Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH2:8][C:9](OC)=[O:10])[CH:5]=[CH:6][CH:7]=1.[Li+].[BH4-].CCOC(C)=O>C1COCC1>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1cccc(Br)c1OC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1c(Br)cccc1CCO
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-(3-bromo-2-methoxyphenypethanol To a solution of methyl (3-bromo-2-methoxyphenyl)acetate (8.2 g, 31.66 mmol) in 200 mL of dry THF under N2 at room temperature was added LiBH4 (32 mL, 63.32 mmol, 2M THF). After 1.5 hours, the reaction was warmed to reflux for 3 hours, and then cooled to room temperature. The solution was poured into EtOAc/1N HCl solution, and the layers were separated. The organic layer was washed with water, saturated Na2CO3 and brine, dried over anhydrous Na2SO4 and concentrated to give 2-(3-bromo-2-methoxyphenyl)ethanol. Step E: methyl 6-bromo-5-methoxy-3,4-dihydro-1H-isochromene-1-carboxylate TiCl4 (9.84 g, 104 mmol) was added over a period of 20 min to an ice-cooled mixture of 2-(3-bromo-2-methoxyphenyl)ethanol (6 g, 26.0 mmol) and ethyl diethoxyacetate (5.5 g, 31.1 mmol) in 60 mL of CH3NO2. After stirred for 10 min, the ice bath was removed and the mixture was allowed to stir at room temperature over night. The mixture was poured onto ice/aqueous 1N HCl. Extracted by DCM and backwashed with 1N HCl and brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified via column chromatograph to give methyl 6-bromo-5-methoxy-3,4-dihydro-1H-isochromene-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([Br:22])=[CH:19][CH:20]=3)[C:15](=[O:23])[N:14]2[CH3:24])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:25]=[C:26]1[NH:31][CH2:30][CH2:29][CH2:28][N:27]1[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([Br:22])=[CH:19][CH:20]=3)[C:15](=[O:23])[N:14]2[CH3:24])[CH2:10][CH2:11][N:35]2[CH2:36][CH2:37][CH:32]([N:27]3[CH2:28][CH2:29][CH2:30][NH:31][C:26]3=[O:25])[CH2:33][CH2:34]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1NCCCN1C1CCNCC1
Reactant: CN1C(=O)c2cc(Br)ccc2C1C(CC=O)c1ccc(Cl)c(Cl)c1
Product: CN1C(=O)c2cc(Br)ccc2C1C(CCN1CCC(N2CCCNC2=O)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 141.7 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(5-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.325 g) was coupled to 4-(2-oxoperhydropyrimidine-1-yl)piperidine (0.139 g) by a method similar to that described in Example 8. The reaction product was not purified by chromatography but converted to the corresponding hydrochloride salt as described in the Example 8 to afford the title compound (0.34 g); mp 195°-205° C. (d); MS: m/z=595(M+); NMR(CD3SOCD3): 1.67-1.92 (m,5), 3.29 (s,3), 4.64 (m,2), 5.21 (s,1), 6.63 (d,1, J=7.6), 6.89 (s,1), 7.20 (d,1, J=8), 7.63-7.82 (m,3). Analysis for C27H31Cl2N4O2Br·0.75 H2O·1.0 HCl: Calculated C, 50.33; H, 5.24, N, 8.70; Found: C, 50.31; H, 5.33; N, 8.43.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:5]=2[CH:4]=1.Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(N(CC)CC)C>CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3[CH2:14][CH2:13][N:12]([CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:5]=2[CH:4]=1
Reactant: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Reactant: ClCCN1CCOCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc2c3c(c(=O)oc2c1)CN(CCN1CCOCC1)CC3
Reaction time: 4 h

Procedure:
A mixture of 10 g (0.043 m) of 1,2,3,4-tetrahydro-8-methoxy-5H-[1]benzopyrano [3,4-c]pyridin-5-one, 11.2 g (0.06 m) of N-(2-chloroethyl)-morpholine HCl and 14.2 g of triethylamine (0.14 m) in 170 ml of abs. EtOH was refluxed with stirring and protection from moisture for 4 hours. The reaction was filtered hot, cooled slightly and treated with dry HCl. The resulting precipitate was filtered and washed with EtOH, then ether; yield 14.6 g (81%). Crystallization from methanol afforded analytical material, mp 237°-40° C.
Reaction SMILES: [Sn:1](Cl)(Cl)(Cl)Cl.O.O.O.O.O.[P:11](=[O:15])([OH:14])([OH:13])[OH:12].[OH-].[Na+]>O>[P:11]([O-:15])([O-:14])([O-:13])=[O:12].[Sn+4:1].[P:11]([O-:15])([O-:14])([O-:13])=[O:12].[P:11]([O-:15])([O-:14])([O-:13])=[O:12].[P:11]([O-:15])([O-:14])([O-:13])=[O:12].[Sn+4:1].[Sn+4:1]
Reactant: Cl[Sn](Cl)(Cl)Cl
Reactant: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=P([O-])([O-])[O-]
Product: [Sn+4]

Procedure:
35 g of SnCl4.5H2O was dissolved in 250 ml of water and added to 250 ml of 3 M phosphoric acid with stirring. Then 0.8 M NaOH was added until a precipitate formed. The mixture was boiled and the precipitate which formed was filtered off and added to 500 ml of 6 M phosphoric acid and refluxed for 24 hours. The solid was filtered off, washed several times with distilled water and air dried overnight. The product was essentially amorphous showing only a few indistinct peaks when exposed to x-radiation. Analysis was close to the composition SnO2.P2O5.4H2O. However, the water content tended to vary from preparation to preparation.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1.[CH:16]1[C:24]2[C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[O:21][C:20]=2[C:19]([C:29]2[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=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>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:32]2[CH:33]=[CH:34][C:29]([C:19]3[C:20]4[O:21][C:22]5[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=5[C:24]=4[CH:16]=[CH:17][CH:18]=3)=[CH:30][CH:31]=2)=[CH:10][CH:9]=1
Reactant: OB(O)c1ccc(-c2cccc3c2oc2ccccc23)cc1
Reactant: COC(=O)CCSCc1ccc(Br)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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)CCSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1
Temperature: 25 °C
Yield: 72.9 %

Procedure:
A solution of 3-(4-bromophenylmethylsulfanyl)-propanoic acid methyl ester (289 mg, 1 mmol), 4-(4-dibenzofuranyl)benzeneboronic acid (302 mg, 1.05 mmol) and Pd(PPh3)4 (52 mg, 5 mol %) in toluene (10 mL) and ethanol (3.0 mL) was treated with 2 M K2CO3 (1.5 mL). The reaction mixture was heated to reflux for 2 h, cooled to room temperature, diluted with ethyl acetate (100 mL). The organic layer was washed successively with 2% aq HCl and sat. aq NaCl, dried over MgSO4 and concentrated. Purification by flash column chromatography (2-10% ethyl acetate in heptane) gave 3-(4′-dibenzofuran-4-yl-biphen-4-ylmethylsulfanyl)-propanoic acid methyl ester (330 mg, 72%) as white solid. 1H NMR (CDCl3), 8.01 (d, J=8 Hz, 2H), 7.94 (d, J=8 Hz, 2H), 7.78 (d, J=8 Hz, 2H), 7.66 (m, 4H), 7.42 (m, 5H), 3.81 (s, 2H), 3.71 (s, 3H), 2.76 (t, J=6 Hz, 2H), 2.56 (t, J=6 Hz, 2H). LCMS 475 (M++23).
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:23]#[N:24])[C:10]([CH3:22])=[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=4[F:21])[C:12]=3F)[N:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:32][N:33]([CH3:39])[C@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1.C(=O)([O-])O.[Na+]>CS(C)=O.C(OCC)(=O)C>[CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:23]#[N:24])[C:10]([CH3:22])=[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=4[F:21])[C:12]=3[N:36]3[CH2:37][CH2:38][C@H:34]([N:33]([CH3:39])[CH3:32])[CH2:35]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(-c2cccc(F)c2F)c(F)c2oc(C3CC3)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(-c2cccc(F)c2F)c(N2CC[C@H](N(C)C)C2)c2oc(C3CC3)nc2c1C#N
Temperature: 90 °C
Reaction time: 23 h
Yield: 85.4 %

Procedure:
2-Cyclopropyl-6-(2,3-difluorophenyl)-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-177) (109 mg, 0.33 mmol) was dissolved in dimethyl sulfoxide (3 ml), then at room temperature, triethylamine (70 μl, 0.50 mmol) and (3S)-3-(dimethylamino)pyrrolidine (55 μl, 0.43 mmol) were added. The solution was stirred under nitrogen atmosphere at 90° C. for 23 hours. After cooling to room temperature, the reaction liquid was fractionated with ethyl acetate and an aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was further extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, then the solvent was evaporated away, and the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=92:8) to obtain a roughly-purified product (119 mg, 85%) as a white solid. This was recrystallized from diisopropyl ether to obtain the entitled compound (71 mg) as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][CH2:8][CH2:9][OH:10])[CH2:3][CH2:2]1.[CH3:11][N:12]1[CH:16]=[C:15]([C:17](O)=[O:18])[N:14]=[CH:13]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(#N)C>[OH:10][CH2:9][CH2:8][N:7]([CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[C:17]([C:15]1[N:14]=[CH:13][N:12]([CH3:11])[CH:16]=1)=[O:18]
Reactant: OCCNC1CCOCC1
Reactant: Cn1cnc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cnc(C(=O)N(CCO)C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
A mixture of 2-(tetrahydro-2H-pyran-4-ylamino)ethanol (3.45 g), 1-methyl-1H-imidazole-4-carboxylic acid (3.00 g), HATU (13.6 g), diisopropylethylamine (12.4 mL) and acetonitrile (52 mL) was stirred at room temperature for 2 hours. The solvents were distilled off under reduced pressure and the resulting residue was purified by column chromatography (silica gel cartridge; chloroform/methanol=98:2 to 96:4) to give the titled compound (2.34 g).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].Br[CH2:7][CH2:8][CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>>[Si:11]([O:10][CH2:9][CH2:8][CH2:7][NH:5][CH2:1][CH2:2][CH2:3][CH3:4])([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: CCCCN
Product: CCCCNCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Butan-1-amine (8 mL) was added to (3-bromopropoxy)(tert-butyl)dimethylsilane (0.8 g) and the resulting mixture stirred overnight at RT. The volatiles were removed by concentration under reduced pressure and the residue was partitioned between saturated sodium bicarbonate solution (20 mL) and ethyl acetate (25 mL). The phases were separated and the aqueous phase was extracted with more ethyl acetate (2×25 mL). The combined organic phases were washed with brine (25 mL), dried over sodium sulphate, filtered and evaporated to give the titled compound as a clear oil. Yield 0.75 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[O:6][C@H:5]([CH2:7][O:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([C:19](O)=[O:20])[CH:17]=3)[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH:11]=2)[CH2:4][O:3]1.CN1CCOCC1.Cl.[CH3:39][NH:40][OH:41]>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1([CH3:30])[O:6][C@H:5]([CH2:7][O:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([C:19]([N:40]([OH:41])[CH3:39])=[O:20])[CH:17]=3)[N:12]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[CH:11]=2)[CH2:4][O:3]1
Reactant: CNO
Reactant: CC1(C)OC[C@@H](COCc2cn(Cc3ccc(F)cc3)c3cnc(C(=O)O)cc23)O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN(O)C(=O)c1cc2c(COC[C@@H]3COC(C)(C)O3)cn(Cc3ccc(F)cc3)c2cn1
Reaction time: 2 h
Yield: 44.4 %

Procedure:
To a solution of 3-({[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}methyl)-1-(4-fluorobenzyl)-1H -pyrrolo[2,3-c]pyridine-5-carboxylic acid (200 mg 0.4828 mmol) in anhydrous DMF (10 mL) was added CDMT (102 mg 0.5793 mmol 1.2 eq.) and NMM (0.064 mL, 0.5793 mmol 1.2 eq.). The mixture, under nitrogen, was stirred for 2 hours, during which it slowly darkened to a deep orange. N-Methylhydroxylamine Hydrochloride (202 mg 2.414 mmol 5.0 eq) was added and stirring continued for 10 hours. The reaction was judged to be complete by HPLC-MS analysis and the volatiles were removed in vacuo (ca. 2 torr) to give a golden yellow oil. This oil was dissolved in EtOAc (30 mL) and washed with water (3×20 mL) and brine (20 mL). The organic phase was separated, dried (Na2SO4), and concentrated in vacuo to afford the crude product which was purified by prep HPLC to give 95 mg (44%) of 3-({[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy)methyl)-1-(4-fluorobenzyl)-N -hydroxy-N-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxamide as a white powder. LC-MS (Eclipse XDB-C8, 0.8 mL/min, gradient 80:20 to 5:95H2O (+0.1% HOAc):CH3CN—5 minutes, ESI, +mode): RT—2.278 min, m/e=444.2 (M+H+, base). 1H-NMR (400 MHz, CDCl3): δ=1.34 (s, 3H), 1.38 (s, 3H), 3.52 (m, 4H), 3.62 (m, 1H), 3.67 (m, 1H), 4.04 (m, 1H), 4.32 (m, 1H) 4.77 (q, 2H), 5.38 (s, 2H), 7.06 (m, 2H), 7.16 (m, 2H), 7.43 (s, 1H), 8.47 (s, 1H), 8.64 (s, 1H).
Reaction SMILES: C([O:3][P:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])C.Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH2:9]([O:8][P:4]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1)([O:5][CH2:6][CH3:7])=[O:3])[CH3:10]
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: CCOP(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1ccc(C(=O)O)cc1)OCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.4 %

Procedure:
Triethylphosphite (9.28 mL, 53.3 mmol) and α-bromo-p-toluic acid (10.4 g, 48.4 mmol) were suspended in toluene (25 mL) and the mixture was heated to reflux for 18 h. The mixture was cooled to room temperature. After 12 h, the resulting white solid was collected by suction filtration, washed with petroleum ether and dried to yield 4-(diethoxyphosphorylmethyl)benzoic acid as a white solid (10.2 g, 77%): mp 117-120° C.; 1H NMR δ 1.26 (t, J=6.8 Hz, 6H), 3.24 (d, J=25.6 Hz, 2H), 4.06 (m, 4H), 7.38-7.40 (m, 2H), 8.02 (d, J=7.6 Hz, 2H), 11.4 (br s, 1H); 13C NMR δ 16.5, 16.6, 33.4, 34.8, 62.8, 62.9, 129.1, 129.2, 130.00, 130.05, 130.10, 130.48, 130.51, 137.3, 137.4, 170.1; FABMS obsd 273.0896, calcd 273.0892; Anal. Calcd. for C12H17O5P: C, 52.94; H, 6.29. Found: C, 52.92; H, 6.28. A suspension of 4-(diethoxyphosphorylmethyl)benzoic acid (9.99 g, 36.7 mmol) in anhydrous THF (40 mL) at 0° C. was treated dropwise over 10 min with borane-THF complex (40.3 mL, 40.3 mmol, 1.0 M in THF). The reaction mixture was stirred at room temperature for 4 h. The reaction was quenched by slow addition of water. The mixture was concentrated and the residue was partitioned between water (100 mL) and CH2Cl2 (100 mL). The aqueous layer was washed with CH2Cl2. The combined organic layers were washed with water, dried (MgSO4), and concentrated to give a yellow oil. Analysis by TLC and 1H NMR spectroscopy showed starting material (˜10%) and the desired benzyl alcohol. The latter (9.56 g) was dissolved in CH2Cl2 and rapidly added to a sample of PCC (10.8 g, 50.1 mmol) in CH2Cl2 (50 mL) with rapid stirring. After 2 h, ethyl ether (150 mL) was added and the organic solution was decanted from the tarry residue. The residue was washed with ethyl ether (3×50 mL). The combined organic solution was filtered through Florisil and concentrated to a brown oil. Kugelrohr distillation (190° C. @ 0.05 Ton) afforded a clear, colorless oil (6.54 g, 77%): 1H NMR δ 1.24 (t, J=7.2 Hz, 6H), 3.21 (d, J=22.4 Hz, 2H), 4.03 (m, 4H), 7.45-7.48 (m, 2H), 7.83 (d, J=7.6 Hz, 2H), 9.99 (s, 1H); 13C NMR δ 16.1, 16.2, 33.0, 34.9, 62.1, 62.2, 77.2, 129.49, 129.53, 129.6, 129.66, 129.71, 130.2, 130.2, 138.8, 138.9, 191.61, 191.63; 31P NMR δ 25.4, 25.9; FABMS obsd 257.0949, calcd 257.0943 (C12H17PO4).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.C([Li])CCC.CCCCCC.[CH3:21][C:22]1[CH:23]=[C:24]([O:27][C:28]=1[CH3:29])[CH:25]=[O:26].O>O1CCCC1>[CH3:21][C:22]1[CH:23]=[C:24]([CH:25]([C:2]2[CH:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=2)[OH:26])[O:27][C:28]=1[CH3:29]
Reactant: COc1ccc(Br)cn1
Reactant: Cc1cc(C=O)oc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COc1ccc(C(O)c2cc(C)c(C)o2)cn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
3-Bromo-6-methoxypyridine (1.67 g) was dissolved in tetrahydrofuran (40 ml) under an argon atmosphere to prepare a solution. A 1.6 M n-butyllithium/hexane solution (5.7 ml) was added dropwise to the solution at −78° C., and the mixture was then stirred at −78° C. for 30 min. A solution of 4,5-dimethylfurfural (1.00 g) in tetrahydrofuran (20 ml) was added dropwise thereto, and the temperature of the mixture was raised to room temperature while stirring. Water was added to the reaction solution to stop the reaction, and the solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-ethyl acetate to give (4,5-dimethylfuran-2-yl)-(6-methoxypyridin-3-yl)-methanol (1.24 g, yield 60%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([S:10][CH3:11])[CH:3]=1.CO.Cl.O>C1COCC1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([S:10][CH3:11])[CH:3]=1
Reactant: CSc1cc(F)ccc1C#N
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CSc1cc(F)ccc1CN
Temperature: 60 °C
Yield: 7.6 %

Procedure:
4-Fluoro-2-(methylthio)benzonitrile (prepared as in Anthony, N. J. et al. PCT Appl. WO 02/30931, 2002) (1.67 g, 0.1 mol) was dissolved in 20 mL THF (under N2) and treated with 10 mL 2M BH3—(CH3)2S. This was heated at 60° C. for 2 hrs. Heating was discontinued and 5 mL MeOH was cautiously added, followed by the cautious addition of 4 mL 6N HCl. Then 20 mL more H2O added and EtOAc and the layers were separated. The aqueous layer was made basic with 1N NaOH and extracted with CH2Cl2. The extracts were dried (MgSO4), filtered, concentrated and dried in vacuum to give the title compound (1.3 g, 76%)as a solid. 1H NMR (500 MHz, CDCl3) δ: 7.20-7.31 (1 H, m) 6.90 (1H, dd, J=2.4 Hz) 6.75-6.86 (1H, m) 3.86 (2H, s) 2.47 (3H, s). LC/MS (M+H): 172.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([OH:43])=O)=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[CH3:48][N:49]1[CH:53]=[C:52]([CH2:54][NH2:55])[CH:51]=[N:50]1>>[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([NH:55][CH2:54][C:52]4[CH:51]=[N:50][N:49]([CH3:48])[CH:53]=4)=[O:43])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: Cn1cc(CN)cn1
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cnn(C)c1
Yield: 76 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (1-methyl-1H-pyrazol-4-yl)methanamine, the title compound was obtained as a colorless solid in 76% yield: 1H NMR (300 MHz, CDCl3) δ 7.45 (s, 1H), 7.39 (s, 1H), 7.30-7.23 (m, 2H), 7.07-6.98 (m, 2H), 6.08 (s, 1H), 5.84 (t, J=4.0 Hz, 1H), 4.44-4.39 (m, 4H), 3.88 (s, 3H), 3.83-3.75 (m, 2H), 3.47-3.39 (m, 2H), 2.48 (s, 3H); MS (ES+) m/z 428.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH:14]=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:19]2[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccccc1-c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2-c2ccc(Cl)cc2)CC1

Procedure:
4′-Chlorobiphenyl-2-carbaldehyde (EXAMPLE 27C) (4.1 g), tert-butyl piperazine-1-carboxylate (4.23 g), and sodium triacetoxyborohydride (5.61 g) in CH2Cl2 (60 mL) were combined stirred for 24 hours. The reaction was quenched with methanol and poured into ether. The solution was washed with water and brine, concentrated, and chromatographed on silica gel with 2-25% ethyl acetate/hexanes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][C@H:15]3[CH2:17][O:16]3)[C:7]=2[N:18]=1.[NH2:19][C@@H:20]1[CH2:24][N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:29][CH2:30][C:31](=[O:35])[NH:32][C:33]=3[N:34]=2)[C:22](=[O:36])[CH2:21]1>C(O)C.O>[OH:16][C@@H:15]([CH2:14][CH2:13][N:8]1[C:9](=[O:12])[CH:10]=[N:11][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:18][C:7]1=2)[CH2:17][NH:19][C@@H:20]1[CH2:24][N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:29][CH2:30][C:31](=[O:35])[NH:32][C:33]=3[N:34]=2)[C:22](=[O:36])[CH2:21]1
Reactant: N[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Reactant: COc1ccc2ncc(=O)n(CC[C@H]3CO3)c2n1
Solvent: CCO
Solvent: O
Product: COc1ccc2ncc(=O)n(CC[C@H](O)CN[C@H]3CC(=O)N(c4ccc5c(n4)NC(=O)CO5)C3)c2n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 31.4 %

Procedure:
In a mixed solvent (12 ml) of ethanol-water (9:1) were suspended 6-methoxy-4-{2-[(2S)-oxiran-2-yl]ethyl}pyrido[2,3-b]pyrazin-3(4H)-one (Reference Example 72; 290 mg, 1.17 mmol) and 6-[(4S)-4-amino-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (Reference Example 22; 291 mg, 1.17 mmol), and the suspension was stirred in a sealed tube at 80° C. for 16 hours. The solvent was removed from the reaction solution under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform/methanol) to yield 182 mg (31%) of the title compound in the form of a yellowish solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][CH2:17][CH2:18][CH3:19])(=O)=O.[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:30][C:31]([NH2:34])([CH3:33])[CH3:32].N1C2C(=CC=CC=2)C(C(C)(C)CN)=C1>>[ClH:20].[NH:26]1[C:27]2[C:23](=[CH:22][CH:21]=[CH:29][CH:28]=2)[C:24]([CH2:30][C:31]([NH:34][CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH2:18][CH3:19])([CH3:32])[CH3:33])=[CH:25]1
Reactant: CCCCOc1ccccc1OCCOS(C)(=O)=O
Reactant: CC(C)(N)Cc1c[nH]c2ccc(Cl)cc12
Agent: CC(C)(CN)c1c[nH]c2ccccc12
Product: CCCCOc1ccccc1OCCNC(C)(C)Cc1c[nH]c2ccccc12
Product: Cl

Procedure:
Proceeding as in Example 3, but replacing 2-[2-(cyclopropylmethyloxy)phenoxy]ethyl methanesulfonate with 2-[2-(but-1-yloxy)phenoxy]ethyl methanesulfonate and [2-(5-chloro-1H-indol-3-yl)-1,1-dimethylethyl]amine with [2-(1H-indol-3-yl)-2-methylprop-1-yl]amine, gave [2-(1H-indol-3-yl)-1,1-dimethylethyl]{2-[2-(but-1-yloxy)phenoxy]ethyl}amine hydrochloride, m.p. 150°-152° C.