Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:14][N:15]1[C:21](=[O:22])[N:20]2[CH2:23][C@H:16]1[CH2:17][CH2:18][C@H:19]2[C:24]([NH:26][NH:27][C:28]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=O)=[O:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:7]([O:14][N:15]1[C:21](=[O:22])[N:20]2[CH2:23][C@H:16]1[CH2:17][CH2:18][C@H:19]2[C:24]1[O:25][C:28]([N:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)=[N:27][N:26]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(NNC(=O)N1CCOCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1N2C[C@@H](CC[C@H]2c2nnc(N3CCOCC3)o2)N1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.1 %

Procedure:
Pyridine (2.0 mL) was added to a solution of N′-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)morpholine-4-carbohydrazide (0.38 g, 0.94 mmol) in dry DCM (10 mL). (CF3SO2)2O (2.0 mL) was then added slowly at −10° C. The reaction mixture was stirred at rt for 0.5 h then saturated NaHCO3 was added at −10° C. very slowly. The organic layer was separated and the aqueous layer was exacted with EtOAc (3×). The combined organic layer was dried with Na2SO4, concentrated, and purified by silica gel column chromatography (0 to 1:50 MeOH/DCM) to give (2S,5R)-6-(benzyloxy)-2-(5-morpholino-1,3,4-oxadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (0.12 g, 33%). ESI-MS (EI+, m/z): 386 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=3)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:23][CH3:24].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:24][O:23][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:5]=1[O:4][CH2:3][CH2:2][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[N:12]=[CH:11][N:10]=[C:9]2[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1
Reactant: COc1cc2c(Nc3cccc(C)c3)ncnc2cc1OCCBr
Reactant: C1COCCN1
Product: COc1cc2c(Nc3cccc(C)c3)ncnc2cc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 7-(2-bromoethoxy)-6-methoxy-4-(3'-methylanilino)quinazoline (0.25 g) and morpholine (4 ml) was stirred at ambient temperature for 4 hours. The mixture was evaporated and the residue was partitioned between methylene chloride and a dilute aqueous sodium bicarbonate solution. The organic phase was dried (MgSO4) and evaporated. The residue was triturated under diethyl ether to give 6-methoxy-4-(3'-methylanilino)-7-(2-morpholinoethoxy)quinazoline (0.198 g), m.p. 168°-170° C. NMR Spectrum: (CD3SOCD3 +CD3CO2D) 2.35 (s, 3H), 3.15 (t, 4H), 3.81 (t, 4H), 3.96 (s, 3H), 6.93 (d, 1H), 7.21 (s, 1H), 7.26 (t, 1H), 7.58 (s, 1H), 7.63 (d, 1H), 7.84 (s, 1H), 8.44 (s, 1H), 9.58 (s, 1H); Elemental Analysis: Found C, 64.3; H, 6.9; N, 13.8; C22H26N4O3. 0.9H2O requires C, 64.3; H, 6.8; N, 13.6%.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([CH2:11][OH:12])[CH:3]=1.[C:13]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14].N1C=CN=C1.O>C(Cl)Cl>[Si:17]([O:12][CH2:11][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cc(CO)ncc1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: Cc1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (4-methyl-5-nitropyridin-2-yl)methanol (1.2 g, 7.1 mmol) in 5 mL of CH2Cl2, were added tert-butylchlorodiphenylsilane (2.0 g, 7.1 mmol) and imidazole (0.049 g, 0.71 mmol) at an ambient temperature. The reaction was stirred at 25° C. for 2 hrs. The reaction was poured into H2O, extracted with ethyl acetate, and dried over MgSO4. The ethyl acetate was concentrated under vacuum and purified over SiO2 to afford the desired compound 2-((tert-butyldiphenylsilyloxy)methyl)-4-methyl-5-nitropyridine in 90% (2.6 g). 1HNMR (CDCl3, 400 MHz) δ 1.12 (s, 9H), 2.78 (s, 3H), 4.85 (s, 2H), 7.21 (s, 1H), 7.24˜7.89 (m, 10H), 9.15 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH2:28][CH2:29][S:30][CH2:31][CH3:32])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=[O:43])=CC=1.ClC1C=C(C=CC=1)C(OO)=O>ClCCl>[Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH2:28][CH2:29][S:30]([CH2:31][CH3:32])=[O:43])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCSCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ccc21
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: CCS(=O)CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ccc21
Reaction time: 0.5 h
Yield: 48.4 %

Procedure:
A solution of N-(4-chlorobenzyl)-1-[2-(ethylsulfanyl)ethyl]-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.10 gm) from Example No. 60 in dichloromethane (2 mL) at 0° C. is added p-toluenesulfonic acid hydrate (0.04 gm) followed by m-chloroperoxybenzoic acid (˜85%) (0.045 gm). The mixture is stirred for 0.5 hrs. The reaction mixture is diluted with dichloromethane, washed with saturated aqueous sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product is purified by flash column chromatography eluting with 3% to 9% methanol in dichloromethane and then by recrystallization from acetonitrile to afford 0.05 gm of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[C-:12]#[N:13].[K+].Cl>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([C:12]#[N:13])[CH:10]=[S:11]
Reactant: S=C=Nc1ccc(Cl)cc1Cl
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: CC#N
Product: N#CN(C=S)c1ccc(Cl)cc1Cl
Yield: 97.9 %

Procedure:
40 ml of acetonitrile solution containing 6.44 g of 2,4-dichlorophenyl isothiocyanate was added dropwise to 40 ml of aqueous solution containing 2.28 g of potassium cyanide at 0° C. over 1 hour. After 3 hours of reaction at room temperature, the reaction solution was poured into a mixed solution of 50 ml of 1N hydrochloric acid and ice. Deposited crystals were separated by filtration and were dried under reduced pressure to obtain 7.14 g of N-(2,4-dichlorophenyl)cyanothioformamide (yield: 97%).
Reaction SMILES: [C:1]([N:5]1[CH2:8][CH:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:31])[CH2:16][NH:17][C:18]3[CH:26]=[C:25]([CH:27]4[CH2:29][CH2:28]4)[C:24]([Cl:30])=[CH:23][C:19]=3[C:20]([NH2:22])=O)[CH2:11][CH2:10]2)[CH2:6]1)(=[O:4])[CH:2]=[CH2:3].CCN(CC)CC.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>C(Cl)Cl>[C:1]([N:5]1[CH2:6][CH:7]([N:9]2[CH2:10][CH2:11][N:12]([C:15](=[O:31])[CH2:16][NH:17][C:18]3[CH:26]=[C:25]([CH:27]4[CH2:28][CH2:29]4)[C:24]([Cl:30])=[CH:23][C:19]=3[C:20]#[N:22])[CH2:13][CH2:14]2)[CH2:8]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)N1CC(N2CCN(C(=O)CNc3cc(C4CC4)c(Cl)cc3C(N)=O)CC2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)N1CC(N2CCN(C(=O)CNc3cc(C4CC4)c(Cl)cc3C#N)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
A mixture of 2-((2-(4-(1-acryloylazetidin-3-yl)piperazin-1-yl)-2-oxoethyl)amino)-5-chloro-4-cyclopropylbenzamide (3 0 mg, 0.067 mmol) and Et3N (41 mg, 0.404 mmol) in DCM (10 mL) at RT, trifluoroacetic anhydride (56 mg, 0.268 mmol) was added. The resulting mixture was stirred at RT for 0.5 h, poured into water and then extracted with dichloromethane. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (1-4% methanol/dichloroethane) to afford the desired product (20 mg, 72% yield). 1H NMR (400 MHz, DMSO-d6) δ: 7.60 (s, 1H), 6.34-6.30 (m, 1H), 6.27 (s, 1H), 6.12-6.07 (m, 1H), 6.01-5.99 (t, J=4 Hz, 1H), 5.69-5.65 (m, 1H), 4.26-4.22 (m, 1H), 4.07-4.04 (m, 3H), 3.96-3.92 (m, 1H), 3.80-3.76 (m, 1H), 3.53-3.51 (m, 4H), 3.19-3.13 (m, 1H), 2.45-2.30 (m, 4H), 2.16-2.09 (m, 1H), 1.08-1.03 (m, 2H), 0.87-0.80 (m, 2H). ESI-MS m/z: 428.4[M+H]+.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH:6]1[S:7][CH:8]=[C:9]2[C:15]=1[C:14](=[O:16])[NH:13][C:12]1[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=1[NH:10]2>O1CCOCC1>[Cl:1][CH2:2][C:3]([N:10]1[C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[NH:13][C:14](=[O:16])[C:15]2=[CH:6][S:7][CH:8]=[C:9]12)=[O:4]
Reactant: O=C1Nc2ccccc2Nc2cscc21
Reactant: O=C(Cl)CCl
Solvent: C1COCCO1
Product: O=C1Nc2ccccc2N(C(=O)CCl)c2cscc21
Reaction time: 3 h

Procedure:
10.4 ml of chloroacetyl chloride are added dropwise at room temperature to a suspension of 18.8 g of 9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one in 500 ml of dioxane, whereupon a clear solution is formed. The solution is left to stand for 3 hours and is then concentrated to dryness; the obtained residue is taken up in toluene; the toluene mixture is washed with sodium bicarbonate solution and then with water, and the toluene solution is dried over sodium sulfate. Concentration of the thus-dried solution yields 4-chloroacetyl-9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepin-10-one (m. 220° C.).
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[C:4]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:39])[C@H:19]([C@@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3C(OC(C)(C)C)=O)[C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)=[C:5]2[CH:11]=[N:10][NH:9][C:6]2=[N:7][CH:8]=1>O1CCOCC1.C(Cl)Cl>[ClH:2].[ClH:1].[Cl:2][C:3]1[C:4]([N:12]2[CH2:13][CH2:14][N:15]([C:18](=[O:39])[C@@H:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@@H:27]3[CH2:31][CH2:30][CH2:29][NH:28]3)[CH2:16][CH2:17]2)=[C:5]2[CH:11]=[N:10][NH:9][C:6]2=[N:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)N1CCN(c2c(Cl)cnc3[nH]ncc23)CC1)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C([C@@H](c1ccc(Cl)cc1)[C@@H]1CCCN1)N1CCN(c2c(Cl)cnc3[nH]ncc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
4N HCl in dioxane (2 mL) was added to a solution of (S)-tert-butyl 2-((S)-2-(4-(5-chloro-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-1-(4-chlorophenyl)-2-oxoethyl)pyrrolidine-1-carboxylate (90 mg, 0.16 mmol) in CH2Cl2 (1 ml). The mixture was stirred at room temperature for 30 minutes. After 30 minutes, the solvent was removed in vacuo, and the resulting residue was triturated with ether. The solid material was filtered, washed with additional ether (2×2 mL) and dried to provide (S)-1-(4-(5-chloro-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-2-((S)-pyrrolidin-2-yl)ethanone dihydrochloride (71 mg, 0.13 mmol, 83% yield) as a cream solid. LCMS (APCI+) m/z 459.1, 461.1 [(M+H]+. NMR (400 Hz, DMSO-d6) δ 9.61 (br s, 1H), 9.08 (br s, 1H), 8.30 (s, 1H), 8.19 (s, 1H), 7.49 (d, 2H), 7.44 (d, 2H), 4.53 (d, 1H), 4.03-3.96 (m, 1H), 3.79-3.70 (m, 3H), 3.69-3.57 (m, 3H), 3.51-3.45 (m, 1H), 3.21-3.14 (m, 2H), 3.09-3.00 (m, 1H), 1.97-1.89 (m, 1H), 1.78-1.71 (m, 1H), 1.63-1.52 (m, 2H).
Reaction SMILES: [CH:1]1([N:4]([CH3:21])[CH:5]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]3[CH:10]=[C:9]([C:17]#[CH:18])[CH:8]=[C:7]([O:19][CH3:20])[C:6]2=3)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][C:27]=1[F:33].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:22][O:23][C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:18]#[C:17][C:9]2[CH:8]=[C:7]([O:19][CH3:20])[C:6]3[CH:5]([N:4]([CH:1]4[CH2:3][CH2:2]4)[CH3:21])[CH2:14][CH2:13][C:12]([CH3:15])([CH3:16])[C:11]=3[CH:10]=2)=[CH:28][C:27]=1[F:33]
Reactant: C#Cc1cc(OC)c2c(c1)C(C)(C)CCC2N(C)C1CC1
Reactant: COC(=O)Cc1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)Cc1ccc(C#Cc2cc(OC)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1F

Procedure:
Following General Procedure B and using 5-(cyclopropyl-methyl-amino)-2-ethynyl-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphthalene (Intermediate 81, 0.085 g, 0.3 mmol), methyl-2-fluoro-4-iodophenylacetate (0.088 g, 0.3 mmol), triethyl amine (8 mL), copper(I)iodide (0.019 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 5-20% ethyl acetate in hexane as the eluent, the title compound was obtained as a yellow solid (0.12 g, 89%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:24][O:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30](O)=[O:31].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:24][O:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=1)=[O:31]
Reactant: COc1ccccc1C=CC(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccccc1OC
Yield: 74.5 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.5 g), triethylamine (3.1 mL), 2-methoxycinnamic acid (2.0 g), WSC.HCl (2.1 g), and methylene chloride (100 mL), to give the captioned compound (2.8 g, 76%) as an amorphous solid product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][C:13]([NH:16][CH2:17][C@@H:18]([C:20]1[CH:21]=[C:22]([NH:26][S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=1)[OH:19])([CH3:15])[CH3:14])[CH:6]=[CH:5]2.N1C=CC=CC=1.[Cl-].[C:43](OC)(=[O:47])[C:44]([O-:46])=[O:45].[OH-].[Na+].C(O)(C(F)(F)F)=O>C1COCC1.CO>[C:30]1([S:27]([NH:26][C:22]2[CH:21]=[C:20]([C@@H:18]([OH:19])[CH2:17][NH:16][C:13]([CH3:14])([CH3:15])[CH2:12][CH2:11][N:7]3[C:8]4[C:4](=[CH:3][C:2]([NH:1][C:43](=[O:47])[C:44]([OH:46])=[O:45])=[CH:10][CH:9]=4)[CH:5]=[CH:6]3)[CH:25]=[CH:24][CH:23]=2)(=[O:29])=[O:28])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)C(=O)[O-]
Reactant: CC(C)(CCn1ccc2cc(N)ccc21)NC[C@H](O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)(CCn1ccc2cc(NC(=O)C(=O)O)ccc21)NC[C@H](O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The free base of N-(3-{(R)-2-[3-(5-amino-indol-1-yl)-1,1-dimethyl-propylamino]-1-hydroxy-ethyl}-phenyl)-benzenesulphonamide-hydrotrifluoroacetate (free base from Example 20; 100 mg, 0.20 mmol) and pyridine (33 μl, 0.41 mmol) are dissolved in 3 ml THF. At 0° C. methyl oxalate chloride (21 μl, 0.22 mmol) is added and the reaction mixture is stirred for 3 hours at RT. The solvent is eliminated in vacuo and the residue is dissolved in 3 ml of methanol. Sodium hydroxide solution (4N; 1.5 ml) is added dropwise to the mixture. Then the reaction mixture is stirred for 18 hours at RT and then acidified with TFA. The solution is chromatographed on Microsorb C18-reverse-phase [acetonitrile (0.1% TFA)/water (0.13% TFA)=10:90→100:0].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH:10]([O-:12])=O.[Na+].[OH-].[Na+]>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.[Pd].O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:2]2[CH:7]=[CH:6][C:5]([O:12][CH3:10])=[CH:4][CH:3]=2)=[CH:3][CH:4]=1
Reactant: O=C[O-]
Reactant: COc1ccc(Br)cc1
Agent: [Pd]
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Solvent: O
Product: COc1ccc(-c2ccc(OC)cc2)cc1
Reaction time: 18 h

Procedure:
18.7 parts of 4-bromoanisole, 6.8 parts of sodium formate, 64 parts of sodium hydroxide liquor (32%), 60 parts of water, 4 parts of cetyl trimethyl ammonium bromide and 3% palladium-on-charcoal (62% paste, 2 parts) are stirred and heated under reflux for 4 hours. A further 6.8 parts of sodium formate are added, and stirring and heating is continued for a further 18 hours. Steam is then passed through the reaction mixture to remove anisole, and the mixture is cooled and filtered. The filter cake is washed with water, dried at 60°, and extracted with 200 parts of chloroform. The palladium catalyst is recovered by filtration of the chloroform extract, and the chloroform is then distilled under vacuum. The white solid residue is triturated with 500 parts of cold water, collected by filtration, and dried at 60°. 5.2 parts of 4,4'-dimethoxybiphenyl, m.p. 172°-173° are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[C:10]=1[CH2:11][CH3:12].C1C=C(O[C:20](OC2N=CC=CC=2)=[S:21])N=CC=1>ClCCl>[CH2:11]([C:10]1[C:6]2[N:7]=[CH:8][O:9][C:5]=2[CH:4]=[CH:3][C:2]=1[N:1]=[C:20]=[S:21])[CH3:12]
Reactant: CCc1c(N)ccc2ocnc12
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Solvent: ClCCl
Product: CCc1c(N=C=S)ccc2ocnc12
Reaction time: 2 h

Procedure:
A solution of 5-amino-4-ethylbenzoxazole (3.98 mmol) in dichloromethane (100 mL) is treated with di-2-pyridyl thionocarbonate (4.39 mmol). The mixture is stirred for two hours. The reaction mixture is concentrated under reduced pressure to yield a brown residue. This material is purified by chromatography (silica gel, 20% ethyl acetate/hexanes) to afford 4-ethyl-5-isothiocyanatobenzoxazole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][CH3:14])[CH2:11][C@H:10]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)[C@@H:9]1[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:45]([O:47][CH3:48])=[O:46].CCOC(C)=O>C(#N)C.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][CH3:14])[CH2:11][C@H:10]([N:15]([CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:20]=[C:19]([C:27]([F:30])([F:28])[F:29])[CH:18]=2)[C:45]([O:47][CH3:48])=[O:46])[C@@H:9]1[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)Cl
Reactant: CC[C@@H]1C[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccccc2)N1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)[C@H](Cc2ccccc2)N1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 51.8 %

Procedure:
To a solution of (2S,3S,5R)-2-benzyl-3-(3,5-bis-trifluoromethyl-benzylamino)-5-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.0377 mmol; 20 mg) and cesium carbonate (0.113 mmol; 36.8 mg) in acetonitrile (0.38 mL) is added methyl chloroformate (0.0754 mmol; 5.9 mg) at room temperature. The reaction mixture is warmed to 80° C. and stirred for 3.5 hours. Additional methyl chloroformate (0.0754 mmol; 5.9 mg) is added to the mixture, and the mixture is stirred for additional 0.5 hours, and then cooled to room temperature. To the mixture is added brine and EtOAc. The organic layer is separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by preparative thin layer chromatography on silica gel (eluent: n-hexane/EtOAc) to give (2S,3S,5R)-2-Benzyl-3-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-5-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (11.5 mg, 52%); ESI-MS m/z: 589 [M+1]+, Retention time 2.63 min (condition A).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[CH2:11]([CH:16]1[O:21][C:20]2[CH:22]=[CH:23][C:24]([C:26](O)=[O:27])=[CH:25][C:19]=2[CH2:18][O:17]1)[CH2:12][CH2:13][CH2:14][CH3:15].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:26]([C:24]2[CH:23]=[CH:22][C:20]3[O:21][CH:16]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[O:17][CH2:18][C:19]=3[CH:25]=2)=[O:27])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(O)cc1
Reactant: CCCCCC1OCc2cc(C(=O)O)ccc2O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCC1OCc2cc(C(=O)Oc3ccc(CCC)cc3)ccc2O1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
0.1 g of 4-(dimethylamino)pyridine and 1.6 g of p-propylphenol are added to a solution of 2.5 g of 2-pentyl-1,3-benzodioxan-6-carboxylic acid in 50 ml of methylene chloride. The mixture is treated portionwise at 0° C. while stirring with 2.4 g of N,N'-dicyclohexylcarbodiimide. After completion of the addition, the mixture is stirred at 0° C. for a further 10 minutes and then at room temperature for 3 hours. The precipitate is filtered off and the filtrate is evaporated. The residue is taken up in 40 ml of methylene chloride and again filtered. The filtrate is washed with saturated sodium carbonate solution and then with water, dried over sodium sulphate, filtered and evaporated. The crude product is dissolved in boiling hexane, filtered hot with active carbon and crystallized from the filtrate. The crystallizate is recrystallized twice more from hexane. There is obtained pure 2-pentyl-1,3-benzodioxan-6-carboxylic acid p-propylphenyl ester; m.p. 97.5° C., cl.p. 74.5° C. (monotropic).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6](=[O:8])[CH3:7])[CH3:2].[Br:10]N1C(=O)CCC1=O>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:10][CH:5]([C:6](=[O:8])[CH3:7])[C:4]([O:3][CH2:1][CH3:2])=[O:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C1CCC(=O)N1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCOC(=O)C(Br)C(C)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 57.4 %

Procedure:
3-Oxobutanoic acid ethyl ester (1.26 mL, 10.0 mmol) was added dropwise to a suspension of N-bromosuccinimide (1.78 g, 10.0 mmol) and p-toluenesulfonic acid (10.0 mg, 0.0581 mmol) in methylene chloride (30.0 mL) at 0° C., and the resultant reaction mixture was stirred at 0° C. for 3 h, then warmed to RT and stirred at that temperature for 1 h. The reaction mixture was concentrated in vacuo and the resultant oily solid was treated with hexanes and the resultant suspension was filtered. The solid was washed with additional hexanes and the filtrate was concentrated in vacuo to give a crude oil. Purification by flash column chromatography (100% hexanes to 30% Et2O/hexanes) gave the desired product (1.20 g, 57%) as an oil.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][OH:14])[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)[N:6]=1)(=O)=O.[C-:27]#[N:28].[Na+]>CS(C)=O>[OH:14][CH2:13][CH2:12][NH:11][C:9]1[CH:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)[N:6]=[C:5]([C:27]#[N:28])[N:10]=1
Reactant: [C-]#N
Reactant: COc1ccc(-c2cc(NCCO)nc(S(C)(=O)=O)n2)cc1C(F)(F)F
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(-c2cc(NCCO)nc(C#N)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.5 %

Procedure:
2-[2-Methanesulfonyl-6-(4-methoxy-3-trifluoromethyl-phenyl)-pyrimidin-4-ylamino]-ethanol (0.68 g) was dissolved in DMSO (10 ml) and sodium cyanide (0.17 g) was added. The mixture was stirred at RT for 48 hours. Mixture was partitioned between ethyl acetate (100 ml) and water (100 ml). Organics were dried and evaporated then flash chromatographed over silica (DCM-2% methanol in DCM) to afford 420 mg of 4-(2-Hydroxy-ethylamino)-6-(4-methoxy-3-trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile as a white solid.