
Yield: 5 %

Procedure:
Reaction of 2-(4-(acetamidomethyl)phenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-dimethylamino-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 68 (5% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.91 (s, 3H), 2.56 and 2.60 (2s, 6H), 2.63 and 2.90 (2t, 2H), 3.48 and 4.04 (2t, 2H), 4.34-4.37 (m, 2H), 4.39 and 4.92 (2s, 2H), 6.31-7.02 (m, 2H), 7.41-7.47 (m, 2H), 7.66-7.78 (m, 1H), 7.88-7.98 (m, 1H), 8.02-8.17 (m, 2H), 8.43-8.51 (m, 3H); MS (ESI) m/z 496 ([M+H]+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]([C:20]([NH2:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)=[CH:2]1>CO.[Pd]>[S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]([C:20]([NH2:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)=[CH:2]1
Reactant: NC(=O)c1cccc(OCCCCC/C=C\c2ccsc2)c1
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1cccc(OCCCCCCCc2ccsc2)c1
Reaction time: 72 h
Yield: 48 %

Procedure:
To a solution of example 62 3-{[(Z)-7-(3-Thienyl)-6-heptenyl]oxy}benzene carboxamide (260 mg, 0.82 mmol) in MeOH (8 ml), 10% Pd/C (30 mg) was added. The mixture was stirred under H2 at r.t for 3 days. The catalyst was removed by filtration through a pad of Celite and the solvent was evaporated under reduced pressure, to a small volume. The precipitant solid was filtered and rinsed with Et2O/pentane to give the desired compound as a white solid (130 mg, 48%), mp 97-100° C. HPLC-MS (method 1): m/z 318 [M+H]+, Rt=4.87 min.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.Cl[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]2[N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:31][C:32]=2[CH3:33])=[N:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:33][C:32]1[O:31][C:30]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[N:29][C:28]=1[CH2:27][O:26][C:23]1[N:24]=[CH:25][C:20]([CH2:19][O:1][C:2]2[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:3]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)Cc1cn(-c2ccccc2)nc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)nc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 77.3 %

Procedure:
A mixture of methyl (3-hydroxy-1-phenyl-1H-pyrazol-4-yl)acetate (406 mg), 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (551 mg), potassium carbonate (484 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give methyl [3-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethoxy]-1-phenyl-1H-pyrazol-4-yl]acetate (690 mg, yield 77%), which was then recrystallized from ethyl acetate-hexane. melting point: 96–97° C.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH2:9])=[O:8].[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22](O)=[O:23])=[O:16])([CH3:13])([CH3:12])[CH3:11].Cl.CN(C)CCCN=C=NCC>C1COCC1>[C:7]([C:3]1[N:2]([NH:1][C:22]([C@@H:18]2[CH2:19][CH2:20][CH2:21][N:17]2[C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])=[O:23])[CH:6]=[CH:5][CH:4]=1)(=[O:8])[NH2:9]
Reactant: NC(=O)c1cccn1N
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nn1cccc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
A mixture of 1-amino-1H-pyrrole-2-carboxamide (3.00 g, 24.0 mmol) and (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (7.18 g, 28.8 mmol) was dissolved in THF (240 mL). To this solution was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.52 g, 28.8 mmol). The reaction was stirred overnight at rt, then concentrated in vacuo. The crude residue was dissolved in CH2Cl2 then washed with water (3×200 mL) and brine (200 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo to a sticky gum, which was dissolved in a 1:1 solution of CH2Cl2/Hex, then concentrated in vacuo to remove most of the CH2Cl2. The precipitate that formed was filtered and dried to give 1A (6.68 g, 78%). 1A had an analytical HPLC retention time=2.132 min (Phenomenex Luna 3.0×50 mm, 10-90% aqueous MeOH over 5 min containing 0.1% TFA) and a LC/MS M++1=357.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][NH2:10])=[N:7][CH:8]=1.C(O[CH2:14][CH2:15][C:16]#[N:17])C>C(O)C>[NH2:17][C:16]1[CH2:15][CH2:14][N:9]([C:6]2[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][N:7]=2)[N:10]=1
Reactant: NNc1ccc(Cl)cn1
Reactant: CCOCCC#N
Agent: [Na]
Solvent: CCO
Product: NC1=NN(c2ccc(Cl)cn2)CC1

Procedure:
A 0.08 g. amount of sodium metal is dissolved in 10 ml. of absolute ethanol, then 2.5 g. of 5-chloro-2-hydrazinopyridine is added, followed by 1.70 g. of beta-ethoxypropionitrile. The procedure of Example 1 is continued to give 1.40 g. of the product of the Example as yellow crystals, m.p. 203°-204.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:21][CH2:20]1>CN(C=O)C>[CH2:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:6]2[C:5]([F:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:20][CH2:21]1)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC(CNc2nc(Cl)ncc2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2,4-dichloro-5-fluoro-pyrimidine (0.67 g, 4.03 mmol) and triethylamine (0.84 mL, 6.04 mmol) in DMF (5 mL) was added benzyl 4-(aminomethyl)piperidine-1-carboxylate (EXAMPLE 13, Step 1) (1.00 g, 4.03 mmol). The resulting reaction solution was stirred at rt for 1 h, and concentrated in vacuo. The residue was purified by silica gel chromatography (CH2Cl2/IPA/hexanes) to give 4-[(2-chloro-5-fluoro-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester. M.S. (M+1): 379.25
Reaction SMILES: [OH-].[K+:2].[C:3]([O:10]C)(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6]>CO>[C:5]([O:7][CH3:8])(=[O:6])[CH2:4][C:3]([O-:10])=[O:9].[K+:2]
Reactant: COC(=O)CC(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)CC(=O)[O-]
Yield: 76 %

Procedure:
111.6 g of KOH (1.8 mol) are dissolved in 500 g of methanol, and the solution is added to 264.2 g of dimethyl malonate (2 mol) in the course of 2 h at room temperature. The KPG agitator is operated during this at 50 rpm. This mixes the reaction suspension inadequately, broad edge zones remain virtually unmixed. The reaction suspension is then filtered and the filtration residue is washed with methanol and dried in vacuo. 214.2 g of KMM are is obtained, equivalent to a yield of 76% of theory having a DKM content of <0.2% by weight.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][N:7]=1)=[O:4].O.C(Cl)[Cl:17]>>[Cl:17][C:9]1[C:10]([CH3:12])=[CH:11][C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:14])([CH3:13])[CH3:1])=[N:7][CH:8]=1
Reactant: Cc1ccnc(NC(=O)C(C)(C)C)c1
Reactant: ClCCl
Solvent: O
Product: Cc1cc(NC(=O)C(C)(C)C)ncc1Cl
Temperature: 0 °C
Reaction time: 1.33 h

Procedure:
2,2-Dimethyl-N-(4-methyl-pyridin-2-yl)-propionamide (42 g, 0.22 mol) from Step 1 was placed in a 3-neck 3 L flask fitted with an overhead stirrer. To this was added water (650 mL), then Na2HPO4 (78 g, 0.55 mol), followed by DCM (220 mL). The mixture was stirred and cooled in an ice-bath to 0° C., then chlorine gas was bubbled slowly through a sparge-frit. The reaction was monitored by TLC (EtOAc/hexanes 1/1), and found to be complete after 80 min. The reaction mixture was poured into a separatory funnel and extracted. The aqueous layer was re-extracted with DCM (2×100 mL). The combined layers were dried over Na2SO4 and concentrated to a crude solid product which was recrystallized from hexanes to yield the purified N-(5-chloro-4-methyl-pyridin-2-yl)-2,2-dimethyl-propionamide (41 g, 0.18 mol). 1H NMR (CDCl3) δ 8.18 (s, 1 H), 8.12 (s, 1 H), 7.94 (br s, 1 H), 2.35 (s, 3H), 1.29 (s, 9H).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:50][C:51]([F:67])([F:66])[O:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([NH2:65])[CH:60]=1>CN(C=O)C>[F:50][C:51]([F:66])([F:67])[O:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([NH:65][C:23]([C:18]2[C:19](=[O:22])[O:20][C:21]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[O:11][CH3:10])=[O:25])[CH:60]=1
Reactant: Nc1cccc(-c2ccccc2OC(F)(F)F)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccccc4OC(F)(F)F)c3)c(=O)oc12
Temperature: 25 °C
Yield: 78.2 %

Procedure:
DIEA (0.011 mL, 0.065 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.013 g, 0.059 mmol) and HATU (0.025 g, 0.065 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′-trifluoromethoxy-biphenyl-3-ylamine (0.015 g, 0.059 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.021 g of product in 76% yield: LCMS (ESI) m/z 456 (MH+).
Reaction SMILES: [CH2:1]([Si:13](Cl)(Cl)Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27]>CCCCCCC>[CH2:1]([Si:13]([O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH3:17])([O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH3:17])[O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: COCCOCCOCCO
Reactant: CCCCCCCCCCCC[Si](Cl)(Cl)Cl
Solvent: CCCCCCC
Product: CCCCCCCCCCCC[Si](OCCOCCOCCOC)(OCCOCCOCCOC)OCCOCCOCCOC

Procedure:
The procedure of Example 1 was repeated with 151.8 g (0.50 mole) of dodecyltrichlorosilane and 200 g. of heptane. Under nitrogen 254.2 g (1.55 mole) of 2-(2-(2-methoxyethoxy)ethoxy)ethanol was added over 3 hours at 80° C. followed by heating of the reaction for an additional 48 hours. Vacuum stripping of all volatiles left 350 g of the clear, pale yellow liquid product.
Reaction SMILES: [C:1]([OH:18])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Na].Cl.[NH2:21][OH:22]>C(O)(=O)C.O>[CH2:5]([C:4]1[CH:3]=[C:2]([C:1]([OH:18])=[O:17])[O:22][N:21]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Reactant: NO
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCc1cc(C(=O)O)on1
Temperature: 60 °C
Reaction time: 25 h

Procedure:
To a stirred, warm (55° C.) solution of hexadecanoic acid, 2,4-dioxo, ethyl ester, monosodium salt (15.50 g, 0.046 mol) in glacial acetic acid (125 mL) was added dropwise a solution of hydroxylamine hydrochloride (6.45 g, 0.093 mol) in water (32 mL) over 10 minutes, and the mixture was stirred at 60° C. for 25 hours. The mixture was allowed to cool and partitioned between H2O (250 mL) and chloroform (400 mL). The organic layer was washed (saturated NaCl), dried (MgSO4), and rotoevaporated. The residue was dissolved (toluene), rotoevaporated, and the solid recrystallized from toluene to give a white solid, yield 5.62 g (43%), mp 119°-122° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[CH:8]([CH3:20])[C:9]([C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]([CH3:19])[CH:12]=1)=[O:10].[F:21][C:22]1[CH:34]=[CH:33][C:25]([CH2:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:24][CH:23]=1>C(O)C>[F:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][CH:27]2[CH2:28][CH2:29][N:30]([CH:8]([CH3:20])[C:9]([C:11]3[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]([CH3:19])[CH:12]=3)=[O:10])[CH2:31][CH2:32]2)=[CH:33][CH:34]=1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: Cc1cc(C(=O)C(C)Br)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C(=O)C(C)N2CCC(Cc3ccc(F)cc3)CC2)cc(C)c1O
Reaction time: 8 h

Procedure:
2.12 g (0.02 mol) of sodium carbonate are added to a mixture of 5.14 g (0.02 mol) of 2-bromo-4'-hydroxy-3',5'-dimethylpropiophenone and 4 g (0.02 mol) of 4-(4-fluorobenzyl)-piperidine in 25 ml of ethanol and the mixture is heated under reflux for 3 hours. It is left to stand overnight and then purified by chromatography on a column of silica using acetone as the eluant. This give 6.6 g of a brown oil, which is used as such.
Reaction SMILES: [Br:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.Cl.[NH2:9][CH2:10][C:11](=[O:15])[CH2:12][CH2:13][CH3:14].C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1([C:5]([NH:9][CH2:10][C:11](=[O:15])[CH2:12][CH2:13][CH3:14])=[O:7])[CH2:4][CH2:3]1
Reactant: O=C(O)C1(Br)CC1
Reactant: CCCC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)CNC(=O)C1(Br)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
A mixture of 2.57 g of 1-bromocyclopropanecarboxylic acid 4 [H. M. R. Hoffmann et al. J. org. Chem. 54, 6096 (1989)], 2.22 g of 1-amino-2-pentanone hydrochloride 5 [M. Jackman et al. J. Am. Chem. Soc. 70, 2884 (1948)] and 3.36 g of N,N′-dicyclohexylcarbodiimide in 234 ml of methylene chloride in the presence of 2.46 ml of triethylamine is stirred overnight at room temperature. Then, it is filtered, the filtrate is concentrated by evaporation, and the residue is chromatographed on silica gel with ethyl acetate/hexane. 2.74 g of 1-bromo-N-(2-oxopentyl)-cyclopropane-1-carbamide 6 is obtained as a crystallizing oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[F:22][C:16]1[CH:15]=[CH:14][C:13]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:18][C:17]=1[N+:19]([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: COc1ccc(B(O)O)cc1
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: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(F)c([N+](=O)[O-])c2)cc1

Procedure:
Tetrakis(triphenylphosphine)palladium (I g) was added to a mixture of 5 g of 4methoxyphenylboronic acid, 6.6 g of 5-bromo-2-fluoronitrobenzene and 30 mL of 2 M sodium carbonate solution in 50 mL of toluene and 50 mL of ethanol. The mixture was refluxed for 2 hours, concentrated, and the residue extracted twice with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried, and concentrated to give a brown oily solid. The solid was chromatographed on silica gel (5% ethyl acetate in hexane) to give crude 4-fluoro-4′-methoxy-3-nitrobiphenyl as a pale yellow solid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:30]=[N+]=[N-].[Na+].N(CC1CC2C=CCC(C3C=CC=C(Cl)C=3Cl)(N)C=2O1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>O1CCCC1.C(O)(C)C>[CH3:29][C:23]1[C:24]([CH3:28])=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH2:30])[CH2:17][C:16]=2[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cccc(C)c4C)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [N-]=[N+]=NCC1CC2=C(O1)C(N)(c1cccc(Cl)c1Cl)CC=C2
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cc1cccc(-c2cccc3c2OC(CN)C3)c1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 54 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with (2,3-dimethyl-phenyl)boronic acid (0.294 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.041 g, 0.052 mmol), and potassium carbonate (0.41 g, 3.25 mmol) generally according to the procedure described for Intermediate 37 provided 0.335 g (62%) of (±)-[7-(2,3-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. Treatment of (±)-[7-(2,3-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate with sodium azide (0.134 g, 2.06 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-7-(2,3-dichlorophenyl)-2,3-dihydro-1-benzofuran-7 amine. To a solution of (±)-2-(azidomethyl)-7-(2,3-dichlorophenyl)-2,3-dihydro-1-benzofuran-7 amine (0.135 g, 1.483 mmol) in tetrahydrofuran (5 mL) was added polymer supported triphenyl phosphine (0.152 g, 0.58 mmol) and the reaction mixture was allowed to stir at room temperature for 12 h. The reaction mixture was filtered (celite) and the solvent removed in vacuo to provide a colorless oil. The oil was re-dissolved in isopropanol (3 mL) and hydrogen chloride (1.0 N in diethyl ether, 10.0 mL) was added. The resulting precipitate was filtered, washed (diethyl ether), and dried to afford 0.075 g (54%) of (±)-1-[7-(2,3-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp >225° C.: