Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].Cl.C[Al](C)C.CO[C:10](=[O:30])[CH2:11][CH:12]([C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[CH:26][NH:27]2)=[CH:23][CH:22]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1>C1C=CC=CC=1.Cl>[NH:27]1[C:28]2[C:24](=[CH:23][CH:22]=[C:21]([CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH2:11][C:10]([NH:2][CH3:1])=[O:30])[CH:29]=2)[CH:25]=[CH:26]1
Reactant: COC(=O)CC(c1cccc(OC)c1)c1ccc2cc[nH]c2c1
Reactant: CN
Agent: C[Al](C)C
Agent: Cl
Solvent: c1ccccc1
Product: CNC(=O)CC(c1cccc(OC)c1)c1ccc2cc[nH]c2c1
Temperature: 5 °C
Yield: 99.8 %

Procedure:
To a 5° C. stirring suspension of MeNH2.HCl (70 mg, 1.04 mmol) in benzene (1 ml) was added Me3Al (2M in toluene, 0.52 ml, 1.04 mmol) dropwise. The reaction mixture was stirred at RT for 1 h and a solution of 3-(1H-indol-6-yl)-3-(3-methoxy-phenyl)-propionic acid methyl ester XXXI (160 mg, 0.52 mmol) in benzene (5 ml) was added. The mixture was stirred at 90° C. for 4 h, cooled to RT, and diluted with HCl (5% in water, 6 ml). The resulting mixture was extracted 3 times with EtOAc. The organic layers were combined, washed with H2O (20 ml) and brine (10 ml), dried over MgSO4, filtered, and concentrated to provide 3-(1H-indol-6-yl)-3-(3-methoxy-phenyl)-N-methyl-propionamide XXXII (160 mg, quantitative yield) as a yellow film.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3](=[O:21])[C:4](=[O:20])[C:5]1[CH:6]=[N:7][CH:8]=[C:9](B2OC(C)(C)C(C)(C)O2)[CH:10]=1.Br[C:24]1[CH:25]=[C:26]2[C:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])=[CH:31][NH:30][C:27]2=[N:28][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].O=[N-]>C(#N)C>[CH3:40][O:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:32]1[C:26]2[C:27](=[N:28][CH:29]=[C:24]([C:9]3[CH:10]=[C:5]([C:4](=[O:20])[C:3]([N:2]([CH3:1])[CH3:22])=[O:21])[CH:6]=[N:7][CH:8]=3)[CH:25]=2)[NH:30][CH:31]=1
Reactant: CN(C)C(=O)C(=O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COc1ccccc1-c1c[nH]c2ncc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [N-]=O
Agent: [Na+]
Solvent: CC#N
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cncc(C(=O)C(=O)N(C)C)c3)cc12
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
Crude N,N-dimethyl-2-oxo-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)acetamide (592 g, 1.32 mol) from the boronic ester synthesis and 5-bromo-3-(2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine 7 (398.5 g, 1.32 mol) were stirred in acetonitrile (5 L) in 10 L reaction vessel. The solution was stirred and purged with N2 for 30 min. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (34 g, 40.8 mmol) and Na2CO3(aq) (312.8 g dissolved in 1.36 L H2O) were added. Stirring and purging with N2 continued for 30 min. Thereafter, the solution was heated to 75° C. and stirred under N2 for two days. After the conversion was confirmed to be complete by NMR, H2O (1700 ml) was added and stirring was continued for 10 min. Then heating was stopped and the reaction mixture was filtered over a pad of Celite®. The Celite® pad was washed with a 1:1 mixture of acetonitrile/H2O (3×1000 ml). The filtrate was concentrated until almost acetonitrile had evaporated and a brownish precipitate formed. The concentrated mixture was then extracted with CH2Cl2 (1×3.6 L, 2×1000 ml). The organic layers were combined and dried over Na2SO4, after which the solvent was evaporated in vacuo. The residue was treated with 1800 ml MeOH and sonicated for 15 minutes. The yellowish solid is filtered off and dried in vacuo. This solid is dissolved in a mixture of 10% MeOH in CH2Cl2 and filtered over a SiO2 plug, and washed off using 10% MeOH in CH2Cl2 (±15 L). Yielding after evaporation of the solvent in vacuo ketoamide (380 g, 0.95 mol, 72% over two steps).
Reaction SMILES: [Cl-].[NH4+:2].C[Al](C)C.C1(C)C=CC=CC=1.C[O:15][C:16]([C:18]1[NH:19][C:20]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[N:35]=2)=[C:21]([C:23]2[CH:33]=[CH:32][C:26]3=[N:27][N:28]([CH2:30]C)[N:29]=[C:25]3[CH:24]=2)[N:22]=1)=O>C1C=CC=CC=1>[CH3:30][N:28]1[N:27]=[C:26]2[CH:32]=[CH:33][C:23]([C:21]3[N:22]=[C:18]([C:16]([NH2:2])=[O:15])[NH:19][C:20]=3[C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[N:35]=3)=[CH:24][C:25]2=[N:29]1
Reactant: CCn1nc2ccc(-c3nc(C(=O)OC)[nH]c3-c3cccc(C)n3)cc2n1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2[nH]c(C(N)=O)nc2-c2ccc3nn(C)nc3c2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 17.1 %

Procedure:
Suspension of ammonium chloride (12 mg, 0.21 mmol) in 2 ml dry benzene was cooled to 0° C. 2M solution of trimethylaluminum in toluene (105 μl, 0.21 mmol) was slowly added and the reaction warmed to room temperature and stirred for 2 hours. This suspension was added to separate suspension of 4-(2-ethyl-2H-benzotriazol-5-yl)-5-(6-methyl-pyridin-2-yl)-1H-imidazole-2-carboxylic acid methyl ester (25 mg, 0.07 mmol) (prepared according to procedures analogous to example 1) in 1 ml dry benzene and the reaction heated at 50° C. overnight. The reaction was quenched by the addition of excess 1M aqueous solution of hydrochloric acid. The reaction was extracted three times with chloroform. Mass spectrometry analysis of organic extracts show no presence of desired product. The remaining aqueous layer was concentrated to dryness. The aqueous extract reside was purified on Biotage Flash 12S silica gel column using chloroform/methanol gradient system (99:1 to 80:20, respectively) as eluent to afford 4-(2-methyl-2H-benzotriazol-5-yl)-5-(6-methyl-pyridin-2-yl)-1H-imidazole-2-carboxylic acid amide (4 mg, 16% yield). HPLC tR=3.70 min, LC-MS=344 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]([C:12]([O:14][CH3:15])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.[O:17]=[C:18]1[N:24]([CH2:25][CH2:26][C:27](O)=[O:28])[C:23]2[CH:30]=[CH:31][CH:32]=[CH:33][C:22]=2[S:21][CH2:20][CH2:19]1.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.C(=O)([O-])O.[Na+]>C(Cl)CCl.CN(C=O)C>[CH3:15][O:14][C:12](=[O:13])[CH:2]([NH:1][C:27](=[O:28])[CH2:26][CH2:25][N:24]1[C:23]2[CH:30]=[CH:31][CH:32]=[CH:33][C:22]=2[S:21][CH2:20][CH2:19][C:18]1=[O:17])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)CCN1C(=O)CCSc2ccccc21
Reactant: COC(=O)[C@H](N)COCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: COC(=O)C(COCc1ccccc1)NC(=O)CCN1C(=O)CCSc2ccccc21
Reaction time: 8 h
Yield: 111.1 %

Procedure:
To DMF (2 ml) solution of D-Ser(Bzl)-OMe hydrochloride (141 mg) and 3-(4-oxo-2,3-dihydro-1,5-benzothiazepin-5-yl)-propionic acid (138 mg), N-methyl morpholine (61 mg), HOBt(92 mg) and EDC(125 mg) were added under cooling on ice-water and then stirring is continued at room temperature overnight. After reaction, reaction mixture was poured into saturated sodium hydrogen carbonate solution (20 ml) and then extracted with ethyl acetate. Ethyl acetate layer was dried on anhydrous sodium sulfate and then evaporated to dryness. Title compound(270 mg) was isolated by using silica gel chromatography(CHCl3:MeOH=100:1).
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[N:7][C:8](SC)=[N:9][CH:10]=2)[N:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])[N:17]=1)[CH:2]=[CH2:3].[C:27]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)(=[O:29])[CH3:28]>>[C:27]([N:30]1[CH2:31][CH2:32][N:33]([C:36]2[CH:42]=[CH:41][C:39]([NH:40][C:8]3[N:7]=[C:6]4[N:5]([C:16]5[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])[N:17]=5)[N:4]([CH2:1][C:2]#[CH:3])[C:12](=[O:13])[C:11]4=[CH:10][N:9]=3)=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)(=[O:29])[CH3:28]
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: C=CCn1c(=O)c2cnc(SC)nc2n1-c1cccc(CC(C)(C)O)n1
Product: C#CCn1c(=O)c2cnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc2n1-c1cccc(CC(C)(C)O)n1

Procedure:
23 mg of the entitled compound was obtained as a yellow solid in the same manner as in Example 113-1 to 113-2, for which, however, 2-allyl-1-[6-(2-hydroxy-2-methylpropyl)pyridin-2-yl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one obtained in Example 81-2 was used in place of 2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one used in Example 113-1, and 4-(4-acetylpiperazin-1-yl)aniline was used in place of 4-(4-methylpiperazin-1-yl)aniline used in Example 113-2.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([N+:11]([O-])=O)[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH:3][CH3:4].[H][H]>[Pd]>[CH2:1]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[NH2:11])[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CC=CCc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Product: CCCCc1cccc(N)c1
Yield: 89.4 %

Procedure:
Treatment of 3-nitrobenzaldehyde (8.2 g) with propyltriphenyl phosphonium bromide (25 g) and n-butyllithium in hexane (64.9 mmol), as described in Example 1a, gave 3-(2-butenyl)nitrobenzene (9.3 g), δ (360 MHz, CDCl3) 1.1 (3H, t, CH3), 2.4 (2H, m, CH2CH3). 5.8 (1H, m, =CH--CH2), 6.3 (1H, m, CH=CH2), 7.2 to 8.0 (4H, m, ArH). Treatment of the above 3-(2-butenyl)nitrobenzene (9.3 g) with hydrogen and palladium on carbon (10%, 0.93 g) as described in Example 1a, gave 3-butylaniline (7.0 g), δ (60 MHz, CDCl2) 0.9 (3H, t, CH3), 1.4 (4H, m, CH2CH2CH3), 2.5 (2H, t, ARCH2), 3.4 (2H, bs, NH2 ) and 6.2 to 7.0 (4H, m, ArH).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH2:37][CH2:38][NH:39][C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[C:42]([CH3:47])[N:41]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:47][C:42]1[CH:43]=[C:44]([CH3:46])[CH:45]=[C:40]([NH:39][CH2:38][CH2:37][NH:36][C:16](=[O:18])[C:15]2[CH:14]=[CH:13][C:12]([O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])=[CH:20][CH:19]=2)[N:41]=1
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)nc(NCCN)c1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)NCCNc2cc(C)cc(C)n2)cc1
Reaction time: 0.75 h
Yield: 78.9 %

Procedure:
4-geranyloxybenzoic acid(2.30 g) was dissolved in chloroform(50 ml) and triethylamine(2.33 ml), and then diphenylphosphinic chloride(1.48 ml) was added thereto while being cooled with ice. After being stirred for 45 minutes, the mixture, with 2-(2-aminoethylamino)-4,6-dimethylpyridine(1.90 g) added thereto, was stirred for 3 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 2.79 g of the aimed compound.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:21]=[C:20]2[N:8]([CH2:9][C:10]3[C:11]2=[N:12][C:13]2[C:18]([CH:19]=3)=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7](=[O:22])[C:6]=1[CH3:23])[CH2:3][CH3:4].[Cl:24][CH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1>O>[Cl:24][CH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([O:1][CH:2]([C:5]2[CH:21]=[C:20]3[N:8]([CH2:9][C:10]4[C:11]3=[N:12][C:13]3[C:18]([CH:19]=4)=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7](=[O:22])[C:6]=2[CH3:23])[CH2:3][CH3:4])=[O:31])=[CH:28][CH:27]=1
Reactant: O=C(O)c1ccc(CCl)cc1
Reactant: CCC(O)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Solvent: O
Product: CCC(OC(=O)c1ccc(CCl)cc1)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2

Procedure:
The title compound was prepared according to the procedure in Example 3A except using (±)-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one and 4-(chloromethyl)benzoic acid. 1H NMR (CDCl3) d 8.33 (s, 1H), 8.16 (m, 3H), 7.91 (br d, J=7.3 Hz, 1H), 7.78 (m, 1H), 7.61 (m, 1H), 7.51 (d, J=8.3 Hz, 2H), 7.40 (s, 1H), 6.11 (dd, J=8.1, 6.1 Hz, 1H), 5.26 (s, 2H), 4.63 (s, 2H), 2.45 (s, 3H), 2.21-1.93 (m, 2H), 1.08 (t, J=7.3 Hz, 3H). Anal. Calcd for C27H23ClN2O3.1/2 H2O: C, 69.30; H, 5.17; N, 5.99. Found: C, 69.39; H, 5.16; N, 6.02.
Reaction SMILES: [OH:1][CH:2]([CH2:8]Cl)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].ClCC(O)C(O)=O.[CH:17]([NH2:20])([CH3:19])[CH3:18].COC1C=C(C=CC=1OC)CCN>>[CH:17]([NH:20][CH2:8][CH:2]([OH:1])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])([CH3:19])[CH3:18]
Reactant: CC(C)N
Reactant: O=C(O)CCC(O)CCl
Agent: COc1ccc(CCN)cc1OC
Agent: O=C(O)C(O)CCl
Product: CC(C)NCC(O)CCC(=O)O

Procedure:
The procedure is repeated in all essential details, except 4-hydroxy-5-chloropentanoic acid is substituted for β-chlorolactic acid and isopropylamine is substituted for 3,4-dimethoxyphenethylamine to produce the intermediate 5-isopropylamino-4-hydroxypentanoic acid. The hydroxy and amino groups are protected as described in Example I. The resulting acid is reacted with 1-naphthol instead of phenol and the protecting groups are removed as in Example I. The resulting compound should be a short acting β-blocker.
Reaction SMILES: C1(CC(C2C=CC(C#CCOC)=CC=2)C(O)=O)CCCC1.NC1SC(C(OCC)=O)=CN=1.C(OC([C:38]1[N:39]=[C:40]([NH:43][C:44](=[O:63])[CH:45]([C:52]2[CH:57]=[CH:56][C:55]([C:58]#[C:59][CH2:60][O:61][CH3:62])=[CH:54][CH:53]=2)[CH2:46][CH:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)[S:41][CH:42]=1)=O)C>>[CH:47]1([CH2:46][CH:45]([C:52]2[CH:53]=[CH:54][C:55]([C:58]#[C:59][CH2:60][O:61][CH3:62])=[CH:56][CH:57]=2)[C:44]([NH:43][C:40]2[S:41][CH:42]=[CH:38][N:39]=2)=[O:63])[CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: CCOC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(C#CCOC)cc2)n1
Agent: CCOC(=O)c1cnc(N)s1
Agent: COCC#Cc1ccc(C(CC2CCCC2)C(=O)O)cc1
Product: COCC#Cc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1

Procedure:
From 3-cyclopentyl-2-[4-(3-methoxy-prop-1-ynyl)-phenyl]-propionic acid and ethyl 2-amino-5-thiazolecarboxylate: 2-{3-cyclopentyl-2-[4-(3-methoxy-prop-1-ynyl)-phenyl]-propionylamino}-thiazole-4-carboxylic acid ethyl ester as a white foam: EI-HRMS m/e calcd for C24H28N2O4S (M+) 440.1770, found 440.1761.
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.[OH-].[K+].[Br:10][C:11]1[C:12](=O)[NH:13][C:14]([S:17][CH3:18])=[N:15][CH:16]=1>O1CCCC1.C(OCC)(=O)C>[Br:10][C:11]1[C:7](=[O:6])[N:15]([CH3:16])[C:14]([S:17][CH3:18])=[N:13][CH:12]=1
Reactant: COS(=O)(=O)OC
Reactant: CSc1ncc(Br)c(=O)[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1ncc(Br)c(=O)n1C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
To a mixture containing 0.70 g (5.5 mmol) of dimethyl sulfate and 0.25 g (4.5 mmol) of potassium hydroxide in 10 ml of tetrahydrofuran was added 0.5 g (2.25 mmol) of 5-Bromo-2-(methylthio)pyrimidin-4(3H)-one in portions over 15 min. After complete addition, the mixture was stirred overnight then diluted with ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via Biotage chromatography eluting with 20% ethyl acetate/dichloromethane gave 0.5 g (94%) of product.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[CH:9]([CH3:11])[CH3:10].[C:14]([O:18][C:19]([NH:21][CH2:22][C@H:23]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:24]([O:26][CH3:27])=[O:25])=[O:20])([CH3:17])([CH3:16])[CH3:15].O>ClCCl>[C:14]([O:18][C:19]([NH:21][CH2:22][C@H:23]([N:28]1[CH2:29][CH2:30][N:31]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[CH2:32][CH2:33]1)[C:24]([O:26][CH3:27])=[O:25])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCNCC1
Reactant: CC(C)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCN(C(=O)C(C)C)CC1
Temperature: 0 °C
Yield: 81.1 %

Procedure:
1.2 ml (8.3 mmol) of triethylamine and then 0.8 ml (7.6 mmol) of isobutyryl chloride are added to a solution of 2.0 g (6.9 mmol) of methyl (S)-3-tert-butoxycarbonylamino-2-piperazin-1-ylpropanoate in 20 ml of dichloromethane, cooled beforehand to 0° C. After stirring at ambient temperature for 1 h 30, water is added. The reaction medium is extracted with dichloromethane. The organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated under vacuum. The crude residue obtained is purified by chromatography on silica gel, elution being carried out with a 50/50 heptane/ethyl acetate mixture. 2.0 g (81%) of methyl (S)-3-tert-butoxycarbonylamino-2-(4-isobutyryl-piperazin-1-yl)propanoate are obtained in the form of a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH:10]([N:13](CC)[CH:14](C)C)(C)C.CNC>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:13]([CH3:14])[CH3:10])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)c1cc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.6 %

Procedure:
A mixture of 2,4,6-trichloropyrimidine (10 g), N,N-diisopropylethylamine (8.5 g), and THF (50 mL) was ice-cooled, and a solution of 50% aqueous dimethyl amine (4.9 g) in THF (10 mL) was added dropwise. The mixture was stirred at room temperature for 1 day, then the reaction mixture was concentrated, and the residue was diluted with chloroform and then washed with saturated aqueous sodium hydrogencarbonate. The organic layer was dried with anhydrous sodium sulfate, the desiccant was removed by filtration, and then the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate=4:1-1:1) to obtain (2,6-dichloropyrimidin-4-yl)dimethylamine (9.9 g).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:18]=[C:17]([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[CH:20]1([N:19]2[C:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)=[CH:16][C:17]([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[N:18]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: COC(=O)CCc1cc(-c2ccc(OCc3ccccc3)cc2)n(C2CCCCC2)n1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1cc(-c2ccc(O)cc2)n(C2CCCCC2)n1
Reaction time: 2 h
Yield: 95.6 %

Procedure:
To a solution of methyl ester 6.1 (71.5 mg, 0.172 mmol) in MeOH (4 ml) was added 20 mg 10% Pd-C prior to atmosphere evacuation and flushed with H2 (3×). The reaction mixture was stirred under H2 for 2 h, filtered, and concentrated to give 54 mg (96%) of 6.3. MS (ESI) 329.3 (MH+), 327.3 (MH−).
Reaction SMILES: [Mg].[CH3:2]I.[C:4]([C:7]1[C:8]([Cl:16])=[N:9][C:10]([CH:13]([F:15])[F:14])=[N:11][CH:12]=1)(=[O:6])[CH3:5].[Cl-].[NH4+]>C(OCC)C>[Cl:16][C:8]1[C:7]([C:4]([OH:6])([CH3:2])[CH3:5])=[CH:12][N:11]=[C:10]([CH:13]([F:15])[F:14])[N:9]=1
Reactant: CC(=O)c1cnc(C(F)F)nc1Cl
Reactant: CI
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(O)c1cnc(C(F)F)nc1Cl
Temperature: 25 °C
Yield: 6.1 %

Procedure:
To a mixture of 470 mg of magnesium and 5 ml of dry ethyl ether, a solution of 2.76 g of methyl iodide dissolved in 15 ml of dry ethyl ether was added dropwise while the reaction mixture was kept under control so as to be refluxed moderately. After the dropwise addition, it was further refluxed for 45 minutes. The reaction mixture was allowed to cool to room temperature, then, 2 g of 5-acetyl-4-chlorodifluoromethylpyrimidine was quickly added dropwise thereto, and the reaction mixture was refluxed for another 1 hour. The reaction mixture was cooled with ice, and stirred while a saturated aqueous solution of ammonium chloride was added thereto. The ether layer was separated by decantation and washed with saturated aqueous salt solution three times in a separatory funnel. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting crude product was subjected to preparatory thin-layer chromatography (developing solvent: chloroform) three times, and as a result, 131 mg of the desired product was obtained as a viscous liquid. nD20.6 1.4982
Reaction SMILES: CN1C=CN=C1.[CH3:7][O:8][N:9]=[CH:10][CH2:11][CH2:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)O.CS([Cl:25])(=O)=O.C(OCC)(=O)C>C(#N)C.O>[Cl:25][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12][CH2:11][CH:10]=[N:9][O:8][CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: CON=CCCC(O)c1ccccc1
Agent: Cn1ccnc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CON=CCCC(Cl)c1ccccc1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
0.24 mL of N-methylimidazole was added to a solution of 0.39 g of 4-(methoxyimino)-1-phenylbutan-1-ol in 4 mL of acetonitrile. Thereafter, 0.19 mL of methanesulfonyl chloride was added to the mixture at a temperature of 0° C. to 10° C., and the thus obtained mixture was then stirred at a temperature of 5° C. or lower for 1.5 hours. Thereafter, 0.24 mL of methanesulfonyl chloride was added to the reaction mixture, ethyl acetate and water were then added thereto, and the water layer was then removed. The organic layer was washed with a saturated sodium chloride aqueous solution, and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained product was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 59/41), so as to obtain 0.07 g of (4-chloro-4-phenylbutylidene)(methoxy)amine in the form of a light yellow oily product.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])(C)C.S(=O)(=O)(O)O.COC[O:25][CH3:26]>>[CH2:1]([C:4]1[CH:1]=[C:5]([CH3:10])[CH:6]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:26]=1[OH:25])[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:6]=1[OH:16]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: COCOC
Agent: O=S(=O)(O)O
Product: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Temperature: 120 °C
Yield: 84.1 %

Procedure:
Into a reactor provided with a stirrer, thermometer and a heating bath there are charged 220 g (1 g.-mol) of 2,6-ditert.butyl-4-methylphenol, 2.2. g of concentrated sulfuric acid and the mixture is heated to the temperature of 120° C. While maintaining the temperature at 120° C., 94 g (1.24 g-mol) of methylal are fed into the reactor for 1.5 hour. On completion of the reaction, the catalyst is separated, volatile products are distilled under vacuum to give 143.0 g of 2,2'-methylene-bis(4-methyl-6-tert.butylphenol) which corresponds to 97.8% of theory as calculated for the reacted 2,6-ditert.butyl-4-methylphenol (conversion degree of the latter is 86.0%).
Reaction SMILES: [OH2:1].O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[F:14][C:15]1[CH:27]=[C:26]([F:28])[C:25]2[C:24]3[C:19](=[CH:20][C:21]([F:31])=[CH:22][C:23]=3[O:29][CH3:30])[CH2:18][C:17]=2[CH:16]=1.O>C(O)(=O)C>[F:14][C:15]1[CH:27]=[C:26]([F:28])[C:25]2[C:24]3[C:19](=[CH:20][C:21]([F:31])=[CH:22][C:23]=3[O:29][CH3:30])[C:18](=[O:1])[C:17]=2[CH:16]=1
Reactant: COc1cc(F)cc2c1-c1c(F)cc(F)cc1C2
Reactant: O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(F)cc2c1-c1c(F)cc(F)cc1C2=O
Yield: 87.3 %

Procedure:
Sodium dichromate dihydrate (2 eq, 0.26 mol, 7.9 g) was added to a solution 2,4,7-trifluoro-5-methoxy-9H-fluorene (3.3 g, 0.013 mol) in 100 mL of acetic acid and the mixture was refluxed for 5 h. The cooled reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extract was washed with saturated aqueous sodium bicarbonate and water, dried over MgSO4, and concentrated to leave 3 g of a yellow solid which was chromatographed on silica gel using 15% ethyl acetate in hexane to provide 2.0 g (57%) of the fluorenone: mp 164°-166° C.