Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][C:23]=2[O:22]1.CN(C)C=O>[Pd].O>[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([C:2]3[CH:3]=[N:4][CH:5]=[C:6]([CH:14]=3)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:24][C:23]=2[O:22]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: CC(C)(C)OC(=O)c1cncc(Br)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cncc(-c2ccc3c(c2)OCO3)c1
Temperature: 90 °C
Reaction time: 15 h
Yield: 88.1 %

Procedure:
In a flask was placed tert-butyl 5-bromonicotinate (1.00 g, 3.87 mmol), 10% w/w palladium on carbon (210 mg, ˜0.2 mmol Pd), potassium carbonate (1.10 g, 7.96 mmol), 3,4-methylenedioxy-phenyl boronic acid (0.96 g, 5.79 mmol), dimethylformamide (50 mL) and water (250 L). The flask was purged with nitrogen and then heated, with stirring, to 90° C. for 15 hr. The reaction mixture was allowed to cool, diluted with water (350 mL) and extracted with CH2Cl2 (4X). The combined extracts was washed with water, dried (MgSO4) and concentrated in vacuo. The crude residue was purified by flash chromatography on silica (gradient, CH2Cl2 to 50% ether/CH2Cl2) to provide an off-white solid (1.02 g, 88%).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:13]([C:15]#[N:16])=[CH:12][N:11]=[C:10]([O:17][CH3:18])[C:9]=3[C:8]([C:19]3[CH:20]=[N:21][NH:22][CH:23]=3)=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:27][C:28]#[N:29].O>C1COCC1>[C:28]([CH2:27][N:21]1[CH:20]=[C:19]([C:8]2[C:9]3[C:10]([O:17][CH3:18])=[N:11][CH:12]=[C:13]([C:15]#[N:16])[C:14]=3[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:7]=2)[CH:23]=[N:22]1)#[N:29]
Reactant: N#CCBr
Reactant: COc1ncc(C#N)c2c1c(-c1cn[nH]c1)cn2C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ncc(C#N)c2c1c(-c1cnn(CC#N)c1)cn2C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-cyclopentyl-4-methoxy-3-(1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine-7-carbonitrile (152.2 mg) obtained in Step A of Example 98 in THF (2 mL) was added sodium hydride (dispersion in mineral oil, 39.6 mg) at 0° C., and the mixture was stirred for 1 hr. To the reaction mixture was added 2-bromoacetonitrile (38 μL) at 0° C., and the mixture was allowed to be warmed to room temperature, and stirred overnight. The reaction mixture was added to water, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (13.7 mg).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:27].[CH3:37][N:38]([CH3:45])[CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16]([N:42]3[CH2:43][CH2:44][CH:39]([N:38]([CH3:45])[CH3:37])[CH2:40][CH2:41]3)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:27]
Reactant: Cc1ccccc1-c1cc(Cl)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Reactant: CN(C)C1CCNCC1
Product: Cc1ccccc1-c1cc(N2CCC(N(C)C)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Yield: 41.4 %

Procedure:
In a similar manner to Example 1, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (47.6 mg) was reacted with 4-(dimethylamino)piperidine (28.8 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-9-[4-(dimethylamino)piperidine-1-yl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (23.1 mg, 41%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][CH2:8][CH2:9][C:10](O)=[S:11])=[N:5][N:4]=[N:3]1.C1CCN2C(=NCCC2)CC1.ClC(OCC(C)C)=O.[CH3:32][N:33]([CH:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)[CH3:34]>O1CCCC1>[CH3:32][N:33]([CH:35]1[CH2:40][CH2:39][CH:38]([NH:41][C:10](=[S:11])[CH2:9][CH2:8][CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][N:5]=2)[CH2:37][CH2:36]1)[CH3:34]
Reactant: Cn1nnnc1CCCC(O)=S
Reactant: CN(C)C1CCC(N)CC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CN(C)C1CCC(NC(=S)CCCc2nnnn2C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
4-(1-Methyl-1,2,3,4-tetrazol-5-yl)thio-butyric acid (45 mmole) is dissolved in tetrahydrofuran (50 ml), and thereto is added DBU (50 mmole). To the mixture is added dropwise with stirring isobutyl chloroformate (50 mmole) under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise 4-(N,N-dimethylamino)cyclohexylamine (54 mmole), and the mixture is further stirred at room temperature for 2 hours. After distilling off the solvent under reduced pressure, the resulting residue is extracted with chloroform. The chloroform layer is washed with 5% aqueous hydrochloric acid, an aqueous saturated sodium hydrogen carbonate solution and an aqueous saturated sodium chloride solution and then dried over anhydrous sodium sulfate. Chloroform is distilled off, and the resulting residue is subjected to silica gel column chromatography (Wakogel C-200, eluting solvent, benzene:chloroform=4:1, V/V) to isolate N-[4-(N,N-dimethylamino)cyclohexyl]-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thiobutyramide (yield: 47%).
Reaction SMILES: [C:1]([N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([N+:14]([O-])=O)[CH:10]=[CH:11]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]>[Pd].C(OCC)(=O)C>[C:1]([N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([NH2:14])[CH:10]=[CH:11]2)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1cc2ccc([N+](=O)[O-])cc2n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)n1cc2ccc(N)cc2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10% Palladium on carbon (1 g) was added to a solution of 2-(tert-butyl)-6-nitro-2H-indazole obtained in the above-described Step (1.1 g) in ethyl acetate (12 mL), and the reaction solution was stirred under hydrogen atmosphere at room temperature for 4 hours. The insolubles were filtrated, and the solvent was evaporated under vacuum. Thereafter, the resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain 2-(tert-butyl)-2H-indazol-6-amine as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[N:18]=[C:17]2[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:16]2=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[N:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][N:14]2[N:18]=[C:17]3[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:16]3=[N:15]2)[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCn1nc2ccc(C)cc2n1
Reactant: FCc1cccc(Br)n1
Product: Cc1ccc2nn(CCC#Cc3cccc(CF)n3)nc2c1
Yield: 40 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (73 mg, 0.39 mmol) and 2-but-3-ynyl-5-methyl-2H-benzo[d][1,2,3]triazole (65 mg, 0.35 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 40 mg (0.14 mmol, 39%) of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-5-methyl-2H-benzo[d][1,2,3]triazole as a yellow solid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:22])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1>CO>[CH2:15]([O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][C:5]([OH:22])=[O:4])=[CH:13][CH:12]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)CCc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCc1ccc(OCc2ccccc2)cc1
Reaction time: 8 h
Yield: 70 %

Procedure:
An aqueous solution of NaOH (1 M, 270 mL) was added to a mixture of the 3-(4-benzyloxyphenyl)propionic acid methyl ester from Step 2 above in MeOH (600 mL) and the reaction was stirred overnight. The crystalline ppt was collected by filtration, air dried and then partitioned between EtOAc/Et2O/1 M HCl (500 mL, 250 mL, 150 mL). The organic phases were dried over MgSO4 and evaporated to give the product as a white solid (16.2 g, 70%, 3 Steps).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[CH2:24][CH2:25][C:26](=[O:28])[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[BH4-].[Na+].[Cl-].[Na+]>CCOCC>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:22])([CH3:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[CH2:24][CH2:25][CH:26]([OH:28])[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCC(C)(C)c1ccc(CCC(C)=O)c(OCc2ccccc2)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CCCCCCC(C)(C)c1ccc(CCC(C)O)c(OCc2ccccc2)c1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a -15° C. solution of 0.5 g. (1.31 mmols.) of 4-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-2-butanone (the product of Example 1) in 5 ml. of methanol is added 50 mg. (1.31 mmols.) of sodium borohydride. The reaction mixture is stirred for 30 minutes and is then added to 100 ml. of saturated sodium chloride-150 ml. ether. The ether extract is washed once with 100 ml. of saturated sodium chloride, dried over magnesium sulfate and evaporated to an oil. The oil is purified via column chromatography on 100 g. of silica gel eluted with 1:1 ether:cyclohexane to yield 419 mg. (84%) of the title compound as an oil.
Reaction SMILES: B.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:9][CH2:8][CH2:7]2.[OH-:20].[Na+].OO>O1CCCC1.O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C@@H:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@H:9]([OH:20])[CH2:8][CH2:7]2
Reactant: COc1ccc2c(c1)CCC=C2c1ccccc1
Reactant: [OH-]
Agent: B
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CC[C@@H](O)[C@@H]2c1ccccc1
Yield: 37 %

Procedure:
Borane in tetrahydrofuran (34 mL of a 1M solution, 34 mmol) was added to tetrahydrofuran (50 mL) and the resultant solution was cooled to 0° C. A solution of 6-methoxy-1-phenyl-3,4-dihydronaphthalene 28 (5.0 g, 21.2 mmol) in tetrahydrofuran (10 mL) was added. The resultant mixture was stirred at ambient temperature for 18 h. A solution of water (5 mL) in tetrahydrofuran (20 mL) was slowly added to the cooled solution which resulted in considerable foaming. Additional water (10 mL) was added followed by 10% aqueous sodium hydroxide (15 mL) and 30% hydrogen peroxide (30 mL). The resultant mixture was stirred at room temperature for 6 h. The organic layer was separated and the aqueous layer was extracted with diethyl ether (2×50 mL). The combined organic solutions were washed with a saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was evaporated in vacuo, and the residue was purified by flash chromatography using 30 to 40% ethyl acetate in hexanes as the eluent, to afford trans-6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ol 29 as an oil (2.0 g, 37%). 1H NMR(CDCl3) δ1.77 (d, 1H), 1.83-1.97 (m, 1H), 2.13-2.22 (m, 1H), 2.94-3.05 (m, 2H), 3.78 (s, 3H), 3.90 (d, 1H), 3.98-4.07 (m, 1H), 6.59-6.70 and 7.16-7.39 (m, 8H).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:18]([O:19]C(=O)C)[C@H:17]([O:23]C(=O)C)[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11](Br)=[CH:12][CH:13]=1)(=O)C.[CH3:27][C:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[CH:30][N:29]=1>>[O:7]([C:8]1[CH:9]=[N:10][C:11]([C:32]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:27])[CH:33]=2)=[CH:12][CH:13]=1)[C@@H:6]1[S:15][CH2:16][C@@H:17]([OH:23])[C@H:18]([OH:19])[C@H:5]1[OH:4]
Reactant: Cc1cc(B(O)O)ccn1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(Br)nc1
Product: Cc1cc(-c2ccc(O[C@@H]3SC[C@@H](O)[C@H](O)[C@H]3O)cn2)ccn1

Procedure:
By carrying out the operation analogously to example 239, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 2-methyl-4-pyridineboronic acid, the desired product is obtained in the form of a white powder (yield=23%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[CH3:9][O:10][C:11]1[C:16]2[N:17]=[C:18]([NH:20][C:21](=[O:30])[C:22]3[CH:27]=[CH:26][C:25]([CH2:28]Cl)=[CH:24][CH:23]=3)[S:19][C:15]=2[C:14]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:13][CH:12]=1>CN(C)C=O>[CH3:9][O:10][C:11]1[C:16]2[N:17]=[C:18]([NH:20][C:21](=[O:30])[C:22]3[CH:23]=[CH:24][C:25]([CH2:28][N:3]4[CH2:7][CH2:6][CH2:5][C:4]4=[O:8])=[CH:26][CH:27]=3)[S:19][C:15]=2[C:14]([N:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)=[CH:13][CH:12]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CN4CCCC4=O)cc3)nc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Sodium hydride (48 ms, 0.48 mmol, 60% in mineral oil) are suspended in dimethyl formamide (2.0 ml) and at 0° C. treated with pyrrolidin-2-one. After stirring for 1 h at 50° C., N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-chloromethyl-benzamide (200 mg, 0.48 mmol) was added and the solution stirred for 5 h at 80° C. Removal of the volatile components in vacuo and flash chromatography (silica, eluent dichloromethane/methanol 19:1) afforded the title compound as off-white crystals (86% yield). MS: m/e=467(M+H+).
Reaction SMILES: [Li]CCCC.CCCCCC.[CH3:12][C:13]1([CH3:28])[C:24]2[C:16](=[CH:17][C:18]3[CH2:19][C:20]([CH3:25])=[CH:21][C:22]=3[CH:23]=2)[C:15]([CH3:27])([CH3:26])[CH2:14]1.[Si:29]([CH3:33])([CH3:32])(Cl)[Cl:30]>CCOCC>[Cl:30][Si:29]([CH:21]1[C:20]([CH3:25])=[CH:19][C:18]2[CH:17]=[C:16]3[C:24]([C:13]([CH3:28])([CH3:12])[CH2:14][C:15]3([CH3:27])[CH3:26])=[CH:23][C:22]1=2)([CH3:33])[CH3:32]
Reactant: C[Si](C)(Cl)Cl
Reactant: CC1=Cc2cc3c(cc2C1)C(C)(C)CC3(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1=Cc2cc3c(cc2C1[Si](C)(C)Cl)C(C)(C)CC3(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
A 2.5 M n-BuLi solution in hexane (3.8 mL, 9.50 mmol, n-BuLi:indacene=1:1) was added dropwise at 0° C. to a solution of 2.16 g of 1,1,3,3,6-pentamethyl-1,2,3,5-tetrahydro-s-indacene (9.54 mmol) in 40 mL of Et2O. At the end of the addition, the resulting light yellow solution was allowed to warm up to room temperature and stirred for 1 h with final formation of a white suspension. An aliquot of this suspension was quenched with CD3OD and dried: the related 1H NMR analysis in CDCl3 showed complete conversion of the starting indacene to the corresponding lithium salt. The latter was then cooled again to 0° C. and added to a solution of Me2SiCl2 (98%, 1.27 g, d=1.064, 9.64 mmol) in 10 mL of Et2O, previously cooled to 0° C. too. The reaction mixture was allowed to warm up to room temperature and stirred for 16 h with final formation of a white suspension. After 40 min stirring at r.t. the conversion was ca. 80% by 1H NMR analysis. The solvents were removed in vacuo and the residue extracted with 70 mL of toluene to remove the LiCl. The filtrate was brought to dryness in vacuo at 40° C. to give a thick yellow oil as product (3.03 g), which tended to crystallize by standing at room temperature. Isolated yield=97.9% (purity 97.9% wt. by 1 H NMR analysis). Starting indacene was still present in 2.1% wt.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.[Cl:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[CH:12][N:11]=1.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:9][C:10]1[N:15]=[C:14]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Clc1nccc(-c2ccsc2)n1
Temperature: 90 °C
Yield: 88.5 %

Procedure:
To a solution of 3-thiopheneboronic acid (500 mg, 3.91 mmol) and 2,4-dichloropyrimidine (1.16 g, 7.81 mmol) in acetonitrile (20 mL) was added a 0.4 M solution of Na2CO3 (20 mL) followed by Pd(PPh3)4 (450 mg, 0.39 mmol). The suspension was degassed and heated at 90° C. for 16 h under nitrogen, cooled down, concentrated and extracted with EtOAc. Organic layer was successively washed with saturated solution of NH4Cl, brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (EtOAc/CH2Cl2: 2/98) to afford the title compound 14 (680 mg, 3.46 mmol, 88% yield). 1H NMR: (400 MHz, CDCl3) δ (ppm): 8.56 (d, J=5.2 Hz, 1H), 8.19 (dd, J=3.2, 1.2 Hz, 1H), 7.66 (dd, J=5.2, 1.2 Hz, 1H), 7.46 (d, J=5.2 Hz, 1H), 7.43 (dd, J=5.2, 2.8 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[CH2:23][CH2:24][C:25]([OH:27])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([NH:35][C@H:36]([C:41]([N:43]1[CH2:48][CH2:47][N:46]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:45][CH2:44]1)=[O:42])[CH2:37][C:38](=[O:40])[NH2:39])=O)(C)(C)C>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][C:10]=1[CH2:23][CH2:24][C:25]([NH:35][C@H:36]([C:41]([N:43]1[CH2:44][CH2:45][N:46]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:47][CH2:48]1)=[O:42])[CH2:37][C:38](=[O:40])[NH2:39])=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)N1CCN(c2ccccc2)CC1
Product: NC(=O)C[C@H](NC(=O)CCc1ccc(OCc2ccccc2)cc1OCc1ccccc1)C(=O)N1CCN(c2ccccc2)CC1
Yield: 32.5 %

Procedure:
Condensation of 3-(2,4-dibenzyloxyphenyl)propionic acid (772 mg) and 1-(N-tert-butoxycarbonyl-L-asparaginyl)-4-phenylpiperazine (964 mg) was carried out in the same manner as in Example 7 (i) to obtain colorless crystal 1-[3-(2,4-dibenzyloxyphenyl)propionyl-L-asparaginyl]- 4-phenylpiperazine (430 mg). Melting point: 96°-98° C.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+]([O-])=O)[C:10]=1C1C=CC=CC=1)[C:5](O)=O.[NH2:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([S:36](=[O:39])(=[O:38])[NH2:37])[C:29]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]([OH:26])=[O:25]>>[CH2:5]([NH:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([S:36](=[O:39])(=[O:38])[NH2:37])[C:29]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]([OH:26])=[O:25])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1-c1ccccc1
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1-c1ccccc1
Product: NS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccccc2)c1-c1ccccc1

Procedure:
By replacing in Example 1, step D, 3-amino-5-nitro-4-phenylbenzoic acid with an equimolar amount of 3-amino-4-phenyl-5-sulfamylbenzoic acid, and following the procedure described, 3-benzylamino-4-phenyl-5-sulfamylbenzoic acid is obtained with a melting point of 221°-222° C. The material is identical (IR, analysis) with the material prepared as in Example 1, step G.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:16]O>>[CH3:16][O:12][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][C:7]([CH:4]2[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]2)=[CH:8][CH:9]=1
Reactant: O=C(O)c1ccc(C2CCNCC2)cc1
Reactant: CO
Product: COC(=O)c1ccc(C2CCNCC2)cc1

Procedure:
4-Piperidin-4-yl-benzoic acid (47 mmol) is dissolved in methanol (300 ml) and 1 ml of concentrated sulfonic acid is added. The mixture is heated under reflux overnight. After evaporation of the solvent, the residue is dissolved in a mixture of water and sodium carbonate (to ensure basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. A brown powder with Rf=0.18 (CH2Cl2/MeOH=9:1) is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[NH3:15].O>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:6]([NH2:15])[CH:7]=1
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Reactant: N
Solvent: CS(C)=O
Solvent: O
Product: Nc1cc(Cl)nc(-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
An ice-cold suspension of pyrimidine 3 (44.34 g; 0.197 mol) in DMSO (366 mL) was saturated with ammonia, during which time a solution formed. After 24 h at rt, water (710 mL) was added dropwise. The suspension was cooled in an ice bath for 1 h then collected by filtration and washed with water (500 mL), yielding a light tan powder after drying in vacuo (37.84 g; 93%). LC (method B) tR=16.0 min; 1H NMR (200 MHz, CDCl3) δ 8.33 (m, 2H), 8.44 (m, 3H), 6.32 (s, 1H), 5.12 (brs, 2H); 13C NMR (50.3 MHz, CDCl3) δ 165.1, 164.0, 160.5, 136.7, 131.0, 128.4, 128.4, 101.4; ESIMS 205.9/207.8 (100/34) [MH+].
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[C:7]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C(Br)C=C>CC#N.C1OCCOCCOCCOCCOCCOC1>[C:7]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:3][CH:2]=[CH2:1])=[CH:24][CH:23]=1)([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8]
Reactant: CC(C)(C)[O-]
Reactant: O=C(NCCCCc1ccc(O)cc1)OCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Solvent: C=CCBr
Product: C=CCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70 %

Procedure:
Potassium tert-butoxide (1.7 g, 15.2 mmol) and 18-crown-6 (0.1 g, 0.3 mmol) were added to a solution of 29 (4.3 g, 14.3 mmol) in dry MeCN (80 mL) and the mixture was stirred for 20 min at room temperature. After this time, allyl bromide (1.2 mL, 14.3 mmol) in MeCN (10 mL) was added. The reaction mixture was stirred overnight at room temperature, then the precipitate was filtered off and washed with ethyl acetate. The organic fractions were combined, the solvent was removed at reduced pressure and the residue was purified twice by flash chromatography (silica gel, 1:1 ethyl acetate/hexanes) to provide compound 30 (3.4 g, 71%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.55 (m, 4H), 2.54 (t, 2H), 3.20 (m, 2H), 4.50 (d, 2H), 5.08 (s, 2H), 5.28 (d, 1H), 5.40 (d, 1H), 6.06 (m, 1H), 6.82 (d, 2H), 7.05 (d, 2H), 7.33 (s, 5H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=1.CN(C)C=O.[H-].[Na+]>O>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[N:11][CH:12]=1
Reactant: Brc1ccc(Br)nc1
Reactant: Oc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccccc1Oc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27 %

Procedure:
To a mixture of 2-fluorophenol (2.1 g, 19 mmol), 2,5-dibromopyridine (3.0 g, 13 mmol) and N,N-dimethylformamide (30 mL) was added sodium hydride (730 mg, 15 mmol, 50% in oil) at 0° C., which was stirred for 10 minutes at room temperature. The reaction mixture was then stirred for 5 hours at 110° C. The reaction mixture was cooled to room temperature and water was added, followed by extraction with ethyl acetate. The organic layer was washed twice with water and then washed with saturated aqueous sodium chloride, was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=15:1) to obtain the title compound (940 mg, 28%).