Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][C:7]([Cl:12])=[N:6][C:5]=2[NH:4][CH:3]=1.[CH:13]1([NH2:17])[CH2:16][CH2:15][CH2:14]1.C(Cl)Cl.O>C(O)CCC>[Br:1][C:2]1[C:10]2[C:9]([NH:17][CH:13]3[CH2:16][CH2:15][CH2:14]3)=[N:8][C:7]([Cl:12])=[N:6][C:5]=2[NH:4][CH:3]=1
Reactant: NC1CCC1
Reactant: Clc1nc(Cl)c2c(Br)c[nH]c2n1
Solvent: ClCCl
Solvent: O
Solvent: CCCCO
Product: Clc1nc(NC2CCC2)c2c(Br)c[nH]c2n1
Yield: 96.4 %

Procedure:
A solution of 5-bromo-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (142 mg, 0.530 mmol), cyclobutylamine (0.090 mL, 1.06 mmol) and TEA (0.150 mL, 1.08 mmol) in nBuOH (6 mL) was stirred at 70° C. for 18 h. CH2Cl2 and H2O were added. The organic phase was separated, washed with 5% NaHCO3, then with 1N HCl, dried over Na2SO4, concentrated in vacuo to give 5-bromo-2-chloro-N-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (154 mg).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:30](O)=[O:31])[CH2:19][C:20]3[CH:28]=[C:27]([CH3:29])[C:23]4[NH:24][CH:25]=[N:26][C:22]=4[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[CH3:66][S:67]([N:70]1[CH2:75][CH2:74][CH:73]([CH:76]2[CH2:81][CH2:80][NH:79][CH2:78][CH2:77]2)[CH2:72][CH2:71]1)(=[O:69])=[O:68]>CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:28]=[C:27]([CH3:29])[C:23]4[NH:24][CH:25]=[N:26][C:22]=4[CH:21]=3)[C:30]([N:79]3[CH2:78][CH2:77][CH:76]([CH:73]4[CH2:72][CH2:71][N:70]([S:67]([CH3:66])(=[O:69])=[O:68])[CH2:75][CH2:74]4)[CH2:81][CH2:80]3)=[O:31])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2nc[nH]c12
Reactant: CS(=O)(=O)N1CCC(C2CCNCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(S(C)(=O)=O)CC3)CC2)cc2nc[nH]c12

Procedure:
A solution of 120 mg (0.22 mmol) (R)-1-carboxy-2-(7-methyl-1H-benzimidazol-5-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 80 mg (0.25 mmol) TBTU, 40 μL (0.29 mmol) triethylamine and 80 mg (0.33 mmol) 1-methanesulphonyl-[4,4′]bipiperidinyl in 1.5 mL DMF was stirred overnight at RT. The reaction mixture was purified by HPLC without working up. The fractions containing the product were combined and lyophilised.
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.NC1C=C2C(=CC=1)CN(C(NC1C=[CH:46][C:45]([C:48](=[O:53])NCCC)=[CH:44]C=1)=O)C2>>[C:48]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1)(=[O:53])[CH:45]([CH3:46])[CH3:44]
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Reactant: O=C(Nc1ccc(C2=CCNCC2)cc1)N1Cc2ccncc2C1
Solvent: CC(=O)Cl
Product: CC(C)C(=O)N1CC=C(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)CC1

Procedure:
The title compound was prepared as described in Example 278, substituting isobutyryl chloride for acetyl chloride and N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.61 (s, 1H), 8.50 (d, J=5.0 Hz, 1H), 8.46 (s, 1H), 7.54-7.57 (m, 2H), 7.43 (d, J=5.1 Hz, 1H), 7.34-7.38 (m, 2H), 6.10-6.13 (bs, 1H), 4.79-4.82 (m, 4H), 4.07-4.21 (m, 2H), 3.67-3.70 (m, 2H), 2.85-3.01 (m, 1H), 2.39-2.55 (m, 2H), 0.97-1.08 (m, 6H); MS (ESI(+)) m/e 391 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](=[O:5])[CH3:4].[N:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1.C(O)C.[OH-].[Na+]>ClCCl>[C:2]([C:3](=[O:5])[CH:4]=[CH:14][C:11]1[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=1)([CH3:7])([CH3:6])[CH3:1]
Reactant: CC(=O)C(C)(C)C
Reactant: O=Cc1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)C(=O)C=Cc1ccncc1
Reaction time: 12 h

Procedure:
A mixture of 3,3-dimethyl-2-butanone (2.5 ml, 20.0 mmol), 4-pyridinecarboxaldehyde (2.15 ml, 22.3 mmol), ethanol (7.6 ml), and 4.5% aqueous sodium hydroxide (4.6 ml) was kept at room temperature for 12 h. It was diluted with dichloromethane, washed with aqueous hydrochloric acid and water, dried and evaporated. Subsequent column chromatography (hexane-ethyl acetate=3:1) provided the title compound. MS (m/z): 190.4 (M+H)+; C12H15NO requir. 189.3.
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])[C:3]([O:5][CH3:6])=[O:4].[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][SH:20])[CH3:16].C(Cl)Cl>C(N(CC)CC)C>[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][S:20][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])[C:3]([O:5][CH3:6])=[O:4])[CH3:16]
Reactant: COC(=O)C(Br)CCCCCCC#N
Reactant: CCOC(CS)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(CSC(CCCCCCC#N)C(=O)OC)OCC

Procedure:
The starting material is prepared as follows: To the mixture of 13.6 g of methyl 2-bromo-8-cyano-octanoate, 11.6 g of 2,2-diethoxy-ethylmercaptan and 150 ml of methylene chloride, 5.56 g of triethylamine are added dropwise while stirring. After overnight-stirring at room temperature the mixture is evaporated, the residue triturated with diethyl ether, washed with water, dried and evaporated, to yield the methyl 2-(2,2-diethoxyethylmercapto)-8-cyano-octanoate showing NMR bands at 4.58, 3.71 and 2.75 ppm.
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:38]4[CH:43]=[CH:42][C:41]([C:44]([OH:46])=[O:45])=[CH:40][C:39]=4[CH3:47])[CH:33]=[CH:34][C:35]=3[O:36][CH3:37])[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O[CH2:52][C:53]([O:55][CH3:56])=[O:54].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(Cl)Cl>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:38]4[CH:43]=[CH:42][C:41]([C:44]([O:46][CH2:52][C:53]([O:55][CH3:56])=[O:54])=[O:45])=[CH:40][C:39]=4[CH3:47])[CH:33]=[CH:34][C:35]=3[O:36][CH3:37])[C@H:14]2[CH3:48])[CH:4]=[C:3]([C:2]([F:1])([F:49])[F:50])[CH:8]=1
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: COC(=O)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1

Procedure:
2″-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid (EXAMPLE 30, 200 mg, 0.281 mmol), methyl hydroxyacetate (0.022 mL, 0.281 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (81 mg, 0.422 mmol) and triethylamine (0.059 ml; 0.422 mmol) were stirred in DCM (2.811 mL) at room temperature overnight. LCMS of aliquot indicated formation of the desired product and complete consumption of starting material. Volatiles were evaporated from the reaction crude. The pot residue was purified by prep HPLC to afford a light yellow solid as the titled compound. LCMS (ESI) calc.=783.19; found=784.0 (M+1)+. 1H NMR (CDCl3, 400 MHz, 1:1 mixture of atropisomers): δ 7.99 (d, J=6.8 Hz, 1H), 7.92 (d, J=8 Hz, 1H), 7.85 (s, 1H), 7.72-7.68 (m, 1.5H), 7.67-7.61 (m, 2.5H), 7.45-7.36 (m, 2H), 7.32-7.26 (m, 1H), 7.13 (s, 1H), 7.08 (d, J=5.6 Hz, 0.5H), 7.06 (d, J=5.6 Hz, 0.5H), 5.59 (d, J=8 Hz, 0.5H), 5.30 (d, J=8 Hz, 0.5H), 4.97 (d, J=14 Hz, 0.5H), 4.93 (d, J=14 Hz, 0.5H), 4.87 (s, 2H), 4.16 (d, J=15.6 Hz, 0.5H), 3.95 (d, J=16 Hz, 0.5H), 3.86 (s, 3H), 3.80 (s, 3H), 3.80-3.75 (m, 1H), 2.37 (s, 1.5H), 2.32 (s, 1.5H), 0.54 (d, J=6.8 Hz, 1.5H), 0.42 (d, J=6.8 Hz, 1.5H).
Reaction SMILES: [OH:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]=1[C:17]([NH:19][CH2:20][C:21]([O:23]CC)=[O:22])=[O:18].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br.C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C)C=O>[OH:1][C:2]1[N:7]([CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[C:28]([O:27][CH3:26])[CH:29]=2)[C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]=1[C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18]
Reactant: CCOC(=O)CNC(=O)c1c(O)[nH]c(=O)n(Cc2ccccc2)c1=O
Reactant: COc1cccc(CBr)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(Cn2c(O)c(C(=O)NCC(=O)O)c(=O)n(Cc3ccccc3)c2=O)c1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 10.7 %

Procedure:
A mixture of ethyl N-{[6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycinate (example 11a, 369 mg, 1.06 mmoles), 3-methoxybenzyl bromide (163 uL, 1.17 mmoles) and sodium carbonate (330 mg, 3.1 mmoles) in dimethylformamide (6.0 mL) was stirred under argon at 100° C. for 2.5 hours. The mixture was cooled, poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The ester was hydrolysed by stirring in a mixture of ethanol (3 mL) and 1 molar sodium hydroxide solution (3 mL) for 3 hours. The mixture was acidified and extracted with ethyl acetate. Purification by preparative HPLC (acetonitrile-water—0.1% TFA, 20-100%) and crystallization from ethanol-water gave the title compound (50 mg, 11%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.10 (br. s., 1 H), 10.12 (t, 1 H), 7.14-7.47 (m, 6 H), 6.69-6.97 (m, 3 H), 5.00 (s, 2 H), 5.03 (s, 2 H), 4.13 (d, J=5.56 Hz, 2 H), 3.71 (s, 3 H).
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[C:15]([F:20])[CH:16]=2)[N:11]([CH2:26][CH3:27])[C:10]1=[O:28])C1C=CC=CC=1.[H][H]>C1COCC1.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH2:26]([N:11]1[C:12]2[C:17](=[CH:16][C:15]([F:20])=[C:14]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:13]=2)[C:18](=[O:19])[N:9]([OH:8])[C:10]1=[O:28])[CH3:27]
Reactant: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCCC3)cc21
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: C1CCOC1
Product: CCn1c(=O)n(O)c(=O)c2cc(F)c(N3CCCC3)cc21
Yield: 99.2 %

Procedure:
Five percent Pd/BaSO4 (60 mg) was added to a solution of 3-benzyloxy-1-ethyl-6-fluoro-7-pyrrolidinyl-1H-quinazoline-2,4-dione (Example E, 0.21 g, 0.55 mmol) in 16 mL of THF. The mixture was shaken under 50 PSI of hydrogen for 31 hours, filtered, and concentrated to afford 0.16 g of a solid. This solid was dissolved in 1N sodium hydroxide and washed with chloroform. The chloroform layer was back extracted with sodium hydroxide, and the combined basic extracts were acidified to pH 3. The aqueous layer was extracted with chloroform, dried over magnesium sulfate, and concentrated to give 0.11 g of the title compound as a solid, mp 170-171° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.CCN(C(C)C)C(C)C.O>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:7])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cc1)N1CCOCC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
4-bromobenzoyl chloride (5 g, 22.78 mmol) was taken up in THF (75 mL) and cooled to 0° C. A solution of morpholine (2.084 mL, 23.92 mmol) and DIPEA (4.38 mL, 25.06 mmol) in THF (25 mL) was added dropwise and the resulting mixture stirred at 0° C. for 3 hours. Water as added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo to give 4-(4-bromobenzoyl)morpholine as a pale yellow gum.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1>O1CCOCC1>[NH2:8][C:4]1[N:3]=[C:2]([NH:1][C:14](=[O:15])[C:13]2[CH:17]=[CH:18][C:10]([F:9])=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(N)n1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: C1COCCO1
Product: Nc1cccc(NC(=O)c2ccc(F)cc2)n1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Dissolve 2,6-diaminopyridine (1.637 g, 15 mmol) in dioxane (15 mL) and cool to 0° C. for 10 min. Add 4-fluorobenzoyl chloride (793 mg, 0.59 mL, 5.0 mmol) slowly. After 40 min, remove ice bath and stir the reaction at room temperature. Use the work-up and purification procedures described in Preparation 43 to provide N-(6-Amino-pyridin-2-yl)-4-fluoro-benzamide as a slightly yellow solid (1.170 g, 100%): mass specturm (ion spray): m/z=232.0 (M+1).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.CN1C(=O)N(C)CCC1.[CH2:18]([O:20][C:21](=[O:33])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1)[CH3:19].I[CH2:35][CH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>CCCCCCC.C1COCC1.C1(CC)C=CC=CC=1.C1COCC1>[CH3:32][S:29]([C:26]1[CH:27]=[CH:28][C:23]([CH:22]([CH2:35][CH:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[C:21]([O:20][CH2:18][CH3:19])=[O:33])=[CH:24][CH:25]=1)(=[O:31])=[O:30]
Reactant: CCOC(=O)Cc1ccc(S(C)(=O)=O)cc1
Reactant: ICC1CCOCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(CC1CCOCC1)c1ccc(S(C)(=O)=O)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
LDA (38.9 mL of a 1.8M solution in n-C7H16-THF-PhEt, 70.0 mmol) was added to a solution of DMPU (59.3 mL, 490.3 mmol) in anhydrous THF (150 mL) at −78° C. The mixture was stirred for 30 min, before being treated dropwise with a solution of ethyl(4-methanesulfonylphenyl)acetate (Preparation 15, 16.97 g, 70.0 mmol) in anhydrous THF (50 mL). Stirring was continued at −78° C. for 45 min, then a solution of 4-iodomethyltetrahydropyran (19.00 g, 84.0 mmol) in anhydrous THF (40 mL) was added. The mixture was allowed to warm to 20° C. over 16 h, before being quenched with 1M HCl (70 mL). The THF was removed under reduced pressure, then more H2O (40 mL) was added and the remainder extracted with EtOAc (2×250 mL). The EtOAc extracts were dried (MgSO4). Filtration, solvent evaporation, and flash chromatography (IH-EtOAc, 9:1 to 1:1) furnished ethyl 2-(4-methanesulfonylphenyl)-3-(tetrahydropyran-4-yl)propionate: m/z (ES+)=698.3 [2M+NH4]+. A solution of this compound (20.27 g, 59.6 mmol) in MeOH (100 mL) and 2M NaOH (62.5 mL, 125.0 mmol) was heated under reflux for 1 h. The solvents were removed under reduced pressure, then the remaining solid was triturated with Et2O (5×100 mL), before being dissolved in H2O (100 mL). The aqueous solution was washed with EtOAc (50 mL), acidified with 2M HCl to pH 1, and extracted with EtOAc (2×1 L). After drying (MgSO4), filtration and solvent evaporation gave the title compound: m/z (ES+)=642.3 [2M+NH4]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][OH:4].C1[C:8]2([CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9]2)[CH2:7][O:6]1>>[OH:6][CH2:7][C:8]1([CH2:9][O:4][CH2:3][CH2:2][Cl:1])[CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10]1
Reactant: C1COCCOCC2(COCCOCCN1)COC2
Reactant: OCCCl
Product: OCC1(COCCCl)COCCOCCNCCOCCO1

Procedure:
The oxetane ring in 2,6,9,15,18-pentaoxa-12-azaspiro[3.15]nonadecane was shown to add hydroxylic compounds by acid-catalyzed reaction with 2-chloroethanol to give 1-hydroxymethyl-1-(4-chloro-2-oxabutyl)-2,5,11,14-tetraoxa-8-azacyclopentadecane. ##EQU13##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[C:5]2[O:10][CH2:9][O:8][CH2:7][C:6]=2[CH:11]=1.[CH2:15]([O:17][C:18]([C:20]1([NH2:29])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)=[O:19])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:15]([O:17][C:18]([C:20]1([NH:29][C:12]([C:4]2[C:5]3[O:10][CH2:9][O:8][CH2:7][C:6]=3[CH:11]=[C:2]([F:1])[CH:3]=2)=[O:14])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)c1cc(F)cc2c1OCOC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cc(F)cc3c2OCOC3)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a solution of 6-fluoro-4H-benzo[1,3]dioxine-8-carboxylic acid (386 mg, 1.95 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (400 mg, 1.95 mmol), HATU (1.11 g, 2.93 mmol) in anhydrous DMF (8 mL) is added DIPEA (484 μL, 2.93 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (70 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 5-50% EtOAc in heptane) to give a pure product (61) as white solid (720 mg, 6%).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18][CH2:19][CH2:20][CH3:21])[N:15]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[C:14]=2[CH:29]=1.[OH-].[Li+]>>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([N:15]2[C:14]3[CH:29]=[C:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:30])=[O:2])[CH:11]=[CH:12][C:13]=3[N:17]=[C:16]2[S:18][CH2:19][CH2:20][CH3:21])=[CH:23][CH:24]=1
Reactant: CCCSc1nc2ccc(OCCCCCC(=O)OC)cc2n1-c1ccc(C)cc1
Agent: [Li+]
Agent: [OH-]
Product: CCCSc1nc2ccc(OCCCCCC(=O)O)cc2n1-c1ccc(C)cc1

Procedure:
128 mg of 6-[[1-(4-methylphenyl)-2-propylmercapto-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was reacted with lithium hydroxide according to general operating instructions 3. 98 mg was obtained.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]([C:12]2[N:13]([CH3:17])[CH:14]=[N:15][CH:16]=2)=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C[Mg+].[Br-].[CH2:21](OCC)C>C1COCC1>[F:1][C:2]1[CH:9]=[C:8]([C:10]([OH:11])([C:12]2[N:13]([CH3:17])[CH:14]=[N:15][CH:16]=2)[CH3:21])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCOCC
Reactant: Cn1cncc1C(=O)c1ccc(C#N)c(F)c1
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: Cn1cncc1C(C)(O)c1ccc(C#N)c(F)c1
Reaction time: 0.25 h

Procedure:
2-Fluoro-4-(3-methyl-3H-imidazole-4-carbonyl)-benzonitrile (0.603 g, 2.63 mmol) was dissolved in anhydrous THF (30 mL). A solution of 3.0M MeMgBr in diethyl ether (2.55 mL, 7.65 mmol) was added and stirred for 15 min. The reaction was quenched with NH4Cl solution, diluted with CH2Cl2 and saturated NaHCO3 solution and seperated. The aqueous layer was back extracted with CH2Cl2 (3×), the combined organic layers dried (MgSO4) and concentrated to give the title compound.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[C:47]([O:51][C:52]([N:54]1[CH2:59][CH2:58][C:57]2([CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)[CH2:56][CH2:55]1)=[O:53])([CH3:50])([CH3:49])[CH3:48].Cl.Br[C:67]1[CH:68]=[N:69][CH:70]=[CH:71][CH:72]=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:47]([O:51][C:52]([N:54]1[CH2:59][CH2:58][C:57]2([CH2:64][CH2:63][N:62]([C:67]3[CH:68]=[N:69][CH:70]=[CH:71][CH:72]=3)[CH2:61][CH2:60]2)[CH2:56][CH2:55]1)=[O:53])([CH3:50])([CH3:48])[CH3:49]
Reactant: Brc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1cccnc1)CC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31 %

Procedure:
BINAP (147 mg, 0.23 mmol) and Pd(OAc)2 (159 mg, 0.74 mmol) was added to a mixture of 3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (3 g, 11.81 mmol), 3-bromopyridine HCl (2.29 g, 11.81 mmol) and sodium tert-butylate (3.4 g, 35.45 mmol) in toluene and the reaction mixture was degassed under argon for 20 minutes and heated under reflux for 4 h. After cooling to room temperature, the mixture was diluted with ethyl acetate, stirred for 15 minutes and filtered over Celite. The reaction mixture was washed with water and sat. NaCl solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography. Yield: 31%
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:8][C:9]=1[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13]1)=[O:4].[CH3:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([C:32](Cl)=[O:33])[CH2:28][CH2:27]1>ClCCCl.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:8][C:9]=1[N:10]([C:32]([CH:29]1[CH2:30][CH2:31][CH:26]([CH3:25])[CH2:27][CH2:28]1)=[O:33])[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13]1)=[O:4]
Reactant: C[C@H]1CC[C@H](C(=O)Cl)CC1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NCC1CCCN(C)C1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)c1sc(-c2ccccc2)cc1N(CC1CCCN(C)C1)C(=O)C1CCC(C)CC1
Yield: 95 %

Procedure:
3-[(1-Methyl-piperidin-3-ylmethyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (162 mg, 0.348 mmol) was dissolved in 1,2-dichloroethane (3.0 mL) and treated with trans-4-Methyl-cyclohexanecarbonyl chloride in 1,2-dichloroethane (1.0 mL, 0.43 mmol). The solution was heated at reflux for 1 day. The solvent was then evaporated and the residue purified by silica gel column chromatography using hexanes:EtOAc as eluent to provide 3-[(4-Methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-3-ylmethyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester as an oil (0.194 g, 95% yield). 1H NMR (CDCl3, 400 MHz): Rotamer 65/35: 7.90 (s, 0.35H), 7.70 (d, 0.65H), 7.62-7.10 (m, 10H), 5.20-5.00 (m, 2H), 4.70 (m, 0.35H), 4.60-4.40 (m, 0.65H), 4.12 (m, 1H), 3.82 (s, 3H), 3.52 (t, 0.65H), 3.20 (t, 0.35H), 2.70 (d, 0.65H), 2.52 (t, 0.35H), 1.90 (m, 1H), 1.80-1.20 (m, 13H), 1.00-0.85 (m, 1H), 0.76 (d, 3H), 0.64 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[NH:7][CH2:8][C:9]#[C:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[C:22]([CH3:24])([CH3:23])[O:21][C:20]([NH:25][C@H:26]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[F:43])[CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])=[N:19][S:18]2(=[O:45])=[O:44])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:46])[NH:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[C:22]([CH3:24])([CH3:23])[O:21][C:20]([NH:25][C@H:26]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[F:43])[CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:34])([CH3:35])[CH3:36])([CH3:32])[CH3:31])=[N:19][S:18]2(=[O:44])=[O:45])=[CH:13][CH:12]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC#Cc1ccc(C2C(C)(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c3ccccc3F)=NS2(=O)=O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCc1ccc(C2C(C)(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c3ccccc3F)=NS2(=O)=O)cc1
Yield: 54.7 %

Procedure:
To a solution of [3-(4-{2-[(S)-3-(tert-Butyldimethylsilanyloxy)-1-(2-fluorophenyl)propylamino]-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda*6*-[1,4,3]oxathiazin-5-yl}phenyl)prop-2-ynyl]carbamic acid tert-butyl ester (89 mg) in methanol (25 ml) was added palladium on charcoal (5%, 25 mg), and the solution was stirred in a hydrogen atmosphere for 1 h. The mixture was filtered and the filtrate was concentrated. This was followed by purification by column chromatography (ethyl acetate/heptane). This gave the product (49 mg) with a molecular weight of 678.0 g/mol (C34H52FN3O6SSi).