Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:51])([CH3:50])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)[CH:9]=1.C1C(=O)N([Br:59])C(=O)C1>CN(C=O)C.CCOC(C)=O>[CH3:49][Si:46]([CH3:48])([CH3:47])[CH2:45][CH2:44][O:43][CH2:42][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:50])[CH3:51])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)[C:9]=1[Br:59]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (3.24 g, 4.44 mmol) in DMF (20 mL) was added NBS (750 mg, 4.21 mmol). After stirring at rt for one hour, NBS (75 mg 0.42 mmol) was added and the resulting mixture was stirred for another 40 minutes to complete the reaction. The reaction mixture was diluted with EtOAc (200 mL), washed with water (2×50 mL), brine (20 mL) and dried (MgSO4). After concentration in vacuo the residue was purified on silica gel. Elution with EtOAc/Hexanes (0-40%) gave the title compound (3 g, 83%).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:9][C:8]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[N:7][C:6]=1[CH2:20][O:21][CH3:22])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.[NH4+].[Cl-]>O1CCCC1>[CH3:22][O:21][CH2:20][C:6]1[N:7]=[C:8]([CH:10]=[CH:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[O:9][C:5]=1[CH2:3][OH:2]
Reactant: COCc1nc(C=Cc2ccc(OC)cc2)oc1C(=O)OC
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCc1nc(C=Cc2ccc(OC)cc2)oc1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
1.10 g 4-Methoxymethyl-2-[2-(4-methoxy-phenyl)-vinyl]-oxazole-5-carboxylic acid methyl ester were dissolved in 15 ml tetrahydrofuran and added to a ice cooled solution of 137 mg lithium aluminium hydride in 7 ml tetrahydrofuran. The reaction mixture was stirred at 0° C. for one hour. Then 50 ml ethyl acetate and 20 ml saturated NH4Cl solution were added. The precipitate was filtered off through a celite pad and washed with ethyl acetate. The organic layer of the filtrate was separated. The aqueous layer of the filtrate was extracted two times with portions of 100 ml ethyl acetate. The combined organic layers were dried over MgSO4. The solvent was removed in vacuo and the residue purified by RP-HPLC to obtain to 420 mg {4-methoxymethyl-2-[2-(4-methoxy-phenyl)-vinyl]-oxazol-5-yl}-methanol as an oil.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:5]=[C:6]([N:10]2[C:15](=[O:16])[C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=[N:11]2)[CH:7]=[CH:8][CH:9]=1.C([O-])(=O)C.[Na+]>ClCCl.O>[Br:1][CH2:3][C:4]1[CH:5]=[C:6]([N:10]2[C:15](=[O:16])[C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=[N:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: BrBr
Reactant: COc1cnn(-c2cccc(C)c2)c(=O)c1OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1cnn(-c2cccc(CBr)c2)c(=O)c1OC
Yield: 89.4 %

Procedure:
While stirring vigorously and exposing to light from a 300 watt incandescent lamp, a solution of 80.0 g of bromine in 400 ml of dichloromethane is dripped into a solution of 105 g of 1-(3'-methylphenyl)-4,5-dimethoxypyridazin-6-one and 51.6 g of sodium acetate in 1.5 liters of dichloromethane and 500 ml of water. The dichloromethane is then separated off and the remainder is washed with a sodium carbonate solution and concentrated. There is obtained 124 g of 1-(3'-bromomethylphenyl)-4,5-dimethoxypyridazin-6-one of m.p. 67°-69° C. and a purity of 90%.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[OH-].[Na+].[OH-].[K+].C1C(C(N)=O)=CN(C2OC(COP(OP(OCC3OC(N4C5N=CN=C(N)C=5N=C4)C(OP([O-])([O-])=O)C3O)([O-])=O)([O-])=O)C(O)C2O)C=C1.[Na+].[Na+].[Na+].[Na+].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)C[C:72]([OH:74])=[O:73]>>[OH:11][C:2]1[C:3]([C:72]([OH:74])=[O:73])=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: NC(=O)C1=CN(C2OC(COP(=O)([O-])OP(=O)([O-])OCC3OC(n4cnc5c(N)ncnc54)C(OP(=O)([O-])[O-])C3O)C(O)C2O)C=CC1
Agent: [K+]
Agent: [Na+]
Product: O=C(O)c1cc2ccccc2cc1O
Yield: 74 %

Procedure:
An autoclave equipped with stirrer is charged with 1,240 parts of β-naphthol, 608 parts of aqueous sodium hydroxide solution (50% strength by weight), 27 parts of aqueous potassium hydroxide solution (85% strength by weight) and 12 parts of the tetrasodium salt of ethylenediaminetetraacetic acid (dissolved in 50 parts of water). The charge is mixed thoroughly under nitrogen and heated until the internal temperature reaches 260° C. 520 parts of 2-hydroxy-naphthalene-3-carboxylic acid (corresponding to 74% of theory, based on β-naphthol converted) are obtained analogously to Example 1. The proportion of resin formed is 11 mole percent, based on β-naphthol employed. 700 parts of β-naphthol are recovered.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:18](=[CH:19][CH:20]=1)[O:17][C:7]1([CH2:12][CH2:11][CH:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:21].[Br-].[CH2:23]1COC[CH2:24]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:18](=[CH:19][CH:20]=1)[O:17][C:7]1([CH2:12][CH2:11][CH:10]([C:13]([CH3:16])([CH3:14])[CH3:15])[CH2:9][CH2:8]1)[CH2:6][C:5]2([CH:23]=[CH2:24])[OH:21]
Reactant: CC(C)(C)C1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2
Reactant: C1CCOC1
Agent: [Br-]
Product: C=CC1(O)CC2(CCC(C(C)(C)C)CC2)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 6-bromo-4′-t-butylspiro[chroman-2,1′-cyclohexan]-4-one (2.155 g, 6.13 mmol) in anhydrous THF (20 mL) at −78° C. is added a solution of vinylmagnesiun bromide in THF (1 M, 9.2 mL, 9.2 mmol) dropwise within 30 min. The reaction temperature is allowed to warm to rt and stirred for another 2 h. The reaction is chilled to 0° C. and quenched with sat. aq. NH4Cl, and extracted with ethyl acetate (2×40 mL). The combined organic phases are washed with H2O and brine, then dried over Na2SO4, and filtered. The filtrate is concentrated and the residue is purified through flash chromatography on silica gel to afford 6-bromo-4′-tert-butyl-4-vinylspiro[chroman-2,1′-cyclohexan]-4-ol as an oil (1.907 g, 82%). MS ESI+ve m/z 361 (M+H—H2O)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26](Br)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:32]([O:36][C:37](=[O:48])[NH:38][CH2:39][CH:40]([NH2:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([CH3:35])([CH3:34])[CH3:33].CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.C([O-])([O-])=O.[K+].[K+]>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].O1CCOCC1>[C:1]([O:5][C:6](=[O:31])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:47][CH:40]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[CH2:39][NH:38][C:37]([O:36][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:48])[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2nccn3c(-c4cccc(Br)n4)cnc23)CC1
Reactant: CC(C)(C)OC(=O)NCC(N)c1ccccc1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCC(Nc1cccc(-c2cnc3c(NC4CCC(NC(=O)OC(C)(C)C)CC4)nccn23)n1)c1ccccc1
Temperature: 135 °C

Procedure:
A sealed tube was charged with the mixture of {4-[3-(6-bromo-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 40 supra) (487 mg, 1.0 mmol), compound (2-amino-2-phenyl-ethyl)-carbamic acid tert-butyl ester (from Example 51 supra) (354 mg, 1.5 mmol), Pd2(dba)3(46 mg, 0.05 mmol), Davephos (78 mg, 0.2 mmol), K2CO3 (207 mg, 1.5 mmol) and dioxane (20 mL). The mixture was bubbled with N2 for several minutes and then heated under N2 at 135° C. for 17 hours. The solution was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography (CH2Cl2:MeOH, 100:1) to give crude (4-{3-[6-(2-tert-butoxycarbonylamino-1-phenyl-ethylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester. (Yield 0.38 g).
Reaction SMILES: [OH:1][CH:2]([CH2:24][OH:25])[CH2:3][C:4]1[CH:5]=[C:6]([F:23])[C:7]([C:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH:11]=2)=[N:8][CH:9]=1.Cl.O1CCOCC1.C(OCC)C>ClCCl>[F:23][C:6]1[C:7]([C:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH:11]=2)=[N:8][CH:9]=[C:4]([CH2:3][CH:2]([OH:1])[CH2:24][OH:25])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ncc(CC(O)CO)cc2F)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOCC
Product: OCC(O)Cc1cnc(C2=CCNCC2)c(F)c1
Yield: 91.3 %

Procedure:
A solution of 42 (0.31 g, 0.868 mmol) in dichloromethane (2.0 mL) was treated at 38° C. with 4 mol/L HCl in 1,4-dioxane (4.34 mmol, 1.1 mL) in a sealed vessel for 16 hrs. The resulting suspension was stirred for 1 h with ethyl ether. The solid precipitate was collected on filter paper and washed several times with ethyl ether to afford 200 mg (70%) of 43 as a tan solid which was used directly for the next step. LC/MS (M+1) 253.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].S([O-])(O)(=O)=O.[K+]>CN(C)C=O>[I:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: Oc1cccc(I)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cccc(I)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a solution of m-iodophenol (1.22 g, 5.55 mmol) in N,N-dimethylformamide (15 ml) were added potassium carbonate (1.40 g, 10.1 mmol) and t-butyl bromoacetate (1.22 ml, 6.25 mmol), and the mixture was stirred for 3 hours at 50° C. Thereto was added an aqueous 5% potassium hydrogensulfate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified with silica gel chromatography (hexane:ethyl acetate=4:1) to give the subject compound (1.85 g, 100%).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[C:13](=O)[C:12]([CH3:15])=[C:11]([CH3:16])[C:10](=[O:17])[C:9]=1[CH2:18][C:19]([CH3:21])=[CH2:20].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>ClCCCl.O.[Ti](Cl)(Cl)(Cl)Cl>[CH3:7][C:8]1[C:9]([CH2:18][C:19]([CH3:21])=[CH2:20])=[C:10]([OH:17])[C:11]([CH3:16])=[C:12]([CH3:15])[C:13]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccccc1
Reactant: C=C(C)CC1=C(C)C(=O)C(C)=C(C)C1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: O
Product: C=C(C)Cc1c(C)c(Nc2ccccc2)c(C)c(C)c1O
Temperature: 90 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
Titanium tetrachloride (2 58 ml 23 4 mmol) was added dropwise to a solution of pyridine (7.60 ml, 93.6 mmol) in 1,2-dichloroethane (40 ml) and, after completion of the addition, the reaction mixture was heated under reflux for 30 minutes in an argon atmosphere. After cooling of the reaction mixture, a solution of 3,5,6-trimethyl-2-(2-methyl-2-propenyl)-1,4-benzoquinone (2.40 g, 11.7 mmol) and aniline (3.35 ml, 35.1 mmol) in 1,2-dichloroethane (5 ml) was added thereto and the mixture was stirred at 90° C. for 2 hours in an argon atmosphere. The reaction mixture was cooled and filtered through Cerite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate, 98:2). The resulting compound was dissolved in tetrahydrofuran (10 ml) and to the solution was added a solution of sodium hydrosulfite (12 g, 69 mmol) in water (30 ml). The mixture was stirred at room temperature for 30 minutes. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The extract was combined with the organic phase and the mixture was washed with water and dried and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexaneethyl acetate, 95:5) to obtain the desired compound as oil (1.41 g, yield: 42.8%).
Reaction SMILES: [CH:1]1([C:8]2([C:13]3[CH:18]=[C:17]([O:19]C)[CH:16]=[C:15]([O:21]C)[CH:14]=3)[S:12][CH2:11][CH2:10][S:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(C1(C2C=C(O)C=C(O)C=2)SCCS1)CCC>CCCCCC.C(OCC)(=O)C>[CH:1]1([C:8]2([C:13]3[CH:14]=[C:15]([OH:21])[CH:16]=[C:17]([OH:19])[CH:18]=3)[S:9][CH2:10][CH2:11][S:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COc1cc(OC)cc(C2(C3CCCCCC3)SCCS2)c1
Agent: CCCCC1(c2cc(O)cc(O)c2)SCCS1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Oc1cc(O)cc(C2(C3CCCCCC3)SCCS2)c1

Procedure:
Compound 19 was prepared from Compound 12 using the same procedure as described above for Compound 16. Yield 0.582 g (41.5%) as a waxy solid. Rf=0.28 (hexane:ethyl acetate 8:2); 1H NMR δ 6.85 (d, J=2.4 Hz, 2H), 6.22 (t, J=2.25 Hz, 1H), 5.16 (br s, 2H), 3.31–3.07 (m, 4H), 2.35–2.28 (m, 1H), 1.97–1.29 (m, 12H); 13C NMR δ 156.07, 149.33, 107.65, 101.25, 50.92, 39.00, 32.55, 27.70, 27.43; MS: (ESI, Pos.) m/z 333 ([M+23]+).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[O:18][CH2:17][O:16]3)=[N:10][C:9]=1[CH2:22][C:23]1[O:27][C:26](/[CH:28]=[CH:29]/[CH2:30][S:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:25][CH:24]=1>O1CCCC1>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[O:18][CH2:17][O:16]3)=[N:10][C:9]=1[CH2:22][C:23]1[O:27][C:26](/[CH:28]=[CH:29]/[CH2:30][S:31]([CH2:32][C:33]([OH:35])=[O:34])=[O:1])=[CH:25][CH:24]=1
Reactant: O=S([O-])OO
Reactant: Cc1oc(-c2ccc3c(c2)OCO3)nc1Cc1ccc(/C=C/CSCC(=O)O)o1
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc3c(c2)OCO3)nc1Cc1ccc(/C=C/CS(=O)CC(=O)O)o1
Temperature: 0 °C
Yield: 72.2 %

Procedure:
A aqueous solution (100 ml) of OXONE (trade mark) (891 mg) was added dropwise to a solution of the compound prepared in Example 3(2) (1.0 g) in tetrahydrofuran (200 ml) over a period of 30 minutes at −2˜−3° C., and the resultant solution was stirred for 10 minutes at 0° C. Ice water was added to the reaction solution, and the resultant solution was extracted with ethyl acetate, and the extract was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1→10:1) to give the title compound (750 mg) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13](OC)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]([CH3:11])([CH3:10])[CH3:9].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.[OH-].[Na+]>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][OH:14])[CH:5]=[CH:6][C:7]=1[C:8]([CH3:9])([CH3:11])[CH3:10]
Reactant: COC(=O)Cc1ccc(C(C)(C)C)c(N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CCO)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.2 %

Procedure:
A solution of methyl 2-(3-amino-4-t-butylphenyl)acetate (11.1 g) in anhydrous tetrahydrofuran (70 ml) was added dropwise to a suspension of lithium aluminium hydride (4.0 g) in anhydrous tetrahydrofuran (150 ml) over a period of 15 minutes. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with tetrahydrofuran (150 ml) and aqueous sodium hydroxide solution (15%) was added to the mixture while cooling in an ice bath in order to decompose the excess lithium aluminium hydride. The insoluble material was filtered off through Celite (trademark) and the solvent of the filtrate was evaporated under reduced pressure to afford the desired compound 10.2 g, Rf=0.49: thin layer chromatography on a silica gel plate using n-hexane:ethyl acetate=1:3 as the eluant).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[C:18]([C@@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=2)=[CH:26][CH:27]=1)([OH:20])=[O:19]
Reactant: N[C@@H](Cc1ccc(Oc2ccc(Cl)cn2)cc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Oc2ccc(Cl)cn2)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(5-chloro-pyridin-2-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: C([N:4]([C:8]1[S:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1)[C:5]#[C:6][CH3:7])(=O)C.CO.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH2:5]([NH:4][C:8]1[S:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1)[C:6]#[CH:7]
Reactant: CC#CN(C(C)=O)c1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C#CCNc1nc2ccccc2s1
Yield: 101.4 %

Procedure:
A mixture of compound (f) (1.0 g), 80% methanol (20 ml) and potassium carbonate (1.0 g) was refluxed by heating for 1 hour and evaporated to remove the solvent. The residue was extracted with chloroform. The extract was washed with water, dried, and evaporated to remove the solvent. The residue was applied to column chromatography on silica gel (20 g) to give 2-(2-propynylamino)benzothiazole (g) (829 mg, yield 100%) from chloroform eluate: mp. 134°-135° C. (acetone-hexane).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:9]=2[CH3:18])[C:5]2[CH:19]=[C:20]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:21]=[C:22]([C:23]([O:25]C)=[O:24])[C:4]=2[N:3]=1.[OH-].[Li+]>O1CCCC1>[Cl:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:9]=2[CH3:18])[C:5]2[CH:19]=[C:20]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[CH:21]=[C:22]([C:23]([OH:25])=[O:24])[C:4]=2[N:3]=1
Reactant: COC(=O)c1cc(N2CCOCC2)cc2c1nc(Cl)n2Cc1cccc(C(F)(F)F)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cn2c(Cl)nc3c(C(=O)O)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Reaction time: 1.17 h
Yield: 90 %

Procedure:
A mixture of methyl 2-chloro-1-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-1H-benzimidazole-4-carboxylate, prepared as described in Example 66 (0.6 g, 1.282 mmol) in Tetrahydrofuran (THF) (10 mL) was added in 2 N lithium hydroxide (6.41 mL, 12.82 mmol). The reaction mixture was stirred at 50 C for 70 min. The reaction was cooled down. The organic solvent was removed in-vacuo. The aqueous mixture was acidified using 1 N HCl. The solid precipitated. Filtration and washing with water gave the product as white solid (0.55 g, 90%). 1H NMR (400 MHz, DMSO-d6) d ppm 2.54 (s, 3H) 3.05-3.16 (m, 4H) 3.67-3.78 (m, 4H) 5.63 (s, 2H) 6.43 (d, J=7.83 Hz, 1H) 7.28 (t, J=7.83 Hz, 1H) 7.36 (d, J=2.27 Hz, 1H) 7.49 (d, J=2.53 Hz, 1H) 7.63 (d, J=8.08 Hz, 1H) 12.90 (s, 1H). MS (ES+) m/e 453.9 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].[C:14]([O:18][C:19]([NH:21][C@@H:22]([C:30](O)=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.C(OCC)(=O)C>[C:14]([O:18][C:19]([NH:21][C@H:22]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:30]([NH:1][C@@H:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13])=[O:31])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: N[C@@H]1CCc2ccccc2NC1=O
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2NC1=O
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 30 mg (0.17 mmol) 3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1; Step B) in 2 mL methylene chloride at room temperature was added 50 mg (0.19 mmol, 1.1 eq) N-(t-butoxycarbonyl)-D-phenylalanine followed by 0.047 mL (34 mg, 0.34 mmol, 2 eq) of triethylamine and 113 mg (0.26 mmol, 1.5 eq) benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate. After 2 hours at room temperature, the mixture was added to 30 mL of ethyl acetate and washed with 5% citric acid (2×), saturated aqueous sodium bicarbonate and brine. The organic layer was removed, dried over magnesium sulfate, filtered and solvents removed under vacuum. The residue was purified by medium pressure liquid chromatography on silica, eluting with ethyl acetate to afford 71 mg (0.17 mmol, 100%) of the product. 1H NMR (200 MHz, CDCl3): 1.38 (s,9H), 1.9 (m,1H), 2.6-3.1 (m,5H), 4.44 (m,2H), 5.10 (br d,7 Hz,1H), 6.95 (d,8 Hz,1H), 7.1-7.3 (m,8H), 8.33 (br s,1H). FAB-MS: calc. for C24H29N3O4 423; found 424 (M+H,65%).
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[C@@H:3]([C:13]([OH:15])=[O:14])[NH:4][C:5]([O:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])=[O:6].[CH2:18](O)CCCC#C>>[CH2:8]([O:7][C:5]([NH:4][C@H:3]([C:13]([OH:15])=[O:14])[C:2]([CH3:17])([CH3:16])[CH3:1])=[O:6])[CH2:9][CH2:10][CH2:11][C:12]#[CH:18]
Reactant: C=CCCCOC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: C#CCCCCO
Product: C#CCCCCOC(=O)N[C@H](C(=O)O)C(C)(C)C

Procedure:
N-[(Hex-5-yn-1-yloxy)carbonyl]-3-methyl-L-valine was prepared according to the procedure for 3-methyl-N-[(pent-4-enyloxy)carbonyl]-L-valine by using hex-5-yn-1-ol instead of 4-pentenol. LRMS (ESI) m/z 256.2 [(M+H)+; calcd for C13H22NO4: 256.1].