Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[C:17](=O)([O-])O.[Na+]>CO>[I:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:17])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1cccc(I)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)CCc1cccc(I)c1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a solution of the mixture of 3-(3-iodophenyl)propionic acid (12.0 g) in methanol (200 ml) was added thionyl chloride (11.0 g, 92.5 mmol), and the mixture was stirred for 30 minutes at 40° C. To the mixture was added an aqueous saturated sodium hydrogencarbonate solution and the mixture was extracted with toluene:ethyl acetate (1:1). The organic layer was washed with water and an aqueous saturated sodium chloride solution, and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was separated and purified with silica gel chromatography (hexane:ethyl acetate=5:1→4:1) to give the subject compound (9.66 g, 61%:total of 3 steps).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:10]2[C:5](=[CH:6][C:7]([N+:22]([O-:24])=[O:23])=[C:8]([NH:11][C:12](=[O:21])[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)[N:4]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:3]1=[O:30].[CH2:32](I)[CH3:33]>C1CCCCC1.CCOC(C)=O>[CH3:31][C:2]1([CH3:1])[C:10]2[C:5](=[CH:6][C:7]([N+:22]([O-:24])=[O:23])=[C:8]([N:11]([CH2:32][CH3:33])[C:12](=[O:21])[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)[N:4]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:3]1=[O:30]
Reactant: CCCCCN1C(=O)C(C)(C)c2cc(NC(=O)CCc3ccccc3)c([N+](=O)[O-])cc21
Reactant: CCI
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CCCCCN1C(=O)C(C)(C)c2cc(N(CC)C(=O)CCc3ccccc3)c([N+](=O)[O-])cc21

Procedure:
N-(3,3-Dimethyl-6-nitro-2-oxo-1-pentyl-2,3-dihydro-1H-indol-5-yl)-N-ethyl-3-phenyl-propionamide is prepared from N-(3,3-dimethyl-6-nitro-2-oxo-1-pentyl-2,3-dihydro-1H-indol-5-yl)-3-phenyl-propionamide (214 mg) and ethyl iodide (46 μl; 0.57 mmol) as described in Example 57b. The compound (55 mg) is obtained by flash chromatography on silica gel eluting with cyclohexane/EtOAc.
Reaction SMILES: [N+:1]([C:4]1[C:5]2[N:6]([N:27]=[N:28][N:29]=2)[C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.[H][H]>[Pt].C(O)C>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][NH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]3[N:27]=[N:28][N:29]=[C:5]3[C:4]=2[NH2:1])[CH:22]=1
Reactant: O=[N+]([O-])c1c(NCCOCCCc2cccnc2)c2ccccc2n2nnnc12
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Product: Nc1c(NCCOCCCc2cccnc2)c2ccccc2n2nnnc12
Yield: 97.2 %

Procedure:
4-Nitro-N-[2-(3-pyridin-3-ylpropoxy)ethyl]tetrazolo[1,5-a]quinolin-5-amine (34.3 g, 87.2 mmol) was added to a 3 liter stainless steel pressure flask containing ethanol (1.25 L, absolute). Platinum on carbon (3.00 g, 5% w/w) was added and the flask was placed on a Parr hydrogenation apparatus. The reaction was shaken under 45 psi (3.15 Kg/cm2) of hydrogen for 24 hours. The catalyst was removed by filtration through Celite™ and the Celite pad was washed with several portions of ethanol. The filtrate was concentrated in vacuo to provide 30.8 g of N5-[2-(3-pyridin-3-ylpropoxy)ethyl]tetrazolo[1,5-a]quinoline-4,5-diamine as an orange/red oil. MS (CI) m/e 364 (MH+), 336.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1.[N:27]1([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)CC)C.O>CN(C)C=O>[CH3:26][N:17]([S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:20])=[O:19])[C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[NH:9][C:8]([C:6]1[S:7][C:3]([CH2:2][N:30]3[CH2:29][CH2:28][N:27]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:32][CH2:31]3)=[CH:4][N:5]=1)=[CH:16]2
Reactant: CCOC(=O)CN1CCNCC1
Reactant: CN(c1cccc2cc(-c3ncc(CCl)s3)[nH]c12)S(=O)(=O)c1cccs1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCN(Cc2cnc(-c3cc4cccc(N(C)S(=O)(=O)c5cccs5)c4[nH]3)s2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.5 %

Procedure:
To a solution of N-{2-[5-(chloromethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (0.700 g) in N,N-dimethylformamide (16 ml) were added ethyl piperazin-1-ylacetate (0.568 g) and triethylamine (0.46 ml), and the mixture was stirred at room temperature for 5 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=50:50-100:0), and recrystallized from ethyl acetate-hexane to give the title compound (0.531 g, yield 57%) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15]C(C3C4N=CC=NC=4C(C4C(Cl)=C(OC)C=C(OC)C=4Cl)=CC=3)=O)=[N:13][CH:14]=2)[CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:62][C:63]1[C:64]([C:68]2[C:77]3[N:76]=[CH:75][CH:74]=[N:73][C:72]=3[C:71]([C:78]([OH:80])=O)=[CH:70][CH:69]=2)=[CH:65][S:66][CH:67]=1.CC1C(B(O)O)=CSC=1>C(Cl)Cl.CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:78]([C:71]3[C:72]4[N:73]=[CH:74][CH:75]=[N:76][C:77]=4[C:68]([C:64]4[C:63]([CH3:62])=[CH:67][S:66][CH:65]=4)=[CH:69][CH:70]=3)=[O:80])=[N:13][CH:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1cscc1-c1ccc(C(=O)O)c2nccnc12
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cc1cscc1B(O)O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CO
Product: Cc1cscc1-c1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)cn2)c2nccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but stirring the reaction mixture at rt overnight, using 2 equiv of 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine hydrochloride (Example 31), TBTU (2 equiv) and 8-(4-methyl-thiophen-3-yl)-quinoxaline-5-carboxylic acid. The carboxylic acid was synthesized as described in Steps 1.2-1.7 but using 4-methyl-3-thiopheneboronic acid in Step 1.4. Title compound: ESI-MS: 459.1 [M+H]+; tR=3.41 min (System 1); TLC: Rf=0.25 (DCM/MeOH, 9:1).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:15][C:14]=1[Cl:24].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[Cl:24][C:14]1[CH:15]=[C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:18][C:13]=1[NH:12][C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Reactant: Fc1ccc2nc(Br)sc2c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Product: COC(=O)Cc1ccc(Nc2nc3ccc(F)cc3s2)c(Cl)c1
Yield: 31.7 %

Procedure:
In xylene (8 ml), 2-bromo-6-fluorobenzothiazole (330 mg, 1.42 mmol), methyl 4-amino-3-chlorophenylacetate (284 mg, 1.42 mmol), and pyridinium p-toluenesulfonate (PPTS) (107 mg, 0.43 mmol) were heated under reflux for 10 hours. After cooling, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (6:1, v/v) eluate fractions, methyl (3-chloro-4-(6-fluoro-2-benzothiazolyl)aminophenyl)acetate (158 mg, 32%) was obtained as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O.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>[F:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([C:16]2[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=2)[CH:11]=1
Reactant: COC(=O)c1ccc(F)cc1Br
Reactant: OB(O)c1ccncc1
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: O
Solvent: COCCOC
Product: COC(=O)c1ccc(F)cc1-c1ccncc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
A mixture of methyl 2-bromo-4-fluorobenzoate (1.5 g), pyridine-4-boronic acid (0.95 g), sodium carbonate (1.0 g), tetrakis(triphenylphosphine)palladium(0) (0.22 g), water (1.5 mL) and DME (9.0 mL) was stirred at 120° C. for 1 hr under microwave irradiation. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous 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 (0.89 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[S:5][C:6]=1[CH:7]([CH3:9])[CH3:8].CCN(CC)CC.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][O:11][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[S:5][C:6]=1[CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)c1sc(CO)cc1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1sc(CO[Si](C)(C)C(C)(C)C)cc1Br
Reaction time: 14 h

Procedure:
A solution of (4-bromo-5-isopropyl-thiophen-2-yl)-methanol (Example Q; 3.4 g, 14 mmol) in CH2Cl2 (4.0 mL) was treated with NEt3 (2.8 mL, 20 mmol), p-dimethylaminopyridine (0.050 g), and t-butyldimethylsilylchloride (2.41 g, 16.0 mmol). The mixture was stirred for 14 hours, then diluted with Et9O and washed with H2O. The organic layer was dried (MgSO4) and the solvent evaporated to provide the crude product, which was used without further purification.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([NH:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:3][CH:2]=1.[CH2:15]1[C:20]2([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:19][CH2:18][O:17][CH:16]1O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(N(CC)CC)C>[C:1]1([CH3:14])[CH:2]=[CH:3][C:4]([NH:7][CH:8]2[CH2:13][CH2:12][N:11]([CH2:18][CH2:19][C:20]3([CH2:15][CH2:16][OH:17])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)[CH2:10][CH2:9]2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(NC2CCNCC2)cc1
Reactant: OC1CC2(CCCCCCC2)CCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1ccc(NC2CCN(CCC3(CCO)CCCCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45.5 %

Procedure:
To a suspension of 4-(p-toluidino)piperidine ditrifluoroacetate (synthesized in Preparation Example 4-5) (1.31 g) in 1,2-dichloroethane (6 mL) was added triethylamine (0.96 mL). The suspension was stirred at room temperature for 5 minutes. Then, a solution of 3-oxaspiro[5.7]tridecan-2-ol (synthesized in Example 72) (0.62 g) in 1,2-dichloroethane (3 mL) was added to the suspension, and it was stirred at room temperature for additional 10 minutes. The reaction solution was ice-cooled and sodium triacetoxyborohydride (0.70 g) was added thereto. The reaction solution was then allowed for its temperature to rise to room temperature, and the solution was stirred for additional 4.5 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution and it was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by chromatography [silica gel, methanol-chloroform (3:97 to 1:9)] to give the title compound (0.53 g).
Reaction SMILES: [CH2:1]1[CH2:6][O:5][CH:4]=[CH:3][CH2:2]1.C(C(N)=O)C(N)=[O:9].C(N)=O.[O-:17][CH2:18][CH3:19].[Na+:20]>CO.C[O-].[Na+].C(O)C>[CH:6]([O:5][CH2:4][CH3:3])=[O:9].[O-:17][CH2:18][CH3:19].[Na+:20].[CH2:1]1[CH2:6][O:5][CH:4]=[CH:3][CH2:2]1
Reactant: NC(=O)CC(N)=O
Agent: C1=COCCC1
Agent: CC[O-]
Agent: C[O-]
Solvent: CCO
Solvent: NC=O
Solvent: CO
Product: CCOC=O

Procedure:
The DHP yield was improved by approximately 30% to a maximum of 81% by A. Sommer, DE-OS 1 200 308 by reacting malonodiamide with formamide in alcoholic solution with more than 2 moles, advantageously with 3.0 to 3.9 moles, of alkali metal alkoxide. As opposed to Brown, this worker employed formamide in the examples in amounts of just over 2 moles per mole of malonodiamide. The alkali metal alkoxides used were sodium ethoxide in methanol and sodium methoxide in ethanol. In the latter case, the methanol was distilled off from the reaction mixture, thus dispensing with filtration of the salts which had precipitated. Ethyl formate instead of formamide yielded, together with sodium ethoxide, DHP in a yield of only 61.5%.
Reaction SMILES: COC(=O)C1C(C)=CC(C2C=CC=C(C(F)(F)F)C=2)=NC=1OC.Cl[C:25]1[N:30]=[C:29]([C:31]([N:33]2[CH2:38][CH2:37][CH:36]([N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:35][CH2:34]2)=[O:32])[C:28]([CH3:44])=[CH:27][C:26]=1[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=1.[CH3:55][O:56][C:57]1[N:62]=[CH:61][C:60](B(O)O)=[CH:59][N:58]=1>>[CH3:55][O:56][C:57]1[N:62]=[CH:61][C:60]([C:25]2[N:30]=[C:29]([C:31]([N:33]3[CH2:38][CH2:37][CH:36]([N:39]4[CH2:43][CH2:42][CH2:41][CH2:40]4)[CH2:35][CH2:34]3)=[O:32])[C:28]([CH3:44])=[CH:27][C:26]=2[C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=2)=[CH:59][N:58]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: COc1ncc(B(O)O)cn1
Agent: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)nc1OC
Product: COc1ncc(-c2nc(C(=O)N3CCC(N4CCCC4)CC3)c(C)cc2-c2cccc(C(F)(F)F)c2)cn1

Procedure:
In analogy to the procedure described for the preparation of intermediate 5C, [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with 2-methoxypyrimidin-5-yl-boronic acid to give the title compound as light brown amorphous solid. MS: 526.2 (MH+).
Reaction SMILES: [CH2:1]([C:4]1[C:17]([OH:18])=[C:16]([CH3:19])[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:20])[C:6]=2[CH:5]=1)[CH:2]=[CH2:3].C(Cl)(Cl)Cl.ClC1C=CC=C(C(OO)=[O:33])C=1.C(=O)([O-])[O-].[K+].[K+]>O>[OH:33][CH2:3][CH:2]1[O:18][C:17]2[C:4](=[CH:5][C:6]3[C:7](=[O:20])[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[O:14][C:15]=3[C:16]=2[CH3:19])[CH2:1]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1cc2c(=O)c3ccccc3oc2c(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1c2c(cc3c(=O)c4ccccc4oc13)CC(CO)O2
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.8 %

Procedure:
To a mixture of 2-allyl-3-hydroxy-4-methyl-9-oxo-9H-xanthene (11 g) and chloroform (800 ml), 9.5 g of m-chloroperbenzoic acid was added and the resulting mixture was stirred at room temperature for 5 hours, followed by standing overnight. To the mixture, potassium carbonate (20 g) and water (500 ml) were added and the resulting mixture was subjected to extraction with chloroform. The chloroform layer was dried and the solvent was distilled off. The residue was recrystallized from ethanol to obtain 10 g of 2,3-dihydro-2-hydroxymethyl-11-methyl-5-oxo-5H-furo[3,2-b]xanthene. m.p. 242°-243° C. This compound gave a mass spectrum having a molecular ion peak at m/e 282.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(N=Nc2ccc(O)cc2)cc1
Reactant: BrCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(N=Nc2ccc(OCCCCCCBr)cc2)cc1
Temperature: 25 °C
Yield: 47 %

Procedure:
0.2 mol (44.6 g) of 4-hydroxy-4′-cyanoazobenzene, 2 mol (488.1 g) of 1,6-dibromohexane, 1.45 mol (220.4 g) of K2CO3 and 800 ml of acetone were charged in a 2-liter three-necked flask and reacted under reflux for 20 hours by using a water bath. After cooling to a room temperature, by-products and excess K2CO3 were removed by filtration. After concentrating to about 1/2 by using a rotary evaporator, the product was left in a refrigeration box to be crystallized. After filtration under suction, crystals were washed with n-hexane and dried under a reduced pressure (0.117 mol (45.3 g, yield; 58.6%)). Further, they were recrystallized in ethanol to obtain 0.094 mol of 4-(6-bromohexyloxy)-4′-cyanoazobenzene (36.3 g, yield: 47.0%)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I:24][C:25]1[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1.O>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[O:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([I:24])[CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc(I)c1
Reactant: O=C(OCc1ccccc1)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cccnc1Oc1cccc(I)c1

Procedure:
A solution 2-Chloro-nicotinic acid benzyl ester (1.7 grams, 6.86 mmole), cesium carbonate (4.5 grams, 13.7 mmole) and 3-iodophenol (1.7 grams, 7.54 mmole) in dimethylformamide (20 ml) was stirred for 2 hours at 70-80° C. The mixture was poured into 150 ml water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to an oil which was purified via flash chromatography on silica using 30% ethyl acetate/hexane as eluent (2.32 g). MW 431.24; MS (m/e) 432 (M++1).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Br:25])[CH:23]=3)[N:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>CO>[Br:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][N:16]=[C:15]2[N:12]1[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3ccc(Br)cc23)CC1
Agent: Cl
Solvent: CO
Product: Brc1ccc2ncnc(N3CCNCC3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HCl (1.0 M in Et2O, 30 mL) was added to a solution of 4-(6-bromo-quinazolin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.50 g, 3.81 mmol) in MeOH (50 mL) and stirred at room temperature overnight. The mixture was concentrated in vacuo to give 6-bromo-4-piperazin-1-yl-quinazoline as the bis-hydrochloride salt (1.3 g, 93%.) MS (APCI+) [M+H]+ 295.1.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)[CH:7]=[C:6]([CH3:16])[C:5]=1[C:17]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]2[C:18]=1[CH2:19][CH2:20][C@H:21]2[O:27][C:28]1[CH:41]=[CH:40][C:31]2[C@H:32]([CH2:35][C:36]([O:38]C)=[O:37])[CH2:33][O:34][C:30]=2[CH:29]=1.Cl>CO.C(OCC)(=O)C.O1CCOCC1>[CH3:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)[CH:7]=[C:6]([CH3:16])[C:5]=1[C:17]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]2[C:18]=1[CH2:19][CH2:20][C@H:21]2[O:27][C:28]1[CH:41]=[CH:40][C:31]2[C@H:32]([CH2:35][C:36]([OH:38])=[O:37])[CH2:33][O:34][C:30]=2[CH:29]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cncnc6)cc5C)ccc(F)c43)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc(-c2cncnc2)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 40 °C
Reaction time: 1 h

Procedure:
1 M aqueous NaOH solution (167 μL) is added to a solution of methyl 2-((S)-6-((R)-4-(2,6-dimethyl-4-(pyrimidin-5-yl)phenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (35 mg) in methanol (3 mL). The mixture is stirred at 40° C. for 1 hour. After addition of 1 N hydrochloric acid (167 μL) the mixture is diluted with ethyl acetate and washed with brine. The organic phase is dried (MgSO4) and concentrated. The product thus obtained is dissolved in 1,4-dioxane and lyophilized to give the title compound. Yield: 29 mg; LC (method 11): tR=1.14 min; Mass spectrum (ESI+): m/z=511 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C@@H:41]([CH2:52][CH3:53])[C@H:42]([N:46]1[CH2:50][CH2:49][NH:48][C:47]1=[O:51])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[OH:32][C@H:3]([C@@H:2]([NH:1][C:43](=[O:44])[C@@H:42]([N:46]1[CH2:50][CH2:49][NH:48][C:47]1=[O:51])[C@@H:41]([CH3:40])[CH2:52][CH3:53])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CCNC1=O
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC[C@H](C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)N1CCNC1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.9 %

Procedure:
A solution of the product of Example 1H (0.020 g, 0.038 mmol) in tetrahydrofuran (0.40 mL) was treated with the product from Example 161B (0.0075 g, 0.038 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.035 mL, 0.201 mmol), stirred at 25° C. for 12 hours and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic layer was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with a gradient starting with dichloromethane and ending with 50% acetone in dichloromethane to give the title compound (0.019 g, 71% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.68 (d, J=6.6 Hz, 3 H), 0.75 (t, J=7.4 Hz, 3 H), 0.80 (s, 9 H), 0.85-0.96 (m, 1H), 1.24-1.35 (m, 2H), 1.48-1.56 (m, 1 H), 1.70-1.79 (m, 1 H), 2.54-2.72 (m, 3 H), 2.79-2.85 (m, 2H), 2.98-3.14 (m, 3H), 3.50-5.58 (m, 4 H), 3.77-3.91 (m, 3 H), 4.11-4.23 (m, 1H), 4.54 (d, J=7.4 Hz, 1 H), 6.31 (s, 1 H), 6.90 (d, J=9.6 Hz, 1 H), 7.09-7.26 (m, 8 H), 7.30-7.34 (m, 1 H), 7.80-7.97 (m, 5 H), 8.64 (m, 1 H).