Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4](Cl)=[O:5])#[N:2].[CH3:7][Si:8]([CH2:19][CH2:20][CH2:21][NH2:22])([O:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[O:9][Si:10]([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C.O>ClCCl>[C:1]([CH2:3][C:4]([NH:22][CH2:21][CH2:20][CH2:19][Si:8]([CH3:7])([O:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[O:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[O:5])#[N:2]
Reactant: N#CCC(=O)Cl
Reactant: C[Si](C)(C)O[Si](C)(CCCN)O[Si](C)(C)C
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)O[Si](C)(CCCNC(=O)CC#N)O[Si](C)(C)C
Yield: 70.4 %

Procedure:
Cyanoacetyl chloride (5.2 g, 0.05 mol) is added dropwise over 20 minutes to a mixture of 3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]disiloxanyl]propylamine (13.93 g, 0.05 mol) and of triethylamine (5 g, 0.05 mol) in 40 ml of dichloromethane. The temperature rises to 32° C. The mixture is refluxed for two hours. The reaction mixture is poured into 150 ml of water and is extracted with dichloromethane. The organic phases are washed with water and dried over sodium sulfate, and the solvent is then evaporated off. After purification by passing through a column of silica (eluent: 70/30 heptane/ethyl acetate), 12.2 g (70% yield) of cyano-N-[3-[1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]disiloxanyl]propyl]acetamide are obtained in the form of a colorless oil, which is used without further purification in the following step.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[O:16]1[C:25]2[CH:24]=[C:23]([CH:26]=O)[N:22]=[CH:21][C:20]=2[O:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(Cl)(Cl)Cl.C(O)(=O)C>[O:16]1[C:25]2[CH:24]=[C:23]([CH2:26][NH:1][CH2:2][CH:3]3[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]3)[N:22]=[CH:21][C:20]=2[O:19][CH2:18][CH2:17]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: CC(C)(C)OC(=O)N1CCCC(CN)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(CNCc2cc3c(cn2)OCCO3)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.65 g of tert-butyl 3-(aminomethyl)piperidine-1-carboxylate in 5 mL of dichloromethane, 0.50 g of (2,3-dihydro(1,4)dioxino(2,3-c)pyridine-7-carbaldehyde and 0.17 mL of acetic acid were added. Subsequently, 0.96 g of sodium triacetoxyborohydride was added thereto and the mixture was stirred at room temperature for 1 hour 15 minutes. The reaction mixture was charged with chloroform and adjusted to pH 8.6 with a saturated aqueous sodium hydrogen carbonate solution and a 20% aqueous sodium hydroxide solution, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.3 g of tert-butyl 3-(((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)methyl)piperidine-1-carboxylate as a yellow oily substance.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:19][NH2:20]>C(O)C>[C:1]1([C:7]2[NH:20][N:19]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CC(=O)c1ccccn1)c1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: c1ccc(-c2cc(-c3ccccn3)n[nH]2)cc1
Yield: 97.6 %

Procedure:
A 250 mL flask was charged with compound (1) (10 g 44 mmol), a magnetic follower and 150 mL of ethanol. Hydrazine monohydrate (2.15 mL, 44 mmol) was added and the mixture refluxed overnight. On cooling the ethanol was removed and the residue recrystallised from methanol to yield 2-(5-phenylpyrazol-3-yl)pyridine (2) as a pale yellow crystalline solid (9.5 g, 97%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([C:14](=[O:22])[NH:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:11]=[C:10]([O:23][CH3:24])[CH:9]=1.C(OC(N1CCC(NC(=O)C2C=C(OCCCC(OC)=O)C=C(OC)C=2)CC1)=O)(C)(C)C.[CH2:58]([O:60][C:61]1[CH:62]=[C:63]([CH:66]=[C:67]([O:70][CH2:71][CH3:72])[C:68]=1[F:69])[CH:64]=O)[CH3:59].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([O:23][CH3:24])[CH:11]=[C:12]([C:14](=[O:22])[NH:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:64][C:63]3[CH:66]=[C:67]([O:70][CH2:71][CH3:72])[C:68]([F:69])=[C:61]([O:60][CH2:58][CH3:59])[CH:62]=3)[CH2:20][CH2:21]2)[CH:13]=1
Reactant: CCOc1cc(C=O)cc(OCC)c1F
Reactant: COC(=O)CCCOc1cc(OC)cc(C(=O)NC2CCNCC2)c1
Agent: COC(=O)CCCOc1cc(OC)cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OCCCC(=O)OC)c3)CC2)cc(OCC)c1F

Procedure:
In analogy to the procedure described in example 50k), 4-[3-methoxy-5-(piperidin-4-ylcarbamoyl)-phenoxy]-butyric acid methyl ester [prepared from 4-[3-methoxy-5-(3-methoxycarbonyl-propoxy)-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester by Boc cleavage in analogy to example 50i)] was reacted with 3,5-diethoxy-4-fluoro-benzaldehyde (example 50 g), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless solid. MS: 547.3 (MH+).
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=1.Cl>O1CCCC1.CO.[OH-].[Na+]>[O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(CN2CCCS2(=O)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CN2CCCS2(=O)=O)cc1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
Methyl 4-(1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)benzoate (1.95 g) described in Preparation Example 17 was dissolved in a solution of tetrahydrofuran (20 mL) and methanol (20 mL), 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature. The reaction mixture was neutralized with 1N hydrochloric acid, and the solvent was evaporated. To the obtained residue was added water, and the insoluble material was collected by filtration to give the title compound (1.62 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:11]([O:15][C:16](=[O:38])[CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][C:25]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:35][CH2:36][CH3:37])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:11]([O:15][C:16](=[O:38])[CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][C:25]([N:27]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:4](=[O:5])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:35][CH2:36][CH3:37])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccccc1F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3ccccc3F)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Fluoro-benzoyl chloride (42 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C30H32FN3O3+H: 502, observed: 502.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:23])[CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1.[NH2:25][OH:26].C[O-].[Na+]>CO>[OH:26][NH:25][C:3](=[O:2])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:23])[CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1
Reactant: COC(=O)C=Cc1cccc(NC(=O)CCCc2ccccc2)c1
Reactant: NO
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(/C=C/c1cccc(NC(=O)CCCc2ccccc2)c1)NO
Temperature: 25 °C
Reaction time: 7 h

Procedure:
(Method G6) To a mixture of 3-[3-(4-phenyl-butyrylamino)-phenyl]acrylic acid methyl ester (3d) (0.323 g, 1.0 mmol) and hydroxylamine (0.278 g, 4.0 mmol) in methanol (7 ml) a 3.43 N solution of sodium methylate (1.75 ml, 6.0 mmol) in methanol was added. The resulting mixture was stirred at ambient temperature for 7 hours, diluted with saturated NaH2PO4 (50 ml) and extracted with ethyl acetate (3×25 ml). The organic layer was washed with saturated NaCl and dried (Na2SO4). The solvent was evaporated and the residue was crystallized from acetonitrile affording the title compound as reddish crystals (0.122 g, 38%). M.p. 152-153° C. (from acetonitrile). 1H NMR (DMSO-d6, HMDSO) δ: 1.69-2.11 (m, 2H); 2.35 (t, 2H, J=7.4 Hz); 2.64 (t, 2H, J=7.0 Hz); 6.45 (d, 1H, J=15.6 Hz); 7.12-7.66 (m, 9H); 7.94 (s, 1H); 9.07 (br s, 1H); 9.98 (s, 1H); 10.81 (br s, 1H). HPLC analysis on Symmetry C18 column: impurities <1% (column size 3.9×150 mm; mobile phase acetonitrile −0.1 M phosphate buffer (pH 2.5), 40:60; detector UV 254 nm; flow rate 1.0 ml/min; sample concentration 0.5 mg/ml). Anal. Calcd for C19H20N2O3, %: C, 70.35; H, 6.21; N, 8.64. Found, %: C, 70.21; H, 6.20; N, 8.61.
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20]C)=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.Br>C(O)(=O)C.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C@@H:14]([OH:20])[CH:15]=[CH:16][C@@H:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: Br
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: CC(=O)O
Product: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Temperature: 20 °C
Reaction time: 16 h
Yield: 64.9 %

Procedure:
A solution of thebaine (6.22 g) in glacial acetic acid (20 ml) was stirred at 15° C. and treated dropwise over 5 minutes with a 45% w/v solution of hydrogen bromide in glacial acetic adid (12.6 ml, 3.5 equivalents). TLC examination of a sample withdrawn 15 minutes after completion of the addition showed that the reaction was complete. The reaction mixture was then added slowly to a stirred slurry of sodium carbonate (62.5 g) in water (150 ml) keeping the temperature below 5° C. Methanol (250 ml) and water (100 ml) were added and the crude codeinone was reduced by portionwise addition of sodium borohydride (0.76 g) with stirring at 20° C. A sample was taken after 16 hours and the reduction was found to be complete (TLC). The reaction mixture was then filtered to remove inorganic solids and the filtrate was concentrated under reduced pressure until most of the methanol had been removed. The residual solid in the filter was washed with chloroform (100 ml) and the chloroform wash was used in two equal portions to extract the above aqueous concentrate. The chloroform extract was washed with water (25 ml), dried over sodium sulphate and the solvent removed under reduced pressure to give the title compound (3.88 g) identical by TLC and GLC with an authentic sample.
Reaction SMILES: C([O:4][CH:5]1[C:10]2[CH:11]=[CH:12][S:13][C:9]=2[CH2:8][CH2:7][CH2:6]1)(=O)C.[Br:14]N1C(=O)CCC1=O.O.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:14][C:12]1[S:13][C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([OH:4])[C:10]=2[CH:11]=1
Reactant: CC(=O)OC1CCCc2sccc21
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: OC1CCCc2sc(Br)cc21
Yield: 82 %

Procedure:
To a solution of 4,5,6,7-tetrahydro-1-benzothien-4-yl acetate (5.1 g, 26 mmol) in chloroform (30 ml) was added N-bromosuccinimide (5 g, 28 mmol) at 0° C. with stirring, and the resulting mixture was stirred at room temperature for 3 hours. After stirring, the reaction mixture was poured into water (40 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo. Subsequently, to a solution of the residue thus obtained in a mixed solvent of tetrahydrofuran (20 ml) and water (20 ml) was added sodium hydroxide (2.3 g, 57 mmol) with stirring, and the resulting mixture was stirred for 2 hours. After stirring, the reaction mixture was poured into water (50 ml) to quench the reaction and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (3:7) as the eluent to afford the title compound (5.0 g) in a yield of 82% as a colourless oily product.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6]3=[C:7]([C:12](=[O:16])[NH:13][C:14](=[O:15])[C:5]3=[CH:4][CH:3]=1)[CH:8]=[CH:9][CH:10]=2.[N:17]1[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=1.S(=O)(=O)(O)O.[OH-].[Na+]>C(O)(=O)C>[N:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[N:1]/[C:2]2[CH:3]=[CH:4][C:5]3[C:14](=[O:15])[NH:13][C:12](=[O:16])[C:7]4[C:6]=3[C:11]=2[CH:10]=[CH:9][CH:8]=4)=[CH:19][CH:18]=1
Reactant: O=Cc1ccncc1
Reactant: Nc1ccc2c3c(cccc13)C(=O)NC2=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C1NC(=O)c2ccc(/N=C/c3ccncc3)c3cccc1c23
Temperature: 80 °C
Reaction time: 2 h

Procedure:
3 g (14.13 mmol) of 4-aminonaphthalene-1,8-dicarboximide and 7.56 g (70.65 mmol) of 4-pyridinecarboxaldehyde in 180 mL of a 2:1 mixture of concentrated sulfuric acid and glacial acetic acid were stirred at 80° C. for 2 hours. The mixture was then poured onto ice and slowly neutralized or adjusted to a slightly alkaline pH (pH=about 8) with NaOH. The resulting precipitate was suction-filtered off, washed with copious amounts of water and then dried under vacuum. Yield: 2.28 g (54% of the theoretical), lustrous yellow powder. 1H-NMR (d6-DMSO/300 MHz): δ=6.46 (s, 1H); 7.52-7.56 (m, 2H, aromatic); 7.20 (d, J=5.7 Hz, 2H, pyridyl); 8.38 (m, 1H, aromatic); 8.65 (d, J=5.7 Hz, 2H, pyridyl), 8.71-8.73 (m, 2H, aromatic); 11.41 (s, 1 H, N—H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([C:10]([F:13])([F:12])[F:11])=[CH:4][N:3]=1.[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[C:17]([O:22][CH3:23])[CH:16]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[N:7]=[C:6]([NH:8][CH3:9])[C:5]([C:10]([F:13])([F:12])[F:11])=[CH:4][N:3]=2)=[C:17]([O:22][CH3:23])[CH:16]=1
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Reactant: COc1cc(Br)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CNc1nc(Nc2ccc(Br)cc2OC)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 914 %

Procedure:
A mixture of 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (0.5 g, 2.36 mmol), 4-bromo-2-methoxyaniline (0.72 g, 0.38 mmol) and p-toluene sulphonic acid (0.49 g, 2.6 mmol) in dioxane (10 mL) was heated at 100° C. for 2 h. The mixture was cooled, filtered and the solid washed with dioxane. The solid was dried in a vacuum oven to give crude N2-(4-bromo-2-methoxyphenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (1.31 g) which was used in the next step without any further purification.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:21]=[CH:20][C:10]([CH2:11][C:12]2[S:13][CH:14]=[CH:15][C:16]=2[CH2:17][CH2:18][OH:19])=[CH:9][CH:8]=1.[Cl:22][C:23]1[CH:24]=[N:25][C:26]([S:29][CH3:30])=[N:27][CH:28]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[OH-].[Na+]>O1CCCC1.O>[F:6][C:7]1[CH:21]=[CH:20][C:10]([CH2:11][C:12]2[S:13][C:14]([C:24]3[C:23]([Cl:22])=[CH:28][N:27]=[C:26]([S:29][CH3:30])[N:25]=3)=[CH:15][C:16]=2[CH2:17][CH2:18][OH:19])=[CH:9][CH:8]=1
Reactant: OCCc1ccsc1Cc1ccc(F)cc1
Reactant: CSc1ncc(Cl)cn1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CSc1ncc(Cl)c(-c2cc(CCO)c(Cc3ccc(F)cc3)s2)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 27.7 %

Procedure:
n-Butyllithium (5.4 mL, 1.6 M in hexanes, 8.63 mmol) was added dropwise to a solution of 2-(2-(4-fluorobenzyl)thiophen-3-yl)ethanol (0.97 g, 4.11 mmol) in anhydrous tetrahydrofuran (15 mL) at −78° C. The resulting mixture was stirred at −78° C. for 1 h and then a solution of 5-chloro-2-(methylthio)pyrimidine (0.79 g, 4.93 mmol) in 1 mL of tetrahydrofuran was added slowly. The mixture was stirred at −78° C. for 1 h and then at −40° C. for 2 h. The reaction was quenched with a solution (1.1 mL) of acetic acid and methanol (1:1) at −40° C. and then a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1.1 g, 4.93 mmol) in tetrahydrofuran (1 mL) was added. After complete addition the reaction was stirred at −40° C. for 1 h, then warmed to rt. 10 mL of aqueous sodium hydroxide (2 M) and 50 mL of water were added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate and filtered. The solvent was evaporated in vacuo and the product purified by flash chromatography eluting with ethyl acetate/hexane (1:4) to afford the title compound (0.45 g, 28%). MS (M+H)+ 395/397.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[CH:6]=[CH:5]2.[NH2:22][C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1.[Na].CCSC(N(CC(C)C)CC(C)C)=O>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].O.O1CCOCC1>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:22][C:23]3[N:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:3]=2)[N:8]=1
Reactant: COc1ccccc1CNc1ccc2cc(Br)ccc2n1
Reactant: Nc1ncccn1
Agent: [Pd]
Agent: CCSC(=O)N(CC(C)C)CC(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccccc1CNc1ccc2cc(Nc3ncccn3)ccc2n1
Yield: 36.4 %

Procedure:
A mixture of (6-bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine (see example 2, step A) (171.6 mg, 0.5 mmol), commercially available 2-amino-pyrimidine (95.1 mg, 1.0 mmol), tert.-butyl-XPhos (34 mg, 0.08 mmol), Pd2 dba3 (18.3 mg, 0.02 mmol), sodium tet.-butylate (52.9 mg, 0.55 mmol) and dioxane (3 ml) was heated in a sealed tube at 100° C. for 17 h. The reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (2×40 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated. Further purification of the crude product by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/hexane) yielded the title compound (65 mg, 36%) as a light yellow solid.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:8]=2[O:7][CH2:6][CH2:5]1.[C:20]1([C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([CH3:29])[CH2:27][SH:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:30]1([C:26]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([CH3:29])[CH2:27][S:28][CH2:2][CH2:3][N:4]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:8]=3[O:7][CH2:6][CH2:5]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(CS)(c1ccccc1)c1ccccc1
Reactant: COC(=O)COc1cccc2c1OCCN2CCO
Product: COC(=O)COc1cccc2c1OCCN2CCSCC(C)(c1ccccc1)c1ccccc1
Yield: 37.5 %

Procedure:
The same process as Example 1 was repeated except that methyl (4-(2-hydroxyethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate (200 mg) and 2,2-diphenylpropanethiol (410 mg) were used to obtain the colorless oily object compound (134 mg, yield 37%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][NH2:11].O=C1CCC(=O)N1[O:19][C:20](=O)[C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28](=[O:37])[N:29]([CH3:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:23][CH:22]=1>>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][NH:11][C:20]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28](=[O:37])[N:29]([CH3:36])[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:23][CH:22]=1)=[O:19]
Reactant: CN(C(=O)Oc1ccc(C(=O)ON2C(=O)CCC2=O)cc1)c1ccccc1
Reactant: NCc1nc2ccccc2[nH]1
Product: CN(C(=O)Oc1ccc(C(=O)NCc2nc3ccccc3[nH]2)cc1)c1ccccc1

Procedure:
The title product was prepared from C-(1H-benzimidazol-2-yl)-methylamine and 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester. The crude product was subjected to preparative HPLC (method C) (8%, off-white crystals). HPLC-MS m/z=401.1 (M+1), Rt: 2.56 min.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([OH:9])=[CH:7][C:6]([OH:10])=[CH:5][C:4]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH3:2].[OH:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:20]([OH:22])=O>B(F)(F)F.CCOCC>[CH2:1]([C:3]1[C:8]([OH:9])=[CH:7][C:6]([OH:10])=[C:5]([C:20](=[O:22])[C:19]2[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:17]([OH:16])[CH:18]=2)[C:4]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH3:2]
Reactant: COc1ccc(C(=O)O)cc1O
Reactant: CCc1c(O)cc(O)cc1CC(=O)OC
Agent: FB(F)F
Solvent: CCOCC
Product: CCc1c(O)cc(O)c(C(=O)c2ccc(OC)c(O)c2)c1CC(=O)OC
Temperature: 80 °C
Reaction time: 5 h
Yield: 62.9 %

Procedure:
Methyl 2-ethyl-3,5-dihydroxyphenylacetate (2.0 g, 9.7 mmol) obtained in Example 7, Step 2 was suspended in boron trifluoride diethyl etherate (40 mL), and 3-hydroxy-4-methoxybenzoic acid (1.7 g, 11 mmol) was added thereto, followed by stirring at 80° C. for 5 hours. After cooling to room temperature, the reaction mixture was added dropwise to ice-cold water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4-9/1) to obtain methyl 2-ethyl-3,5-dihydroxy-6-(3-hydroxy-4-methoxybenzoyl)phenylacetate (2.2 g, 65%).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:11][N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([NH:37][CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])=[O:36])=[CH:31][CH:30]=1>>[CH:1]1([CH:7]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:36])=[CH:33][CH:34]=2)[C:9]2[C:10]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:11][N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC(c1cn(-c2ccccc2)nc1CCc1ccccc1)C1CCCCC1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: O=C(O)CCNC(=O)c1ccc(NC(c2cn(-c3ccccc3)nc2CCc2ccccc2)C2CCCCC2)cc1
Yield: 40.6 %

Procedure:
Using cyclohexyl[1-phenyl-3-(2-phenylethyl)-1H-pyrazol-4-yl]methanol (0.50 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.33 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.31 g, 41%) was obtained as a white solid.