Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:20](COCC[Si](C)(C)C)[N:19]=[CH:18][C:17]=3[C:29]#[N:30])=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl>C(O)C>[N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[NH:20][N:19]=[CH:18][C:17]=3[C:29]#[N:30])=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1ncc(C#N)c1Nc1ccc(C(=O)N2CCOCC2)cc1
Agent: Cl
Solvent: CCO
Product: N#Cc1cn[nH]c1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
5-(4-(Morpholine-4-carbonyl)phenylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbonitrile (880 mg, 2.06 mmol) was dissolved in 40 mL of ethanol. Hydrochloric acid (2N) was added and the mixture was stirred at room temperature overnight. After 16 hrs at room temperature, LC/MS indicated 60% desired material and 40% un-reacted starting material. The mixture was heated to 65° C. and stirred for 2 hrs. LC/MS indicated complete consumption of the starting material and the formation of the desired product. The mixture was treated with sodium hydroxide solution (4 g NaOH in 40 mL of water) under ice bath. The resulting mixture was extracted with ethyl acetate twice (350 mL). The organic layer was washed with brine and dried over sodium sulfate. TLC indicated a clean spot. Solvents were evaporated and the residue was triturated with dry ether to give 5-[4-(morpholine-4-carbonyl)-phenylamino]-1H-pyrazole-4-carbonitrile as a white solid (530 mg, 86.6% yield). H-NMR is consistent with the desired structure. LC/MS is clean and consistent with the desired molecular weight. LC/MS clacd for C15H15N5O2 (m/e) 297.12, obsd 298.0 (M+H, ES+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9]Cl)[C:5]([CH:11]=[CH2:12])=[CH:4][N:3]=1.[C:13](=[S:16])([S-:15])[S-:14].[Na+:17].[Na+]>O.CO>[C:13](=[S:14])([S-:16])[S:15][CH2:9][C:6]1[C:5]([CH:11]=[CH2:12])=[CH:4][N:3]=[C:2]([CH3:1])[C:7]=1[OH:8].[Na+:17]
Reactant: S=C([S-])[S-]
Reactant: C=Cc1cnc(C)c(O)c1CCl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=Cc1cnc(C)c(O)c1CSC(=S)[S-]
Temperature: 50 °C
Reaction time: 4 h

Procedure:
2-Methyl-3-hydroxy-4-chloromethyl-5-vinylpyridine (20 g.) is suspended in water/methanol (100:25 v/v) and treated with disodium trithiocarbonate (33%) (45 g.). The mixture is stirred at b 50° C. for 4 hours under nitrogen and adjusted to pH 6.2-6.5 with dilute acid. The precipitate is recrystallized from DMF/water to give sodium (2-methyl-3-hydroxy-5-vinyl-4-pyridinyl)methyl trithiocarbonate.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[N:20])[CH:17]=3)[N:12](C3CCCCO3)[N:11]=2)=[CH:6][CH:5]=1)[CH3:3].[N:27]([Sn](CCCC)(CCCC)CCCC)=[N+:28]=[N-:29].O1CCOCC1.Cl>C1(C)C=CC=CC=1.[OH-].[Na+]>[CH3:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]4[N:20]=[N:27][NH:28][N:29]=4)[CH:17]=3)[NH:12][N:11]=2)=[CH:8][CH:9]=1)[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CC(C)c1ccc(-c2nn(C3CCCCO3)c3ccc(C#N)cc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CC(C)c1ccc(-c2n[nH]c3ccc(-c4nn[nH]n4)cc23)cc1
Yield: 80 %

Procedure:
The title compound was prepared from 3-[4-(methylethyl)phenyl]-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.095 g, 0.307 mmol), azidotributyl tin (0.744 g, 0.689 mL, 2.33 mmol) in toluene (10 mL) as described for the preparation of compound 167. Deprotection was effected by treating a dioxane solution (5 mL) with 5 mL of 6.0 N aqueous solution of hydrogen chloride. The solid obtained upon completion of the reaction was partially dissolved in 2.0 N aqueous sodium hydroxide and was extracted in ethyl acetate (4×15 mL). (0.260 g, 0.85 mmol, 80% yield over 2 steps): 1H NMR (DMSO-d6) δ 13.5 (br s, 1H), 8.7 (s, 1H), 8.1 (d, 1H), 7.9 (d, 2H), 7.8 (d, 1H), 7.4 (d, 2H), 3.0 (septet, 1H), 1.3 (d, 6H); ES-MS (m/z) 305 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH:11]=[N:10][C:9]=1[C:17]([OH:19])=O.C(Cl)(=O)C(Cl)=O.[NH3:26]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[CH:11]=[N:10][C:9]=1[C:17]([NH2:26])=[O:19]
Reactant: CC(C)Cn1cnc(C(=O)O)c1-c1ccccc1Br
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: CC(C)Cn1cnc(C(N)=O)c1-c1ccccc1Br
Yield: 80.5 %

Procedure:
A 0.2 M solution of 5-(2-bromophenyl)-1-isobutyl-1H-imidazole-4-carboxylic acid (1.42 g; 4.4 mM) in anhydrous THF is added drop by drop, at 0° C., with oxalyl chloride (376 μl; 4.4 mM), then left to react at room temperature for about one hour, thus obtaining 5-(2-bromophenyl)-1-isobutyl-1H-imidazole-4-chlorocarbonyl. The mixture is then added drop by drop with 3 ml of conc. NH3 and reacted for one hour, then extracted with ethyl acetate, dried over Na2SO4, filtered and evaporated under reduced pressure, thereby obtaining 1.14 g of 5-(2-bromophenyl)-1-isobutyl-1H-imidazole-4-carboxamide which is used directly in the subsequent reaction. (Yield: 80.5%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([C:15]([CH2:19][CH3:20])(O)[CH2:16][CH3:17])=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[C:21]1([CH3:28])[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][CH:22]=1.B(F)(F)F.O(CC)CC>CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([C:15]([CH2:19][CH3:20])([C:23]3[CH:24]=[CH:25][C:26]([OH:27])=[C:21]([CH3:28])[CH:22]=3)[CH2:16][CH3:17])=[CH:10][CH:11]=2)[CH:6]=1)=[O:4]
Reactant: Cc1ccccc1O
Reactant: CCC(O)(CC)c1ccc2ccc(C(=O)OC)cc2c1
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc2ccc(C(=O)OC)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
Cool a CH2CL2 (20 mL) solution of 7-(1-ethyl-1-hydroxypropyl)naphthalene-2-carboxylic acid methyl ester (0.73 g, 2.68 mmol) and o-cresol (1.54 mL, 15.0 mmol) to −78° C.; then dropwise add BF3-OEt2 (0.76 mL, 6.0 mmol). Allow the reaction mixture to warm to RT and stir for 1 h. Quench the reaction with ice water. Dilute the resulting mixture with EtOAc (200 mL). Wash the mixture with brine, dry the organic layer over Na2SO4, filter and concentrate the filtrate. Purify by silica gel radial chromatography (5:95 to 35:65 EtOAc:hex) to give the title compound as a yellow oil (0.93 g, 86%). MS (ES) m/e 363 (M+1).
Reaction SMILES: [C:1]1([N:7]([CH2:11][CH2:12][OH:13])[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[C:1]1([N:7]2[CH2:11][CH2:12][O:13][C:22](=[O:24])[O:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCN(CCO)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1OCCN(c2ccccc2)CCO1
Yield: 55.3 %

Procedure:
The procedure of Example 1 was followed using N-phenyldiethanolamine (15.2 g, 83.9 mmol), triethylamine (24.0 mL, 167.8 mmol), dry THF (600 mL) and triphosgene (8.3 g, 28.8 mmol). The filtrate was concentrated yielding a clear oil containing a mixture of products. The product was purified using a column chromatography EtOAc:Hexanes (3:1) yielding 3.3 g (19%) of a clear oil which turned brown over time.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([O:23]CC)=O)[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.Cl.[NH2:28][CH2:29][CH2:30][S:31]([N:34]([CH3:36])[CH3:35])(=[O:33])=[O:32].C(N(CC)CC)C>>[CH3:35][N:34]([CH3:36])[S:31]([CH2:30][CH2:29][NH:28][C:21]([C:14]1[C:15](=[O:20])[N:16]([CH3:19])[C:17]2[C:12]([C:13]=1[OH:26])=[N:11][CH:10]=[C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH:18]=2)=[O:23])(=[O:33])=[O:32]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Reactant: CN(C)S(=O)(=O)CCN
Agent: Cl
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)CCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Yield: 48.9 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (30 mg, 0.084 mmol) described in example 92, 2-amino-N,N-dimethylethanesulfonamide hydrochloride (200 mg, 1.09 mmol), and triethylamine (0.5 mL, 3.27 mmol), was prepared N-{2-[(dimethylamino)sulfonyl]ethyl}-7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (19 mg, 49% yield) as a brown solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.55 (br s, 1 H), 8.55 (s, 1 H), 7.38 (s, 1 H), 7.16-7.12 (m, 2 H), 7.03-6.98 (m, 2 H), 4.12 (s, 2 H), 3.89 (m, 2 H), 3.57 (s, 3 H), 3.24 (m, 2 H), 2.89 (s, 6 H); HRMS m/z calcd for C21H24FN4O5S: 463.1446 Found: 463.1451.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][NH:18][CH2:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.B(O)(O)[C:23]1[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=1.C(N(CC)CC)C>C1COCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][N:18]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)[CH2:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CNCC3)cc1
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(N2CCc3ncnc(Nc4ccc(C(F)(F)F)cc4)c3C2)cc1
Reaction time: 6 h
Yield: 9.8 %

Procedure:
N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (100 mg, 0.34 mmol) was dissolved in anhydrous THF (2 mL). To the mixture was added p-tolylboronic acid (92 mg, 0.68 mmol), Cu(OAc)2 (124 mg, 0.68 mmol) and triethylamine (0.68 g, 0.095 mL). The mixture was agitated for 6 h and the solvent was removed under a vacuum. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as reddish powder (12.8 mg, 10%).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[CH:41]=[CH:42][C:43]([O:46][CH2:47][CH2:48][O:49][CH3:50])=[N:44][CH:45]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[CH:45]=[N:44][C:43]([O:46][CH2:47][CH2:48][O:49][CH3:50])=[CH:42][CH:41]=2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COCCOc1ccc(CCl)cn1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: COCCOc1ccc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)nc3)cn2)cn1
Yield: 79 %

Procedure:
By the reaction and treatment in the same manner as in Example, 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 5-chloromethyl-2-(2-methoxyethoxy)pyridine (0.61 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(1-{[6-(2-methoxyethoxy)pyridin-3-yl]methyl}pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.77 g) was obtained.
Reaction SMILES: [O:1]1[CH2:12][CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.[CH3:13][CH:14]([NH2:23])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCCCCC>CCOCC>[CH3:13][CH:14]([NH:23][CH2:12][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1)[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(N)COc1ccccc1
Reactant: Oc1cccc(OCC2CO2)c1
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(COc1ccccc1)NCC(O)COc1cccc(O)c1
Yield: 38 %

Procedure:
A mixture of 1.66 g. (10 mmole) of 3-(2,3-epoxy-1-propoxy)-phenol and 4.5 g. (30 mmole) of 1-methyl-2-phenoxyethylamine was heated at 80° C. overnight. The mixture was taken up in ether, and hexane was added to precipitate the product. Recrystallization from ethyl acetate gave 1-(1-methyl-2-phenoxyethylamino)-3-(3-hydroxyphenoxy)-2-propanol (38%); mp 124°-127° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:5]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[N:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:5]=[C:4]([C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccc(C)cc2)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccc(C)cc2)nc1-c1ccc(C)cc1
Temperature: 100 °C

Procedure:
To a solution of methyl 2-(4-methyl-2,6-dip-tolylpyrimidin-5-yl)pentanoate (86 mg; 0.221 mmol) in methanol (2.214 ml) was added a 10 N sodium hydroxide solution (221 μl; 2.21 mmol) and the mixture was heated at 100° C. overnight. The volatiles were removed under reduced pressure and the mixture was acidified by adding 6N hydrochloric acid. The suspension was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulphate and concentrated under reduced pressure.
Reaction SMILES: Cl.[CH3:2][NH:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].C([BH3-])#N.[Na+].[C:13]1([CH2:19][CH2:20][CH:21]2[C:25]3[CH:26]=[C:27]([CH:30]=O)[CH:28]=[CH:29][C:24]=3[O:23][CH2:22]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH2:20]([CH:21]1[C:25]2[CH:26]=[C:27]([CH2:30][NH:6][CH:5]([CH3:7])[C:4]([NH:3][CH3:2])=[O:8])[CH:28]=[CH:29][C:24]=2[O:23][CH2:22]1)[CH2:19][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CNC(=O)[C@H](C)N
Reactant: O=Cc1ccc2c(c1)C(CCc1ccccc1)CO2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CNC(=O)C(C)NCc1ccc2c(c1)C(CCc1ccccc1)CO2
Reaction time: 12 h
Yield: 76.1 %

Procedure:
To a solution of N-methyl-alaninamide hydrochloride (0.50 g, 3.61 mmol) in methanol (10 ml), in the presence of molecular sieves (1.00 g), sodium cyanoborohydride (0.36 g, 5.69 mmol) and a solution of 3-(2-phenylethyl)-2,3-dihydro-1-benzofuran-5-carboxaldehyde (0.90 g, 3.61 mmol) in methanol (10 ml) were added at room temperature. The reaction mixture was kept under stirring and an argon atmosphere for 12 h. Then, the solvent was evaporated under vacuum and the residue was purified by flash chromatography on silica gel (ethyl acetate/methanol=98/2) affording 0.93 g of title compound (77% yield).
Reaction SMILES: [CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)[CH2:2][CH:3]=[CH2:4].ClC1C=C(C=CC=1)C(OO)=[O:17]>C(Cl)Cl>[O:17]1[CH2:4][CH:3]1[CH2:2][CH2:1][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCOC1CCCCO1
Solvent: ClCCl
Product: C1CCC(OCCC2CO2)OC1
Temperature: 0 °C
Yield: 96.2 %

Procedure:
Into a 500-mL flask containing 2-(3-butenyloxy)tetrahydropyran (49.0 g, 0.314 mol) in CH2Cl2 (500 mL) under a nitrogen atmosphere and cooled to 0° C. was added freshly crystallized m-chloroperoxybenzoic acid (95 g, 0.55 mol). The mixture was maintained at 0° C. for a period of 24 h. The precipitated benzoic acid was removed via vacuum filtration. The filtrate thus obtained was washed successively with 10% aqueous sodium hydroxide (500 mL) and saturated aqueous sodium sulfite (500 mL), respectively, the organic layer dried over anhydrous MgSO4 and concentrated in vacuo to afford tetrahydro-2-(oxiranylethoxy)-2H-pyran as a pure clear colorless liquid (52 g, 95%), which was used without any further purification: 1H NMR (CDCl3, 300 MHz) δ 4.62 (s, 1H], 3.86-3.92 [m, 2H], 3.52-3.55 [m, 2H], 3.08 [br, 1H], 2.78-2.81 [t, J=3 Hz, 1H], 2.53-2.55 [t, J=3 Hz, 1H], 1.53-1.88 [m, 8H].
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22])[CH2:13][CH2:12]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:30]1[C:31]([CH3:39])=[CH:32][C:33]2[N:34]([N:36]=[CH:37][N:38]=2)[N:35]=1>O1CCCC1>[C:23]1([CH:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][C:30]3[C:31]([CH3:39])=[CH:32][C:33]4[N:34]([N:36]=[CH:37][N:38]=4)[N:35]=3)[CH2:13][CH2:12]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: OCCOCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: Cc1cc2ncnn2nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc2ncnn2nc1OCCOCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Yield: 64.4 %

Procedure:
190 mg of 60% sodium hydride in oil was suspended in 15 ml of tetrahydrofuran; 1.47 g of 4-(diphenylmethoxy)-1-[2-(2-hydroxyethoxy)ethyl]piperidine was added, followed by heating and refluxing for 1 hour. After cooling, 660 mg of 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine was added, followed by heating and refluxing for 3 hours. After cooling, ice water was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. After the dry product was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol (10:1). The desired fraction was collected; the crystal precipitated was collected by filtration, washed with ethyl ether and dried to yield 1.23 g of the title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9]1[C:28]([Br:29])=[CH:27][C:12]2[C:13]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:14]([C:16]3(O)[CH2:20][CH2:19][CH2:18][CH2:17]3)[O:15][C:11]=2[CH:10]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:8][C:9]1[C:28]([Br:29])=[CH:27][C:12]2[C:13]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:14]([C:16]3[CH2:20][CH2:19][CH2:18][CH:17]=3)[O:15][C:11]=2[CH:10]=1
Reactant: CCOC(=O)c1c(C2(O)CCCC2)oc2cc(N)c(Br)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(C2=CCCC2)oc2cc(N)c(Br)cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.1 %

Procedure:
TFA (1.5 mL) was added into a solution of ethyl 6-amino-5-bromo-2-(1-hydroxycyclopentyl)benzofuran-3-carboxylate (2.9 g, 7.89 mmol) in DCM (30 mL), then the mixture was stirred at 25° C. for 12 hours. The reaction mixture was poured into ice water, adjusted to pH=7 with NaHCO3 (a.q.), then the residue was extracted with DCM (50 mL*3), dried over Na2SO4, and concentrated to give the product of ethyl 6-amino-5-bromo-2-(cyclopent-1-en-1-yl)benzofuran-3-carboxylate (2.6 g, yield: 94%). 1H-NMR (CDCl3, 400 MHz) δ 7.99 (s, 1H), 7.11 (t, J=7.2 Hz, 1H), 6.83 (s, 1H), 4.43 (q, J=7.2 Hz, 2H), 2.86˜2.91 (m, 2H), 2.59˜2.63 (m, 2H), 2.01 (t, J=8.0 Hz, 2H), 1.46 (t, J=3.2 Hz, 3H). MS (M+H)+: 350/352.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[Cl:16][C:17]1[CH:28]=[CH:27][C:20]([CH2:21][C@@H:22]([C:24]([OH:26])=[O:25])[NH2:23])=[CH:19][CH:18]=1>>[C:24]([C@@H:22]([NH:23][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:20]1[CH:27]=[CH:28][C:17]([Cl:16])=[CH:18][CH:19]=1)([OH:26])=[O:25]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@@H](Cc1ccc(Cl)cc1)C(=O)O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Cl)cc1)C(=O)O
Yield: 63 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 4-chloro-L-phenylalanine to provide the title compound in 63% yield as yellow needles (recrystallization from EtOH/water).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([NH:9][CH2:10][CH:11]3[CH2:15][CH2:14][NH:13][CH2:12]3)[O:8][C:4]=2[CH:3]=1.Cl.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[C:22]=1[C:23](Cl)=[O:24].CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([NH:9][CH2:10][CH:11]3[CH2:15][CH2:14][N:13]([C:23]([C:22]4[C:26]([O:30][CH3:31])=[CH:27][CH:28]=[CH:29][C:21]=4[O:20][CH3:19])=[O:24])[CH2:12]3)[O:8][C:4]=2[CH:3]=1
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: Clc1ccc2nc(NCC3CCNC3)oc2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(OC)c1C(=O)N1CCC(CNc2nc3ccc(Cl)cc3o2)C1
Yield: 22.3 %

Procedure:
A mixture of 20 mg (0.07 mmol) (6-chloro-benzooxazol-2-yl)-pyrrolidin-3-ylmethyl-amine; hydrochloride, 15 mg (0.77 mmol) 2,6-dimethoxybenzoyl chloride and 10 mg (0.1 mmol) NEt3 in 2 mL DCM was shaken at room temperature over night. After evaporation the residue was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The product containing fractions were evaporated to yield 6.5 mg (22%) of the title compound. MS (m/e): 416.2 (MH+).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:9]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:44]12[CH2:51][CH2:50][CH:47]([CH2:48][CH2:49]1)[C@@H:46](O)[CH2:45]2>C1COCC1>[F:2][C:3]1[CH:4]=[C:5]([CH:9]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10]([O:12][C@@H:46]2[CH:47]3[CH2:50][CH2:51][N:44]([CH2:49][CH2:48]3)[CH2:45]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)C(c1cccc(F)c1)N1CCCCC1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(c1cccc(F)c1)N1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.4 %

Procedure:
2-(3-Fluorophenyl)-2-(piperidin-1-yl)acetic acid hydrochloride (225 mg, 0.82 mmol), DCC (339 mg, 1.64 mmol), and HOBT (252 mg, 1.64 mmol) were dissolved in dry THF (9 ml). (R)-quinuclidin-3-ol (314 mg, 2.47 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. THF was evaporated, the residue was taken up with EtOAc and washed with sat. NaHCO3, water and brine. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography (DCM/MeOH=9/1) to obtain (R)-quinuclidin-3-yl 2-(3-fluorophenyl)-2-(piperidin-1-yl)acetate (166 mg, 58.3 yield).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH:19]([C:22]1[O:23][C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:25]([C:27](O)=[O:28])[N:26]=1)([CH3:21])[CH3:20]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:27]([C:25]3[N:26]=[C:22]([CH:19]([CH3:21])[CH3:20])[O:23][C:24]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:28])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC(C)c1nc(C(=O)O)c(-c2ccccc2)o1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3nc(C(C)C)oc3-c3ccccc3)n2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-isopropyl-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.08 min; [M+H]+=419.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[CH:31][C:32]([F:41])=[C:33]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:34]=2)[CH2:25][CH2:24]1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[CH:30]=[CH:31][C:32]([F:41])=[C:33]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:34]=3)[CH2:27][CH2:28]2)=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCCC(=O)Nc1cc(C2CCN(CCCN)CC2)ccc1F
Product: CCCC(=O)Nc1cc(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)ccc1F

Procedure:
Example 104 was prepared from bis(4-fluoro phenyl)acetic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.33–8.14 (m, 1H), 7.89–7.67 (br, 1H), 7.51–6.60 (m, 10H), 4.98–4.79 (br, 1H), 4.75 (s, 1H), 3.46–3.29 (m, 2H), 3.29–3.08 (m, 2H), 2.79–2.63 (m, 2H), 2.63–2.46 (m, 1H), 2.46–2.21 (m, 4H), 1.97–1.60 (m, 8H), 1.01 (t, 3H, J=7.2 Hz); ESMS m/e: 552.3 (M+H)+.