Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][OH:10].[H-].[Na+].Br.Cl[C:15]1[CH:16]=[C:17]([CH3:25])[C:18]2[N:19]([C:21]([NH2:24])=[N:22][N:23]=2)[N:20]=1.O>CN(C=O)C>[CH3:25][C:17]1[C:18]2[N:19]([C:21]([NH2:24])=[N:22][N:23]=2)[N:20]=[C:15]([O:10][CH2:9][CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH:16]=1
Reactant: Cc1cc(Cl)nn2c(N)nnc12
Reactant: OCCOC1CCCCO1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCCOC2CCCCO2)nn2c(N)nnc12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
2-(Tetrahydropyran-2-yloxy)ethanol (3.85 ml) was initially charged in DMF (25 ml), admixed under argon with sodium hydride (681 mg) and stirred at 40° C. for 0.5 h. Subsequently, 6-chloro-8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.002; 1.5 g), dissolved in DMF (25 ml), was added dropwise. After 40 min, the mixture was admixed with water and extracted by shaking four times with dichloromethane. To eliminate the excess alcohol, the mixture was chromatographed first through a short silica gel column with MtB ether and then with 8:2 dichloromethane/methanol. The clean product fractions were combined and dried. 678 mg of the title compound were obtained.
Reaction SMILES: C([CH:5]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:14]3[CH:15]=[CH:16][CH:17]=[C:7]([C:8]=23)[S:6]1(=[O:19])=[O:18])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[S:6]1(=[O:18])(=[O:19])[C:7]2=[CH:17][CH:16]=[CH:15][C:14]3=[CH:13][CH:12]=[CH:11][C:9](=[C:8]23)[NH:10][CH2:5]1
Reactant: CC(C)(C)C1Nc2cccc3cccc(c23)S1(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S1(=O)CNc2cccc3cccc1c23
Reaction time: 22 h

Procedure:
0.06 g of 2-tert-butyl-2,3-dihydro-naphtho[1,8-de][1,3]thiazin-1,1-dioxide is dissolved in 1 mL of dichloromethane and 0.02 mL of trifluoroacetic acid is added. Then the mixture is stirred for a total of 22 hours at reflux temperature and for 96 hours at ambient temperature, while during this period a total of 0.07 mL of trifluoroacetic acid is added. The reaction mixture is evaporated down in vacuo and purified by chromatography. Yield: 0.034 g; m.p.: 206° C.–207° C.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[NH2:21][C@@H:22]([CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)[C:23]([N:25]([CH3:27])[CH3:26])=[O:24].ClC1C=C2C(=CC=1)N(S(C1C=CC(OC)=CC=1OC(F)(F)F)(=O)=O)C(=O)C2(N[C@@H](CC(N)=O)C(N(C)C)=O)C1C=CC=CC=1OC>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:21][C@@H:22]([CH2:28][C:29]1[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=1)[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CN(C)C(=O)[C@@H](N)Cc1ccncc1
Agent: COc1ccc(S(=O)(=O)N2C(=O)C(N[C@@H](CC(N)=O)C(=O)N(C)C)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Product: COc1ccccc1C1(N[C@@H](Cc2ccncc2)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 0.78 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and 0.54 g of the compound obtained in Step 83-2 as starting materials, 268 mg of a diastereoisomer mixture of the title compound (pale yellow amorphous) was obtained by a similar method to Step 4-2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:11]([OH:13])=[O:12])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:15]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:11]([O:13][CH3:15])=[O:12])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)C1(c2cccc(Br)c2)CC1
Agent: Cl
Product: COC(=O)C1(c2cccc(Br)c2)CC1
Temperature: 60 °C

Procedure:
To a solution 1-(3-bromophenyl)cyclopropanecarboxylic acid (530 mg, 2.2 mmol) in methanol (5 mL) was added HCl (2.0 M in Et2O, 0.5 mL). The mixture was heated at 60° C. overnight. The solvent was evaporated and water (10 mL) was added to the residue. The mixture was neutralized with saturated NaHCO3 solution until pH 7-8. The mixture was extracted with CH2Cl2 (10 mL×2). The combined organics were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to afford methyl 1-(3-bromophenyl)cyclopropanecarboxylate (530 mg), which was used without further purification. ESI-MS m/z 255/257 (M+1)+. Retention time 1.68 minutes.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[N:10]([C:19]([N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])[CH2:11][C:12](=O)[NH:13]2.C(OP(Cl)(OCC)=O)C.[N+:35]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])#[C-:36]>C1COCC1>[F:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[N:10]([C:19]([N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])[CH2:11][C:12]1[N:13]2[CH:36]=[N:35][C:37]=1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]
Reactant: O=C1CN(C(=O)N2CCCC2)c2c(F)cccc2N1
Reactant: [C-]#[N+]CC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: CCOP(=O)(Cl)OCC
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ncn2c1CN(C(=O)N1CCCC1)c1c(F)cccc1-2
Reaction time: 0.5 h

Procedure:
Potassium tert-butoxide (1M, 3.8 ml) is added to 5-fluoro-1,2,3,4-tetrahydro-4-[(pyrrolidino)carbonyl]quinoxalin-2-one (XXXII, EXAMPLE 29, 0.908 g) at 0° in THF (20 ml). The mixture is stirred for 30 min and then diethylchlorophosphate (0.55 ml) is added. The reaction is stirred for 1 hr at 0°, then cooled at -78°. tert-butyl isocyanoacetate (0.58 g) is added, followed by potassium tert-butoxide (1 M, 4.14 ml). The reaction is stirred at -78° for 4 hr, then allowed to warm to 20°-25° over 1 hr. The mixture is then partitioned between ethyl acetate, water, and saline. The organic layers are dried over magnesium sulfate and concentrated. The crude product is chromatographed on silica gel (250 ml) eluting with a gradient of ethyl acetate/dichloromethane (20/80 to 40/60). The appropriate fractions are pooled, concentrated and crystallized from dichloromethane/hexane to give the title compound; mp 213.5-214.5°; MS (m/z) at 386; IR (mineral oil) 1689, 1677, 1217, 1363 and 1157 cm-1 ; NMR (CDCl3) 1.63, 1.88, 3.36, 5.08, 7.08, 7.20, 7.33 and 8.00 δ.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]4)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[NH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28].C(O)C.C([BH3-])#N.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[CH2:4]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[CH:18]=[C:17]([CH2:22][NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:16]=[CH:15]4)[CH2:7][CH2:6]2)[CH2:1][CH2:2][CH2:3]1
Reactant: NCCC(=O)O
Reactant: O=Cc1ccc2cc(OC3CCC4(CCCC4)CC3)ccc2c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCNCc1ccc2cc(OC3CCC4(CCCC4)CC3)ccc2c1
Temperature: 25 °C
Yield: 31 %

Procedure:
A solution of 6-(Spiro[4.5]dec-8-yloxy)-naphthalene-2-carbaldehyde (229.5 mg, 0.7441 mmol) and Beta-alanine (66.3 mg, 0.744 mmol) in ethanol (1 mL, 20 mmol) was heated to reflux for 2 h. The yellow solution was cooled to rt and sodium cyanoborohydride (56.1 mg, 0.893 mmol) was added and was heated to reflux for 1 h. After cooled down to rt, citric acid was added and concentrated down. Extraction with DCM and prep HPLC gave product as a white solid (88 mg, 31%). LCMS Rt=1.52 min m/z=382.30 [M+1]. 1H NMR (400 MHz, MeOD) δ=7.89 (s, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.80 (d, =9.0 Hz, 1H), 7.48 (dd, J=1.7, 8.5 Hz, 1H), 7.27 (s, 1H), 7.19 (dd, J=2.3, 8.9 Hz, 1H), 4.55-4.44 (m, 1H), 4.35 (s, 2H), 3.36-3.32 (m, 2H), 2.76 (t, J=6.8 Hz, 2H), 2.09-1.33 (m, 16H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]([NH:14][C:15](=[O:38])[CH2:16][C:17](=O)[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3C(COC4CCCCO4)=[CH:27][N:26]=[N:25]3)[CH:19]=2)=[CH:12][C:11]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:40]=2[F:46])=[C:10]([N:47]([CH3:49])[CH3:48])[CH:9]=1)(C)(C)C.[C:51]([OH:57])([C:53](F)(F)F)=O>C(Cl)Cl>[F:46][C:40]1[C:41]([F:45])=[CH:42][CH:43]=[CH:44][C:39]=1[C:11]1[C:10]([N:47]([CH3:49])[CH3:48])=[CH:9][C:8]2[N:7]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N:24]4[C:53]([CH2:51][OH:57])=[CH:27][N:26]=[N:25]4)[CH:19]=3)[CH2:16][C:15](=[O:38])[NH:14][C:13]=2[CH:12]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1-c1cccc(F)c1F
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1-c1cccc(F)c1F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[2-dimethylamino-2′,3′-difluoro-5-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-biphenyl-4-yl]-carbamic acid tert.-butyl ester (Example M7) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (26 mg).
Reaction SMILES: CC1C=C([C:9]2(C3C=CC(N)=C(C)C=3)[C:21]3[CH:20]=[C:19](C#C[Si](C)(C)C)[CH:18]=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][C:12]([C:28]#[C:29][Si](C)(C)C)=[CH:13][CH:14]=3)C=CC=1N.C[Si]([C:46]#[CH:47])(C)C.CC(O)(C#C)C.CC1C=C(C2(C3C=CC(N)=C(C)C=3)C3C=C(CC(O)(C)C#C)C=CC=3C3C2=CC(CC(C)(O)C#C)=CC=3)C=CC=1N>>[C:28]([C:12]1[CH:13]=[CH:14][C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:9][C:10]=2[C:11]=1[C:46]#[CH:47])#[CH:29]
Reactant: Cc1cc(C2(c3ccc(N)c(C)c3)c3cc(C#C[Si](C)(C)C)ccc3-c3ccc(C#C[Si](C)(C)C)cc32)ccc1N
Reactant: C#C[Si](C)(C)C
Agent: C#CC(C)(C)O
Agent: C#CC(C)(O)Cc1ccc2c(c1)C(c1ccc(N)c(C)c1)(c1ccc(N)c(C)c1)c1cc(CC(C)(O)C#C)ccc1-2
Product: C#Cc1ccc2c(c1C#C)Cc1ccccc1-2

Procedure:
Diethynylfluorene was synthesized by the same method as in the synthesis method of 9,9-bis(3-methyl-4-aminophenyl)-2,7-bis(trimethylsilylethynyl)fluorene represented by Example 1 except that trimethylsilylacetylene was replaced with 2-methyl-3-butyne-2-ol. The obtained compound was measured by the NMR and then the compound was 9,9-bis(3-methyl-4-aminophenyl)-2,7-bis(2-hydroxy-2-methyl-3-butynyl)fluorene represented by the following formula (3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(OCC)(=O)C.[N:15]#[C:16]Br.[OH-].[Na+]>O>[NH2:15][C:16]1[O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: N#CBr
Reactant: Nc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1nc2ccccc2o1
Temperature: 45 °C
Reaction time: 12 h
Yield: 88.2 %

Procedure:
A mixture of 2.5 g 2-aminophenol (7-1) and 20 ml ethyl acetate was heated to 45° C. 3 g of cyanogen bromide was added to the mixture. The mixture was stirred at 45-50° C. for 12 hours. After cooling to room temperature, 1.5 g of sodium hydroxide in 15 ml of water was added. The organic layer was separated and washed with brine until neutral pH. Toluene (5 ml) was added and the solvent was removed to yield 2.71 g (88%) 2-aminobenzoxazol (7-2).
Reaction SMILES: [I:1]NC(=O)CCC(N)=O.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[F:18].S(=O)(=O)(O)O>C(O)(=O)C>[Cl:10][C:11]1[C:12]([F:18])=[CH:13][C:14]([OH:17])=[C:15]([I:1])[CH:16]=1
Reactant: Oc1ccc(Cl)c(F)c1
Reactant: NC(=O)CCC(=O)NI
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Oc1cc(F)c(Cl)cc1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.8 %

Procedure:
To a suspension of N-iodosuccinamide (6.1 g, 27.3 mmol) in glacial acetic acid (23 mL) was added 4-chloro-3-fluorophenol (4.0 g, 27.3 mmol) and after 5 minutes sulphuric acid was added (0.5 mL, 8.2 mmol) and the reaction mixture was left to stir at room temperature for 16 hours. The reaction was quenched by addition of water (30 mL) and the compound was extracted into dichloromethane (3×30 mL). The combined organic layers were washed with 10% sodium metabisulphite aqueous solution (2×20 mL), then saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo. The crude material was purified by flash column chromatography (silica, toluene) to afford the desired product as an oil (4.0 g, 54%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[NH2:37])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[NH:37][C:13](=[O:15])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH3:16])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1ccccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (S)-2-benzyloxycarbonylaminopropionic acid (230 mg, 1.03 mmol), 4-(2-aminophenylamino)piperidine-1-carboxylic acid tertbutyl ester (200 mg, 0.686 mmol), HOBt (102 mg, 0.755 mmol), 4-methylmorpholine (166 μL, 1.51 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (197 mg, 1.03 mmol) in DCM (7 mL) was stirred at RT for 3 h. The reaction mixture was then diluted with additional DCM and the organic layer was washed with water, then dried and concentrated in vacuo affording 4-[2-((S)-2-benzyloxycarbonylaminopropionylamino)phenylamino]piperidine-1-carboxylic acid tertbutyl ester as a purple/brown oil (436 mg, quantitative). LCMS: RT 3.66 min [M+H]+ 497.2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[C:17]3[CH:18]=[C:19]4[O:24][CH2:23][O:22][C:20]4=[CH:21][C:16]=3[CH2:15][CH:14]([C:25]([NH2:27])=[O:26])[NH:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].O.[C:29](OC(=O)C)(=[O:31])[CH3:30]>>[C:29]([N:13]1[CH:14]([C:25]([NH2:27])=[O:26])[CH2:15][C:16]2[CH:21]=[C:20]3[O:22][CH2:23][O:24][C:19]3=[CH:18][C:17]=2[C:11]([C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=2)=[N:12]1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C2=NNC(C(N)=O)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Solvent: O
Product: CC(=O)N1N=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc3c(cc2CC1C(N)=O)OCO3
Temperature: 25 °C
Reaction time: 48 h
Yield: 81 %

Procedure:
3.68 g (10.0 millimoles) of (±)-7,8-dihydro-5-(3-methyl-4-nitro-phenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine-8-carboxylic acid-amide are suspended in 30 ml of acetic anhydride and stirred at room temperature for 48 hours. The reaction mixture is cooled with icecold water, the precipitated product is filtered and washed with 20 ml of diethyl ether. Thus 3.32 g of the desired compound are obtained, yield 81%, mp.: 157–161° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([NH2:15])[CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[CH:16](OC)(OC)OC>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]3[O:14][CH:16]=[N:15][C:10]=3[CH:9]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(O)c(N)c2)CC1
Reactant: COC(OC)OC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(c2ccc3ocnc3c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
To a solution of 1-(3-amino-4-hydroxy-phenyl)-cyclopropanecarboxylic acid methyl ester (3.00 g, 14.5 mmol) in DMF were added trimethyl orthoformate (5.30 g, 14.5 mmol) and a catalytic amount of p-tolueneslufonic acid monohydrate (0.3 g) at room temperature. The mixture was stirred for 3 hours at room temperature. The mixture was diluted with water and extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give crude 1-benzooxazol-5-yl-cyclopropanecarboxylic acid methyl ester (3.1 g), which was directly used in the next step. 1H NMR (CDCl3, 400 MHz) δ 8.09 (s, 1), 7.75 (d, J=1.2 Hz, 1H), 7.53-7.51 (m, 1H), 7.42-7.40 (m, 1H), 3.66 (s, 3H), 1.69-1.67 (m, 2H), 1.27-1.24 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=1.C(N(CC)CC)C.[OH-].[Na+]>C(Cl)Cl>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][N:25]([C:6](=[O:7])[C:5]3[CH:9]=[CH:10][CH:11]=[C:3]([N:2]([CH3:12])[CH3:1])[CH:4]=3)[CH2:26][CH2:27]2)=[CH:16][CH:15]=1
Reactant: Clc1ccc(CCN2CCNCC2)cc1
Reactant: CN(C)c1cccc(C(=O)Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1cccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6.51 g of 3-dimethylaminobenzoyl chloride in 130 ml of methylene chloride is added dropwise, over a period of 10 minutes, to a solution, stirred at room temperature, of 7.97 g of 1-[2-(4-chlorophenyl)-ethyl]-piperazine and 3.6 g of triethylamine in 150 ml of methylene chloride. The reaction mixture is stirred overnight at room temperature, diluted with methylene chloride, rendered alkaline with 2N NaOH and washed with water, dried over sodium sulphate and concentrated to dryness by evaporation. The residue is recrystallised from ethanol. 1-[2-(4-chlorophenyl)-ethyl]-4-(3-dimethylaminobenzoyl)-piperazine having a melting point of 110°-112° is thus obtained.
Reaction SMILES: [Si]([O:8][C@H:9]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH2:32][OH:33])[CH:26]=1)[CH2:10][NH:11][C:12]([CH3:24])([CH3:23])[CH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=O)(C(C)(C)C)(C)C.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:58]([O:60][C:61]1[CH:69]=[CH:68][C:64]([CH2:65][CH2:66][NH2:67])=[CH:63][C:62]=1[O:70][CH3:71])[CH3:59].F.F.F.C(N(CC)CC)C>CN(C)C(=O)C>[CH2:58]([O:60][C:61]1[CH:69]=[CH:68][C:64]([CH2:65][CH2:66][NH:67][C:17](=[O:19])[C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([CH2:13][C:12]([NH:11][CH2:10][C@H:9]([OH:8])[C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH2:32][OH:33])[CH:26]=3)([CH3:24])[CH3:23])[CH:15]=2)=[CH:63][C:62]=1[O:70][CH3:71])[CH3:59]
Reactant: CCOc1ccc(CCN)cc1OC
Reactant: CC(C)(Cc1cccc(C(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCOc1ccc(CCNC(=O)c2cccc(CC(C)(C)NC[C@H](O)c3ccc(O)c(CO)c3)c2)cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 30 %

Procedure:
Solutions of 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxy methylphenyl)ethylamino]-2-methylpropyl}benzoic acid (preparation 37) (90 mg, 0.19 mmol) in N,N-dimethylacetamide (1 mL) and 0-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (61 mg, 0.16 mmol) in N,N-dimethylacetamide (0.5 mL) were added to a solution of 4-ethoxy-3-methoxyphenethylamine (37 mg, 0.19 mmol) in N,N-dimethylacetamide (0.5 mL). The resulting mixture was stirred for 72 hours at room temperature. The solvent was removed in vacuo and the residue was partitioned between dichloromethane (4 mL) and saturated sodium hydrogen carbonate solution (1 mL). The mixture was then filtered through a phase separation tube and the organic solution was concentrated in vacuo. The residue was dissolved in dimethylsulfoxide (700 μL), triethylamine trihydrofluoride (30 μL, 0.19 mmol) was added and the mixture was stirred at room temperature for 72 hours. The reaction mixture was then purified directly by HPLC using a Phenomenex Luna C18 system, eluting with water/0.05% diethylamine:acetonitrile, 5:95 to 95:5, to afford the title compound in 30% yield (30.9 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].C(N(CC)C(C)C)(C)C.Br[CH2:24][CH2:25][CH:26]=[CH2:27]>CN(C)C=O>[CH2:27]([O:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[NH:8][C:7](=[O:12])[CH:6]=1)[CH2:26][CH:25]=[CH2:24]
Reactant: O=c1cc(O)c2cc(Cl)ccc2[nH]1
Reactant: C=CCCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCOc1cc(=O)[nH]c2ccc(Cl)cc12
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of 6-chloro-4-hydroxyquinolin-2(1H)-one (800 mg, 4.09 mmol) and N,N-diisopropylethylamine (1415 μl, 8.18 mmol) in dimethylformamide (13.6 ml) was added 4-bromo-1-butene (415 μl, 4.09 mmol). The solution was heated to 60° C. and stirred for 18 hours. The reaction mixture was purified by column chromatography to provide the title compound.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])=[N:4][N:3]=[N:2]1.[C:13](Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15].Cl>N1C=CC=CC=1>[C:13]([O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]1[NH:1][N:2]=[N:3][N:4]=1)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: Oc1ccccc1-c1nnn[nH]1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccccc1-c1nnn[nH]1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
2-(1H-Tetrazol-5-yl)phenol (4.86 g) was dissolved in pyridine (20 ml), and pivaloyl chloride (7.2 g) was added to the solution at room temperature. After being stirred for 15 h, the mixture was poured into ice water and acidified with dilute hydrochloric acid. The resulting crystals were collected by filtration and dried to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[SH:17].C([O-])(=O)C.[Pb+4].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.O>C(O)(=O)C>[Br:1][C:2]1[C:7]([C:8]2[S:17][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccccc1S
Reactant: O=Cc1cccnc1Br
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CC(=O)O
Solvent: O
Product: Brc1ncccc1-c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6.58 g (34.0 mmol) of 2-bromo-3-pyrdinecarboxaldehyde and 5.5 mL (50.9 mmol) of 2-aminothiophenol were dissolved in 150 mL of acetic acid. The solution was agitated at room temperature for 30 minutes. Next, 19.0 g (40.8 mmol) of lead (IV) acetate was added thereto. The resulting product was agitated at 50° C. for 1 hour. Then, water was added to the acquired reactant. The mixture was extracted with ethyl acetate and treated under reduced pressure to remove the solvent, obtaining 5.55 g (Y=55%) of a white solid.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[CH:6][C:5]=1[Cl:11].[F:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:22](Cl)=[O:23].O>CN(C)C=O>[Cl:11][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Cl:10])[C:4]=1[NH:3][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:19]([O:18][CH:14]2[CH2:15][CH2:16][CH2:17][CH:13]2[F:12])[CH:20]=1
Reactant: COc1ccc(C(=O)Cl)cc1OC1CCCC1F
Reactant: Nc1c(Cl)cncc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1OC1CCCC1F
Reaction time: 0.67 h

Procedure:
A suspension of sodium hydride (0.3; 60% oil dispersion) in dimethylformamide (5 mL) is treated with 4-amino-3,5-dichloropyridine (0.62 g) and the mixture is stirred for 40 minutes. A solution of 3-(2-fluoro-cyclopentyloxy)-4-methoxybenzoyl chloride in dimethylformamide (12 mL) is added, and the mixture is stirred at 80-90° C. for 1 day. The solution is cooled, poured into water (75 mL) and extracted with dichloromethane (3×50 mL). The combined organic extracts are washed with brine (50 mL), dried over magnesium sulfate and concentrated. The residue is subjected to flash chromatography, eluting with a mixture of ethyl acetate and petroleum ether (1:3 v/v), to give N-(3,5-dichloropyrid-4-yl)-3-(2-fluorocyclopentyloxy)-4-methoxybenzamide (0.26 g), m.p. 167-169° C. [Elemental analysis: C,53.8; H,4.2; N,6.75; Cl,17.8%; calculated: C,54.15; H,4.3; N,7.0; Cl,17.8%].