Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[F:21][C:17]1[C:15]2[N:16]=[C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[O:13][C:14]=2[CH:20]=[CH:19][CH:18]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2c(F)cccc2o1
Product: Fc1cccc2oc(CCC#Cc3ccccn3)nc12
Yield: 50000 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (29.2 mg, 0.18 mmol) and 2-(but-3-ynyl)-4-fluorobenzo[d]oxazole (35 mg, 0.18 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 24 mg (90 mmol, 49%) of 4-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as an orange solid (M.P.=89-89.5° C.).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:20]=[C:13]2[C:14]([O:16]C(=O)[NH:18][C:12]2=[CH:11][CH:10]=1)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[NH2:18][C:12]1[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])=[CH:20][C:13]=1[C:14]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=1)=[O:16]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: COc1ccc(N)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(NC(=O)c2cc(O[Si](C)(C)C(C)(C)C)ccc2N)cc1
Temperature: 80 °C
Yield: 58.7 %

Procedure:
A mixture of 5-(tert-butyldimethylsilyloxy)isatoic anhydride (734 mg, 2.50 mmol) and p-anisidine (339 mg, 2.75 mmol) in toluene (6 mL) was heated at 80° C. for 3 h. The reaction mixture was cooled and silica gel (3.5 g) was added. The mixture was concentrated in vacuo and the resulting material was chromatographed (silica gel, 1% ethyl acetate/99% methylene chloride to 4% ethyl acetate/96% methylene chloride) to give 547 mg (59%) of the title compound as a light tan solid; mp 82.5-83.5° C. (dec).
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:17]([F:20])([F:19])[F:18])=[C:12]([CH:16]=2)[C:13](O)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO>C1COCC1>[C:1]1([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:17]([F:18])([F:19])[F:20])=[C:12]([CH2:13][OH:14])[CH:16]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cc(Oc2ccccc2)ccc1C(F)(F)F
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cc(Oc2ccccc2)ccc1C(F)(F)F
Reaction time: 0.5 h

Procedure:
To a stirred solution of crude 5-(phenyloxy)-2-(trifluoromethyl)benzoic acid (for a preparation see Intermediate 36)(0.519 g, 1.84 mmol) in dry THF (40 ml) under nitrogen was added 1.0 M borane-tetrahydrofuran complex (6 ml, 6.0 mmol, Aldrich) dropwise. The solution was stirred for 30 min then heated at gentle reflux for 21 h. To the solution at ambient temperature was added methanol (10 ml) dropwise and then heated at reflux for 30 min. The solvent was removed in vacuo and then water added to the residue. The mixture was diluted with 2 M hydrochloric acid and the mixture was extracted with chloroform. The organic extract was concentrated in vacuo to give [5-(phenyloxy)-2-(trifluoromethyl)phenyl]methanol as a colourless oil (0.494 g).
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N:9][N:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:11]=2[CH:12]([CH3:14])[CH3:13])[C:3]1=[O:22].[NH2:23][C:24]1[N:29]=[CH:28][N:27]=[C:26]2[NH:30][N:31]=[C:32]([C:33]#[N:34])[C:25]=12.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:23][C:24]1[N:29]=[CH:28][N:27]=[C:26]2[N:30]([CH:2]3[CH2:6][CH2:5][N:4]([C:7]4[CH:8]=[N:9][N:10]([C:15]5[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=5)[C:11]=4[CH:12]([CH3:14])[CH3:13])[C:3]3=[O:22])[N:31]=[C:32]([C:33]#[N:34])[C:25]=12
Reactant: N#Cc1n[nH]c2ncnc(N)c12
Reactant: CC(C)c1c(N2CCC(Br)C2=O)cnn1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1c(N2CCC(n3nc(C#N)c4c(N)ncnc43)C2=O)cnn1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
A mixture of 3-bromo-1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-yl]pyrrolidin-2-one (0.055 g, 0.15 mmol), 4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile (0.050 g, 0.31 mmol) and K2CO3 (0.050 g, 0.36 mmol) in DMF (2.0 mL) was stirred at 60° C. for 1 hr. The mixture was then cooled to room temperature, quenched with water (30 mL), and extracted with IPA:CHCl3 (1:2 v/v, 100 mL). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by flash chromatography (SiO2, 0˜10% MeOH/EtOAc gradient elution) to give 4-amino-1-[1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-yl]-2-oxo-pyrrolidin-3-yl]pyrazolo[3,4-d]pyrimidine-3-carbonitrile (0.055 g, 82%).
Reaction SMILES: [OH:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].Cl.O.C(=O)([O-])O.[Na+].[CH2:20](O)[CH3:21]>>[OH:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH2:20][CH3:21])=[O:4]
Reactant: O=C(O)C(O)Cc1ccccc1
Reactant: CCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(O)Cc1ccccc1
Reaction time: 8 h
Yield: 82 %

Procedure:
A solution of 2-hydroxy-3-phenylpropanoic acid (2.10 g, 12.6 mmol) in ethanol (50 mL) was saturated with gaseous hydrochloric acid and allowed to stand at room temperature overnight. The reaction mixture was poured into water, neutralized with solid sodium hydrogen carbonate and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to give ethyl 2-hydroxy-3-phenylpropanoate as a peach-colored oil (2.00 g, 82%); 1HNMR (200 MHz, DMSO-d6): δ7.15-7.35 (m, 5H), 5.4-5.6 (br, 1H), 4.15-4.3 (br, 1H), 4.05 (q, 2H, J=7.3 Hz), 2.75-3.0 (m, 2H), and 1.2 ppm (t, 3H, J=7.4 Hz).
Reaction SMILES: [CH2:1]([NH:11][C:12](=[O:30])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]2[CH2:25][CH:24]([C:26]([OH:28])=[O:27])[CH2:23][C:22]2=[O:29])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:31]OCCOC.[N+](=C)=[N-]>C(O)(=O)C.CCOCC>[CH2:1]([NH:11][C:12](=[O:30])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]2[CH2:25][CH:24]([C:26]([O:28][CH3:31])=[O:27])[CH2:23][C:22]2=[O:29])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: COCCOC
Reactant: CCCCCCCCCCNC(=O)C=Cc1cccc(N2CC(C(=O)O)CC2=O)c1
Agent: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCCCCCCCCNC(=O)C=Cc1cccc(N2CC(C(=O)OC)CC2=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of 415 mg. of N-decyl-3-(3-[4-carboxy-2-oxo-pyrrolidino]phenyl)propenamide and 15 ml. of 1,2-dimethoxyethane is added a solution of 1.5 mmoles of diazomethane in 5 ml. of ether. The reaction mixture is stirred at room temperature for 16 hours, and then the excess diazomethane is decomposed by the addition of a few drops of acetic acid. The total solvents are removed by evaporation in vacuo, and the residue is dissolved in ethyl acetate. The ethyl acetate solution is washed with 1 N sodium hydroxide, followed by water, followed by saturated sodium chloride solution, and then dried using sodium sulfate. Evaporation of the dried ethyl acetate solution in vacuo affords the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].Cl[C:8]1[C:17]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.[CH:24]1([C:27]2[O:31][N:30]=[C:29]([CH2:32][N+:33]#[C-:34])[N:28]=2)[CH2:26][CH2:25]1>CN(C=O)C>[CH:24]1([C:27]2[O:31][N:30]=[C:29]([C:32]3[N:33]=[CH:34][N:9]4[C:10]5[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=5)[N:16]=[C:17]([N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)[C:8]=34)[N:28]=2)[CH2:26][CH2:25]1
Reactant: Clc1nc2ccccc2nc1N1CCOCC1
Reactant: [C-]#[N+]Cc1noc(C2CC2)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)nc(N1CCOCC1)c1c(-c3noc(C4CC4)n3)ncn12
Temperature: 20 °C

Procedure:
A solution of potassium t-butoxide (3.7 g, 32 mmol) in dry DMF (25 ml) was added to a stirred solution of 2-chloro-3-morpholino-quinoxaline (4 g, 16 mmol) and 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole in dry DMF (50 ml), the temperature being kept at 0°-5° C. Then the temperature was raised to 20° C. and the solvent was evaporated in vacuo. The residue was partitioned between water (50 ml) and dichloromethane (50 ml). The organic phase was dried and evaporated and the residue was triturated with a small amount of ethyl acetate. The resulting crystalline product was collected by filtration and dried to give 3.2 g of the title compound, m.p. 169°-173° C. (Compound 9).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4](O)[C:5]2[N:13]3[C:8]([C:9]([C:14]4[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=4[CH3:22])=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:6]=2[N:23]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:4]1[C:5]2[N:13]3[C:8]([C:9]([C:14]4[C:15]([CH3:22])=[CH:16][C:17]([CH3:21])=[CH:18][C:19]=4[CH3:20])=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:6]=2[N:23]=[C:2]([CH3:1])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(C)c(-c2cccn3c2cc2nc(C)nc(O)c23)c(C)c1
Product: Cc1cc(C)c(-c2cccn3c2cc2nc(C)nc(Cl)c23)c(C)c1
Temperature: 25 °C

Procedure:
Heat at 100° C. for 2 h a solution of 2-methyl-9-(2,4,6-trimethylphenyl)pyrimidino[4,5-b]indolizin-4-ol (120 mg) in phosphorus oxychloride (2 mL), cool to ambient temperature, and concentrate in vacuo. Partition the residue into ice water and CH2Cl2. Extract the aqueous phase twice with CH2Cl2 and wash the combined organic extracts with a saturated NaHCO3 solution. Dry the solution over Na2SO4, filter, and concentrate in vacuo. Purify the dark residue by column chromatography on silica gel (eluent: 10% to 20% EtOAc in hexane) to obtain the title compound as a greenish yellow foam: 1H NMR (400 MHz, CDCl3) δ 1.99 (s, 6H), 2.38 (s, 3H), 2.79 (s, 3H), 6.80 (m, 1H), 7.00 (s, 2H), 7.19 (m, 2H), 9.27 (d, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][C:15]=1[O:23][CH3:24].[O:25]1[C:30]2[CH:31]=[CH:32][C:33]([CH:35]=O)=[CH:34][C:29]=2[O:28][CH2:27][CH2:26]1>>[O:25]1[C:30]2[CH:31]=[CH:32][C:33](/[CH:35]=[C:20](/[C:17]3[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[C:15]([O:23][CH3:24])[CH:16]=3)\[C:21]#[N:22])=[CH:34][C:29]=2[O:28][CH2:27][CH2:26]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: COc1cc(CC#N)ccc1OCCCCCCCCCCCO
Product: COc1cc(/C(C#N)=C/c2ccc3c(c2)OCCO3)ccc1OCCCCCCCCCCCO
Yield: 80 %

Procedure:
(2Z)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-{4-[(11-hydroxyundecyl)oxy]-3-methoxyphenyl}prop-2-enenitrile is prepared starting from {4-[(11-hydroxyundecyl)oxy]-3-methoxyphenyl}acetonitrile and commercial 1,4-Benzodioxan-6-carboxaldehyde according the same procedure following for example 1 in 80% yield.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1B(O)O)=O)(C)(C)C.C(=O)([O-])O.[Na+].I[C:26]1(C(OC(C)(C)C)=O)[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([N:35]([S:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[O:52][C:53]([F:56])([F:55])[F:54])(=[O:45])=[O:44])C(OC(C)(C)C)=O)[CH:33]=2)[N:28]=[N:27]1>CN(C)C=O>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([NH:35][S:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[O:52][C:53]([F:54])([F:55])[F:56])(=[O:45])=[O:44])[CH:33]=2)[NH:28][N:27]=1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Reactant: CC(C)(C)OC(=O)N(c1ccc2c(c1)C(I)(C(=O)OC(C)(C)C)N=N2)S(=O)(=O)c1ccccc1OC(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1)c1ccccc1OC(F)(F)F
Temperature: 120 °C
Yield: 58.3 %

Procedure:
N-[3-(1H-Indol-2-yl)-1H-indazol-5-yl]-2-trifluoromethoxybenzenesulfonamide can be obtained in the following way: 213.3 mg N-tert-butoxycarbonylindole-2-boronic acid in dimer form and 243 μl of a saturated sodium hydrogencarbonate solution and then 63.4 mg of tetrakis(triphenylphosphine)palladium[0] are added to a solution of 150 mg of tert-butyl 3-iodo-5-(N-tert-butoxycarbonyl-2-trifluoromethoxybenzenesulfonylamino)indazolecarboxylate in 4.5 ml of dimethylformamide. The suspension is heated in the region of 120° C. for 18 hours. After cooling to a temperature in the region of 20° C., the catalyst is filtered through sintered glass with Celite® 535, and the filtrate is concentrated to dryness under reduced pressure in a rotary evaporator. The reaction crude is purified by preparative HPLC chromatography coupled to a mass detector (LC/MS, conditions A). The fractions containing the expected product are pooled and concentrated, and then the base is released from the trifluoroacetate salt by being taken up in 10 ml of dichloromethane and washed with 10 ml of a saturated sodium hydrogencarbonate solution. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. 60.5 mg of N-[3-(1H-indol-2-yl)-1H-indazol-5-yl]-2-trifluoromethoxy-benzenesulfonamide are thus obtained in the form of a white solid melting at 172-174° C. (analytical LC/MS analysis: Tr=3.73 minutes; [M+H]+=473.07).
Reaction SMILES: [NH2:1][C:2]1[N:11]([CH2:12][CH2:13][C:14]([N:16]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH3:17])=[O:15])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:24](O)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:8]=2)[N:3]=1.O=[Si]=O>CO.Cl.CC(O)C.[Pd]>[NH2:1][C:2]1[N:11]([CH2:12][CH2:13][C:14]([N:16]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH3:17])=[O:15])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:8]=2)[N:3]=1
Reactant: CN(C(=O)CCN1Cc2cc(C(O)c3ccccc3)ccc2N=C1N)C1CCCCC1
Agent: [Pd]
Agent: Cl
Agent: O=[Si]=O
Solvent: CC(C)O
Solvent: CO
Product: CN(C(=O)CCN1Cc2cc(Cc3ccccc3)ccc2N=C1N)C1CCCCC1

Procedure:
A mixture of 3-[2-amino-6-(hydroxy-phenyl-methyl)-4H-quinazolin-3-yl]-N-cyclohexyl-N-methyl-propionamide (0.0012 mol) in methanol (40 mL) and HCl/2-propanol (0.5 mL) was hydrogenated at 50° C. with 10% Pd/C (0.4 g) as a catalyst. After uptake of H2 (1 equiv.), the reaction mixture was filtered over Dicalite and the solvent was evaporated. The residue was triturated under diisopropyl ether, then the resulting solids were filtered off and dried to yield the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1.[CH2:16]([C:18]([O-:20])=[O:19])[CH3:17].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>>[CH3:21][S:22]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1)(=[O:24])=[O:23].[CH2:16]([C:18]([O-:20])=[O:19])[CH3:17]
Reactant: Nc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Reactant: CS(=O)(=O)Cl
Agent: CCC(=O)[O-]
Product: CS(=O)(=O)Nc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Yield: 46 %

Procedure:
This compound is prepared according to synthesis 37, from 50 mg (0.18 mmol) of 8-amino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate (synthesis 64) and 17 μL (0.20 mmol) of methanesulfonyl chloride. After recrystallization from methanol, 29 mg (45%) of 8-methanesulfonylamino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:27][O:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:32]5[CH:31]=[N:30][C:29]([O:28][CH3:27])=[N:34][CH:33]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COc1ncc(B(O)O)cn1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5cnc(OC)nc5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-methoxy-5-pyrimidineboronic acid following a procedure analogous to that described for Intermediate 6. LC (method 2): tR=1.10 min; Mass spectrum (ESI+): m/z=467 [M+H]+.
Reaction SMILES: [Cl-:1].[Mn+2:2].[Cl-:3].[CH2:4]([CH:22]1[CH2:36][NH:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24][NH:23]1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CO>[Cl:1][C:22]1([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:36][NH:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24][N:23]1[Cl:3].[Mn+2:2]
Reactant: [Cl-]
Reactant: CCCCCCCCCCCCCCCCCCC1CNCCNCCNCCNCCN1
Agent: [Mn+2]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCC1(Cl)CNCCNCCNCCNCCN1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a refluxing solution of anhydrous manganese(II) chloride (0.18 g, 1.4 mmol) in anhydrous methanol (50 ml) was added 2-octadecyl-1,4,7,10,13-pentaazacyclopentadecane prepared as in example 28I (0.65 g, 1.4 mmol). The resulting solution was refluxed under a dry nitrogen atmosphere for 2 h and then stirred at room temperature overnight. The solvent was removed in vacuo, the oily residue redissolved in hot THF (20 ml) and filtered. The solution was concentrated and hot ethyl ether was added with stirring to give 0.62 g (75% yield) of the product as a white solid: FAB mass spectrum (NBA) m/z (relative intensity) 556/558 [(M-Cl)+, 100/34]; Exact mass (M-Cl)+ : calcd., 557.3996; found, 557.4058 (C28H61N5MnCl).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH:6]([N:9]([C:16]1[CH:21]=[CH:20][C:19]2[O:22][CH2:23][O:24][C:18]=2[CH:17]=1)C1C=CC=CC=1)([CH3:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[CH:6]([N:9]([C:16]1[CH:21]=[CH:20][C:19]2[O:22][CH2:23][O:24][C:18]=2[CH:17]=1)[C:3](=[O:4])[CH2:2][Br:1])([CH3:8])[CH3:7]
Reactant: CC(C)N(c1ccccc1)c1ccc2c(c1)OCO2
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N(C(=O)CBr)c1ccc2c(c1)OCO2
Reaction time: 8 h

Procedure:
Bromoacetyl bromide (6.0 mL) in methylene chloride (100 mL) is added dropwise to a 0° C. solution of N-Isopropyl-N-(3,4-methylenedioxy-phenyl) aniline, prepared as in Part A, (12.0 g) in methylene chloride (100 mL) and triethylamine (9.41 mL) and the resultant mixture is allowed to attain RT overnight. The reaction mixture is washed with 1N hydrochloric acid (3×80 mL), water (2×80 mL), brine (80 mL), dried, (MgSO4) and concentrated in vacuo to afford crude N-Isopropyl-N-(3,4-methylenedioxy-phenyl) bromoacetamide (16.3 g) as a black mobile oil which is used without further purification: 1H NMR (300 MHz, CDCl3) δ6.82 (d, 1H, J=8.2), 6.61 (m, 2H), 4.90 (m, 1H, J=6.8), 3.58 (s, 2H), 1.07 (m, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.[OH-:16].[Na+].O.Cl>O1CCOCC1>[CH2:13]([NH:12][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:7]=[C:2]([OH:16])[N:3]=1)[CH2:14][CH3:15]
Reactant: [OH-]
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCCNc1nc(O)nc(NCCC)n1
Temperature: 140 °C
Yield: 74.8 %

Procedure:
A vial was charged with 6-chloro-N2,N4-dipropyl-1,3,5-triazine-2,4-diamine (XXXIV) (800 mg, 3.48 mmol), NaOH (696 mg, 17.40 mmol), water (3 mL) and 1,4-dioxane (3 mL). The reaction mixture was heated at 140° C. for 30 min under microwave irradiation. The mixture was acidified with 1N HCl to pH 5, precipitate were filtered, washed with water. The product was dissolved in 50% trifluoroacetic acid (30 mL), the indissoluble residue was filtered off. The filtrate was neutralized with saturated NaHCO3 solution, the formed precipitate was filtered, washed with water, acetone and dried to give 550 mg (75%) of 4,6-bis(propylamino)-1,3,5-triazin-2-ol (CLXXVIII). 400 MHz 1H NMR (DMSO-d6+CF3COOD, ppm) 3.18-3.34 (4H, m), 1.45-1.59 (4H, m), 0.86 (6H, t). ESI-MS (m/z): 212 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=1)[C:16]([CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1)=[O:17].[N-:30]=[N+:31]=[N-:32].[Na+].Cl.[NH+]1C=CC=CC=1.O>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=1)[C:16]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]2[NH:32][N:31]=[N:30][N:24]=2)=[CH:25][CH:26]=1)=[O:17]
Reactant: N#Cc1ccc(CC(=O)c2cccc(OCc3ccc4ccccc4n3)c2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1ccc(-c2nnn[nH]2)cc1)c1cccc(OCc2ccc3ccccc3n2)c1

Procedure:
A heterogenous mixture of 4-(3-(2-quinolinylmethyloxy)benzoylmethyl)benzonitrile (1.35 mmol). NaN3 (6.77 mmol), pyridinium hydrochloride (6.77 mmol) in DMF (3 ml) is heated at 100° C. for 3 hours under nitrogen. The reaction mixture is poured into water and the product is collected on a filter. Recrystallization from EtOAc-DMF gives 5-(4-(3-(2-quinolinylmethyloxy)benzoylmethyl)phenyl)tetrazole.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1.O.ON1C2C=CC=CC=2N=N1.[CH:21]1([N:25]2[CH2:31][CH2:30][C:29]3[CH:32]=[CH:33][C:34]([O:36][C:37]4[N:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=4)=[CH:35][C:28]=3[CH2:27][CH2:26]2)[CH2:24][CH2:23][CH2:22]1>ClCCl>[CH:21]1([N:25]2[CH2:26][CH2:27][C:28]3[CH:35]=[C:34]([O:36][C:37]4[N:42]=[CH:41][C:40]([NH:43][C:7]([CH:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[O:9])=[CH:39][CH:38]=4)[CH:33]=[CH:32][C:29]=3[CH2:30][CH2:31]2)[CH2:22][CH2:23][CH2:24]1
Reactant: Nc1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Reactant: O=C(O)C1CCOCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1)C1CCOCC1
Reaction time: 16 h

Procedure:
Tetrahydro-pyran-4-carboxylic acid (252 mg, 1.94 mmol), 1-hydroxy benzotriazole hydrate (262 mg, 1.94 mmol) and N-cyclohexylcarbodiimide N′-methyl polystyrene (1.7 mmol/g, 2.3 g, 3.88 mmol) were stirred at room temperature in dichloromethane (10 ml) for 15 minutes. 6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinamine (E236) (300 mg, 0.97 mmol) was added and stirring continued for 16 hours. The reaction mixture was applied to a SCX ion exchange cartridge (Varian bond-elute, 5 g) and washed with methanol and then a mixture of 0.880 ammonia/methanol. The combined basic fractions were concentrated in vacuo and the resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.5:4.5:95) to afford the title product (E241); MS (ES+) m/e 422 [M+H]+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]=[C:10]1[N:11]=[C:12]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:13][C:14](=[O:32])/[C:15]/1=[CH:16]/[C:17](/[C:20]([C:22]1[N:30]2[C:25]([CH:26]=[CH:27][CH:28]=[CH:29]2)=[CH:24][C:23]=1[CH3:31])=[O:21])=[CH:18]\[CH3:19]>C(Cl)Cl.CN1C(=O)CCC1>[Br:1][C:24]1[C:23]([CH3:31])=[C:22]([C:20](/[C:17](=[CH:18]/[CH3:19])/[CH:16]=[C:15]2\[C:10](=[CH2:9])[N:11]=[C:12]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[O:13][C:14]\2=[O:32])=[O:21])[N:30]2[C:25]=1[CH:26]=[CH:27][CH:28]=[CH:29]2
Reactant: O=C1CCC(=O)N1Br
Reactant: C=c1nc(-c2ccccc2)oc(=O)/c1=C/C(=C\C)C(=O)c1c(C)cc2ccccn12
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: C=c1nc(-c2ccccc2)oc(=O)/c1=C/C(=C\C)C(=O)c1c(C)c(Br)c2ccccn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.6 %

Procedure:
N-Bromosuccinimide (10.64 g; 59.8 mmol) is added portionwise to a solution of (5E)-4-methylidene-5-{(2E)-2-[(2-methylindolizin-3-yl)carbonyl]but-2-en-1-ylidene}-2-phenyl-4,5-dihydro-6H-1,3-oxazin-6-one (22.8 g; 59.8 mmol) in 350 mL of DCM and 105 mL of NMP. After 10 min of stirring at ambient temperature, the yellow precipitate formed is filtered off, washed with DCM and dried under vacuum to give 23.2 g (85%) of the yellow powder.