Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Cl:21])[C:7]([CH3:20])=[C:8]([C:18]#[N:19])[C:9]=1[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)(=[O:3])[CH3:2].[OH-:22].[K+].Cl>C(O)C>[C:1]([C:4]1[CH:5]=[C:6]([Cl:21])[C:7]([CH3:20])=[C:8]([C:18]([NH2:19])=[O:22])[C:9]=1[C:10]1[CH:11]=[C:12]([F:17])[CH:13]=[C:14]([F:16])[CH:15]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(Cl)c(C)c(C#N)c1-c1cc(F)cc(F)c1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CC(=O)c1cc(Cl)c(C)c(C(N)=O)c1-c1cc(F)cc(F)c1
Yield: 29 %

Procedure:
A mixture of 6-acetyl-4-chloro-3′,5′-difluoro-3-methylbiphenyl-2-carbonitrile (0.20 g, 0.65 mmol) and potassium hydroxide (0.074 g, 1.3 mmol) in ethanol (0.9 mL) was refluxed for 2 hours. After cooled, the mixture was acidified with 1 N HCl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated to dryness under reduced pressure. The crude mixture was purified on silica gel, eluting with 0 to 80% ethyl acetate in hexane, to yield the desired product (61 mg, 29%). LCMS calculated for C16H13ClF2NO2 (M+H)+: m/z=324.1. found: 324.0.
Reaction SMILES: [OH-:1].[NH4+].[NH4+].[NH4+].[OH:5][P:6]([O-:9])([O-:8])=[O:7].O.O.O.O.[N+:14]([O-:17])([O-:16])=[O:15].[Ca+2:18].[N+:19]([O-:22])([O-:21])=[O:20]>O>[OH2:5].[OH2:15].[OH2:20].[OH2:1].[N+:14]([O-:17])([O-:16])=[O:15].[Ca+2:18].[N+:19]([O-:22])([O-:21])=[O:20].[P:6]([O-:9])([O-:8])([O-:7])=[O:5].[Ca+2:18].[Ca+2:18].[Ca+2:18].[P:6]([O-:9])([O-:8])([O-:7])=[O:5]
Reactant: [OH-]
Reactant: O=P([O-])([O-])O
Agent: O=[N+]([O-])[O-]
Agent: [Ca+2]
Agent: [NH4+]
Solvent: O
Product: O=P([O-])([O-])[O-]
Reaction time: 8 h

Procedure:
Tricalcium phosphate (β-whitlockite crystalline form) was prepared by the following technique. A solution of 141.7 grams of calcium nitrate tetrahydrate in 400 ml of water was prepared and the pH adjusted to about pH 11 with concentrated ammonium hydroxide. This solution was then diluted to about 900 ml with water and placed in a three liter flask fitted with a dropping funnel and mechanical stirring apparatus. Separately, 66.1 grams of ammonium phosphate dibasic was added to 750 ml of water. The pH of the resulting solution was adjusted to about pH 11 with concentrated ammonium hydroxide resulting in the formation of a precipitate which was subsequently dissolved by the addition of water (about 2000 ml total volume of the solution). The ammonium phosphate dibasic solution was then slowly added to the reaction flask containing the calcium nitrate tetrahydrate solution and the resulting mixture was stirred overnight. A precipitate formed which was collected by centrifugation, washed with water and again collected by centrifugation. The precipitate was then suspended in a 2 percent aqueous ammonium sulfate solution and filtered leaving a residue which was subsequently dried in vacuo at 90° C. leaving 63.7 g of tricalcium phosphate. The tricalcium phosphate was then sintered at 1150° C. for one hour, and then ground to a fine powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([CH3:13])[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2O.P(Cl)(Cl)([Cl:22])=O.N>>[Cl:22][C:5]1[C:4]2[C:9](=[CH:10][C:11]([F:12])=[C:2]([F:1])[CH:3]=2)[N:8]=[C:7]([CH3:13])[C:6]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(C)nc2cc(F)c(F)cc2c1O
Agent: N
Product: CCOC(=O)c1c(C)nc2cc(F)c(F)cc2c1Cl

Procedure:
A suspension of 4-hydroxy quinoline 60 was refluxed with phosphorus oxychloride for 30 minutes. To the cooled reaction mixture was added aqueous ammonia and the product was obtained by extracting with methylene chloride, dried over sodium sulfate and concentrated in vacuo. 1H NMR (CDCl3) δ (ppm): 1.44 (3H, t, J=7.14 Hz), 2.70 (3H, s), 4.50 (2H, q, J=7.14 Hz), 7.62 (1H, t, J=7.69 Hz), 7.78 (1H, dd, J=10.71, 7.69 Hz), 7.95 (2H, d, J=10.72, 8.24 Hz). m/z 286.7 (MH+).
Reaction SMILES: [CH:1]([C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1)([CH3:3])[CH3:2].Br[CH2:14][C:15]1[CH:34]=[CH:33][C:18]2/[C:19](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:20]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=3[O:22][CH2:23][C:17]=2[CH:16]=1>>[F:28][C:25]1[CH:26]=[CH:27][C:20]2=[C:21]([CH:24]=1)[O:22][CH2:23][C:17]1[CH:16]=[C:15]([CH2:14][N:8]3[C:7]4[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=4[N:5]=[C:4]3[CH:1]([CH3:3])[CH3:2])[CH:34]=[CH:33][C:18]=1/[C:19]/2=[C:29](/[CH3:32])\[C:30]#[N:31]
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Reactant: CC(C)c1nc2ccccc2[nH]1
Product: C/C(C#N)=C1/c2ccc(Cn3c(C(C)C)nc4ccccc43)cc2COc2cc(F)ccc21
Yield: 98 %

Procedure:
Using 2-isopropyl-1H-benzo[d]imidazole (Angewandte Chemie, International Edition, 2010, vol. 9, p 1656; 89 mg, 0.56 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (200 mg, 0.56 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (240 mg, 98%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[C:9]([C:17](Cl)=[O:18])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:17](=[O:18])[C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)c1ccccc1
Reactant: Cc1ccc(N)cn1
Product: Cc1ccc(NC(=O)C(=O)c2ccccc2)cn1

Procedure:
In analogy to the procedure described for the synthesis example 41 (step 1), the title compound N-(6-methyl-pyridin-3-yl)-2-oxo-2-phenyl-acetamide (MS m/e: 241.2 [M+H]+) was prepared from 6-methyl-pyridin-3-ylamine and benzoylformic acid chloride.
Reaction SMILES: [H-].[Na+].[CH:3]([O:5][CH2:6][CH3:7])=[O:4].[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][CH2:16][C:17](OCC)=[O:18])[CH:9]=1.Cl>CN(C)C=O>[CH:17]([CH:16]([CH2:15][CH2:14][C:10]1[CH:9]=[N:8][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:18]
Reactant: CCOC(=O)CCCc1cccnc1
Reactant: CCOC=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C=O)CCc1cccnc1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
A suspension of 2.53 g. of sodium hydride in 35 ml. of anhydrous dimethyl formamide was prepared. The suspension was cooled to about 0° C. with stirring. Next, a mixture of 9.56 g. of ethyl formate and 19 g. of ethyl 4-(3-pyridyl)butyrate were added. The consequent reaction mixture was stirred at about 0° C. for 1 additional hour and then at room temperature for about 3 days. The reaction mixture was acidified with 2N aqueous hydrochloric acid and the acidic aqueous solution evaporated to a very small volume in vacuo. The acidity of the solution was adjusted to pH=6 by the addition of solid potassium carbonate. The neutral aqueous layer was then extracted with ether. The ether layer was separated and dried. Evaporation of the ether yielded 16.4 g. of ethyl 2-formyl-4-(3-pyridyl)butyrate (formed in the above reaction) as an orange oil.
Reaction SMILES: [Br:1]Br.[CH2:3]([C:5]1[C:13]2[N:12]3[C@H:14]([CH3:18])[CH2:15][NH:16][CH2:17][C@H:11]3[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH3:4].C([O-])(=O)C.[Na+]>C(O)(=O)C.ClCCl>[Br:1][C:7]1[CH:6]=[C:5]([CH2:3][CH3:4])[C:13]2[N:12]3[C@H:14]([CH3:18])[CH2:15][NH:16][CH2:17][C@H:11]3[CH2:10][C:9]=2[CH:8]=1
Reactant: CCc1cccc2c1N1[C@@H](CNC[C@H]1C)C2
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1cc(Br)cc2c1N1[C@@H](CNC[C@H]1C)C2
Yield: 31.8 %

Procedure:
Bromine (0.2 M solution in acetic acid, 0.48 mL, 96 μmol) was added dropwise at room temperature to a solution of (4R,10aR)-6-ethyl-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole (21 mg, 97 mol) and sodium acetate (8.0 mg, 97 μmol) in acetic acid (0.5 mL). After 30 min the reaction mixture was diluted with dichloromethane and extracted with 2 M aq. potassium hydroxide solution, dried (MgSO4), and evaporated. Chromatography on SiO2 (CH2Cl2/MeOH/NH4OH 95:5:0.1) yielded the title compound (9 mg, 31%). Yellow oil. ISP-MS: m/e=295.3, 297.3 ([M+H]+).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1.[F:11][CH:12]([F:22])[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[CH:21])[CH:15]=1.N>>[F:11][CH:12]([F:22])[O:13][C:14]1[CH:15]=[C:16]([C:20]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[N:8][CH:9]=3)[CH:21]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: ON=C(Cl)c1cncnc1
Reactant: C#Cc1cccc(OC(F)F)c1
Agent: N
Product: FC(F)Oc1cccc(-c2cc(-c3cncnc3)no2)c1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 44B (79 mg, 0.5 mmol) and 1-(difluoromethoxy)-3-ethynylbenzene (Fluorochemicals, 84 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.33-7.46 (m, 2H), 7.56-7.74 (m, 2H), 7.81 (dt, J=7.9, 1.1 Hz, 1H), 7.87 (s, 1H), 9.33 (s, 2H), 9.35 (s, 1H) ppm; MS (DCI/NH3) m/z 290 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[CH3:11])C=O.ClC1C=C(C=CC=1)[C:18]([O:20]O)=[O:19]>C(Cl)Cl>[CH:18]([O:20][C:5]1[CH:8]=[C:9]([O:12][CH3:13])[C:10]([CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:19]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(C=O)cc(OC)c1C
Solvent: ClCCl
Product: COc1cc(OC=O)cc(OC)c1C
Temperature: 25 °C
Reaction time: 19 h
Yield: 88 %

Procedure:
To a solution of 3,5-dimethoxy-4-methylbenzaldehyde (3.0 g, 16.8 mmol) in CH2Cl2 (35 mL) was added meta-chloroperoxybenzoic acid (77% purity; 5.8 g, 25.9 mmol). After stirring at room temperature for 19 hrs, additional meta-chloroperoxybenzoic acid (77% purity; 3.5 g, 15.6 mmol) was added. After heating for 4 hrs at 40° C. and cooling to room temperature, 10% aqueous Na2S2O5 was added and the mixture was stirred for 30 min. The mixture was diluted with CH2Cl2 and the layers separated. The organics were washed with 10% aqueous Na2S2O5, ˜5% aqueous NaHCO3 and brine then dried over MgSO4 and concentrated to give 3,5-dimethoxy-4-methylphenyl formate as a yellow solid (2.9 g, 88% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]=[CH:6][C:7]([C:10]([O:12][CH3:13])=[O:11])=[N:8][CH:9]=1.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>ClCCl>[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:1][CH2:2][CH2:3][C:4]1[N:5]=[CH:6][C:7]([C:10]([O:12][CH3:13])=[O:11])=[N:8][CH:9]=1
Reactant: COC(=O)c1cnc(CCO)cn1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cnc(CCOC2CCCCO2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(2-hydroxyethyl)pyrazine-2-carboxylate (1.07 g) in dichloromethane (20 mL) were added 3,4-dihydro-2H-pyrane (1.6 mL) and pyridinium p-toluenesulfonate (295 mg) at room temperature, followed by stirring at room temperature overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The crude product obtained by concentration was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:2) to obtain methyl 5-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]pyrazine-2-carboxylate (1.25 g) as a pale yellow oily substance.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[OH:24])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].Cl[CH2:26][C:27]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]=1[O:39][CH3:40]>>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:26][C:27]2[CH:36]=[C:35]([O:37][CH3:38])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[O:39][CH3:40])=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: COc1cc(CCl)c(OC)c2ccccc12
Reactant: C=CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: C=CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cc(OC)c3ccccc3c2OC)cc1

Procedure:
(a) In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-(4-allyloxy-phenyl)-3-hydroxy-piperidine-1-carboxylate [Example 86(b)] with 2-chloromethyl-1,4-dimethoxy-naphthalene [J.Org.Chem. (1983),48(19),3265-3268) there was obtained tert-butyl (3RS,4RS)-4-(4-allyloxy-phenyl)-3-(1,4-dimethoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a pale yellow solid; MS: 534 (M+H)+.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][CH:8]([CH3:31])[CH:9]([NH:14][C:15]([C:17]1[S:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=2)=[CH:20][N:21]=1)=[O:16])[C:10]([O:12][CH3:13])=[O:11].[C:32]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl>[C:32]([C:36]1[CH:37]=[CH:38][C:39]([C:40]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([C:19]3[S:18][C:17]([C:15]([NH:14][CH:9]([CH:8]([CH3:31])[CH3:7])[C:10]([O:12][CH3:13])=[O:11])=[O:16])=[N:21][CH:20]=3)=[CH:23][CH:24]=2)=[O:41])=[CH:43][CH:44]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc(NC(=O)c3ccc(C(C)(C)C)cc3)cc2)s1)C(C)C
Reaction time: 0.08 h

Procedure:
Pyridine (0.11 ml) was added to a solution of methyl 2-(5-(4-aminophenyl)thiazole-2-carboxamido)-3-methylbutanoate (Intermediate 2, 150 mg) in DCM (3 ml) and the reaction mixture was stirred for 5 minutes. 4-tert-butylbenzoyl chloride (0.125 ml) was then added and the reaction mixture was stirred for 1 h. The reaction mass was quenched with water. The organic layer was dried over Na2SO4 and evaporated under reduced pressure to get dark brown solid which was purified by silica gel column chromatography (EtOAc:CHCl3, 2:8) to get off white solid. The solid was crystallized in CHCl3/pet ether to give the title compound. Yield: 160 mg (72%) white solid. 1HNMR (DMSO-d6, 300 MHz): δ 10.38 (s, 1H), 8.76 (d, 1H), 8.41 (s, 1H), 7.94 (d, 2H), 7.91 (d, 2H), 7.8 (d, 2H), 7.58 (d, 2H), 4.33 (m, 1H), 3.69 (s, 3H), 2.27 (m, 1H), 0.95 (d, 6H); MS (ES+): m/z 494 (M+1).
Reaction SMILES: C[Al](C)C.[CH3:5][NH:6][CH2:7][CH2:8][CH3:9].[C:10]([C:12]1[C:17]2[N:18]=[C:19]([C:21]([O:23]CC)=O)[O:20][C:16]=2[C:15]([F:26])=[C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:13]=1[CH3:33])#[N:11].Cl>ClCCl.C1(C)C=CC=CC=1>[C:10]([C:12]1[C:17]2[N:18]=[C:19]([C:21]([N:6]([CH3:5])[CH2:7][CH2:8][CH3:9])=[O:23])[O:20][C:16]=2[C:15]([F:26])=[C:14]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:13]=1[CH3:33])#[N:11]
Reactant: CCOC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reactant: CCCNC
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCN(C)C(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reaction time: 0.67 h
Yield: 55.4 %

Procedure:
Under nitrogen atmosphere, trimethylaluminium (1.03 M n-hexane solution) (2.40 ml, 2.47 mmol) was dropwise added at room temperature to a toluene (6 ml) solution of N-methylpropylamine (127 μl, 1.23 mmol), followed by stirring for 40 minutes. Subsequently, a dichloromethane (2 ml) solution of ethyl 4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-2-carboxylate (I-111) (200 mg, 617 μmol) was dropwise added, followed by stirring for 48.5 hours. After the reaction, aqueous 1 N hydrochloric acid solution was added to the reaction liquid with cooling with ice, followed by stirring at room temperature, then the reaction liquid was extracted with chloroform. Next, the combined organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by middle-pressure liquid chromatography (eluent, n-hexane:ethyl acetate=2:1, v/v) to obtain the entitled compound (120 mg, 55%) as a pale yellow solid.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][C@@H:10]1[CH2:15][CH2:14][C@H:13]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:12]([CH2:27][OH:28])[CH2:11]1.N1C=CN=C1>CN(C=O)C>[Si:1]([O:28][CH2:27][C@@H:12]1[CH2:11][C@H:10]([OH:9])[CH2:15][CH2:14][C@@H:13]1[NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(N[C@H]1CC[C@@H](O)C[C@H]1CO)OCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@H](O)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 57 %

Procedure:
tert-Butyldimethylsilylchloride (2.78 g, 18.5 mmol) in DMF (30 mL) was added dropwise over 3 h to the alcohol from Step 1 (5.43 g) and imidazole (1.33 g) in DMF (50 mL) at 0° C. After the addition was complete the ice bath was removed and the reaction warmed to room temperature overnight. The DMF solution was diluted with ether (400 mL) then washed with water (2×75 mL), sat'd NaHCO3 (1×75 mL), and brine (1×075 mL). The organic layer was dried over MgSO4, filtered, and then evaporated to dryness. The product was purified by flash chromatography (silica gel, 20-40% ethyl acetate/hexanes) to provide benzyl (1S,2R,4R)-2-((tert-butyldimethylsilyloxy)methyl)-4-hydroxycyclohexylcarbamate (4.15 g) as a color less oil. MS found: (M+H)+=394.
Reaction SMILES: [C:1]([OH:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]=[C:11]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:12]([OH:14])=[O:13].C>CC(C)=O.CN(C)C1C=CN=CC=1>[C:1]([S:8][CH2:10][CH:11]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:12]([OH:14])=[O:13])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(=S)c1ccccc1
Reactant: C=C(CCC(=O)O)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CC(C)=O
Product: O=C(O)CCC(CSC(=O)c1ccccc1)C(=O)O
Temperature: 60 °C

Procedure:
To a cooled solution (5° C.) of thiobenzoic acid (5.5 g, 39.8 mmol) in acetone (75 mL), was added 2-methyleneglutaric acid (5.25 g, 36.4 mmol) with stirring. To the resulting solution, 4-dimethylaminopyridine (0.5 g, 4.1 mmol) was added and the solution was stirred for 5 hours at 5° C. The temperature was slowly raised to 60° C. and refluxed for 20 hours. The resulting solution was treated with activated charcoal (1 g) and filtered. The clear solution was evaporated to a thick liquid and cold distilled water (100 ml) was added with rapid stirring. The white precipitate formed was filtered and suspended in a saturated aqueous solution of NaHCO3. After stirring for 15 minutes, the suspension was filtered and the clear filtrate extracted with three portions of EtOAc. The aqueous fraction was then acidified with 18% HCl. The white precipitate formed was collected by filtration, washed with cold distilled water, and dried at 50° C. The crude product was crystallized from aqueous ethanol to yield white shiny crystals, representing a yield of 7.71 g (75%) of the captioned product (mp 144° C.).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][CH2:17][C:18]([N:20]1[CH2:62][CH2:61][CH2:60][C@H:21]1[C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:46]([N:48]1[CH2:59][CH2:58][CH2:57][C@H:49]1[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[O:47])[C@@H:39]([CH3:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:36])[CH2:26][CH2:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:23])=[O:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]>CO.[C].[Pd]>[NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][CH2:17][C:18]([N:20]1[CH2:62][CH2:61][CH2:60][C@H:21]1[C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:46]([N:48]1[CH2:59][CH2:58][CH2:57][C@H:49]1[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[O:47])[C@@H:39]([CH3:45])[O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:36])[CH2:26][CH2:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:23])=[O:19])=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: C[C@@H](OC(C)(C)C)[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CN)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C

Procedure:
858 mg of Z-Gly-Phe-Gly-Pro-Glu(OtBu)-Thr(tBu)-Pro-OtBu are hydrogenated in 150 ml of methanol in the presence of 200 mg of palladium-carbon catalyst (10% Pd). The product is triturated with ether×hexane (1:1) to form an amorphous powder. In the thin-layer chromatogram on silica gel it shows the following values:
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)C.[ClH:27].[OH:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[OH:38])[CH2:32][CH2:33][NH2:34].C(O)CCC>O>[ClH:27].[CH2:17]([O:16][C:14]([N:6]([CH2:5][CH:4]1[C:35]2[C:31](=[CH:30][C:29]([OH:28])=[C:37]([OH:38])[CH:36]=2)[CH2:32][CH2:33][NH:34]1)[C:7]1[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(CN(C(=O)OCc1ccccc1)c1ccc(F)cc1)OCC
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: O=C(OCc1ccccc1)N(CC1NCCc2cc(O)c(O)cc21)c1ccc(F)cc1
Yield: 44.6 %

Procedure:
N-benzyloxycarbonyl-p-fluoroanilinoacetaldehyde diethyl acetal (6 g) and 3,4-dihydroxyphenethylamine hydrochloride (2.5 g) were added to a mixture of n-butyl alcohol (60 ml) and water (8.5 ml). The mixture was then refluxed for 11 hours in a stream of nitrogen. In the course of the reaction, amounts of the above-mentioned acetal (0.6 g and 1.2 g) were added to the mixture after 4.5 hours and 6 hours, respectively, from the beginning of the reaction. The reaction mixture was concentrated to dryness and the residue was washed with ether and dissolved in water. The solution was washed with ether and concentrated to dryness to give amorphous 1-(N-benzyloxycarbonyl-p-fluoroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.7 g), mp 122° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27](O)=[O:28])[CH:22]=[CH:23][C:24]=1[OH:25]>CN(C)C1C=CN=CC=1.CN(C)C=O>[NH2:1][C:2]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:27](=[O:28])[CH2:26][C:21]3[CH:22]=[CH:23][C:24]([OH:25])=[C:19]([OH:18])[CH:20]=3)[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C(O)Cc1ccc(O)c(O)c1
Reactant: Nc1nc(C2CCNCC2)c2ccccc2n1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: Nc1nc(C2CCN(C(=O)Cc3ccc(O)c(O)c3)CC2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To an ice-cold solution of 2-amino-4-(4-piperidinyl)quinazoline (600 mg, 2.63 mmol) obtained in example 11(1), 3,4-dihydroxyphenylacetic acid (530 mg, 3.16 mmol) and 4-dimethylaminopyridine (386 mg, 3.16 mmol) in dimethylformamide (20 ml) was added 1-ethyl-3-(N,N'-dimethylaminopropyl)carbodiimide hydrochloride (605 mg, 3.16 mmol) under a nitrogen atmosphere. The mixture was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was crystallized from methanol to give the titled compound (599 mg).