Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]C)[C:4]=1[NH2:5])C.Cl[CH2:13][CH:14]=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:3]([CH3:1])[C:4]=1[NH:5][CH2:13][CH:14]=[O:15]
Reactant: CCc1cccc(CC)c1N
Reactant: O=CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cccc(C)c1NCC=O
Temperature: 150 °C

Procedure:
2,6-Diethylaniline (100 grams), the dimethyl acetal of 2-chloroacetaldehyde (37.5 grams) and sodium carbonate (31.8 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at 150°C for a period of about 30 hours. After this time the mixture was filtered and the filtrate was distilled to yield the desired product the dimethyl acetal of 2-(2,6-dimethylanilino)acetaldehyde having a boiling point of 120°C at 1 mm of Hg pressure.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][C:9](=[O:13])[CH2:8]2)=[CH:3][CH:2]=1.[H-].[K+].[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O.O.[Cl-].[Na+].O.[Cu]I>[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([N:10]2[CH2:11][CH2:12][N:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH2:8][C:9]2=[O:13])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CN(c2ccncc2)CCN1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: [Cu]I
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CN(c2ccncc2)CCN1c1ccc(OCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
To a stirred suspension of 4-(4-pyridyl) piperazin-2-one (880 mg) in dimethyl formamide (20 ml) was added potassium hydride (1.0 ml of a 20% dispersion) and the mixture stirred for 0.5 hr, after which time was added copper (I) iodide (1.0 g). After 0.25 hr there was added 4-benzyloxybromobenzene (1.2 g) and the mixture stirred at 140° C in an argon atmosphere for 2 hr. The reaction mixture was diluted with water and brine and extracted with dichloromethane (3×40 ml); the combined extracts were washed with water and brine, dried (PS paper) and evaporated to give crude product as a pasty solid (2.0 g). This was purified by flash chromatography on silica, eluting with dichloromethane/methanol/conc- ammonia (97:2.5:0.5 v/v) to give 4-benzyloxy [4-(4-pyridyl)piperazin-2-one-1-yl]benzene as a colourless solid (1.1 g) NMR δ (d6 DMSO) :3.7-3.9 (4H,m); 4.1 (2H,s); 5.1 (2H,s); 6.85 (2H,d); 7.05 (2H,d); 7.25 (2H,d); 7.3-7.6 (5H,m); 8.2 (2H,d); m/e 360 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([CH2:9][C:10]([OH:12])=O)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][CH:14]1[C:27](=[O:28])[N:16]2[C:17]([C:24]([OH:26])=[O:25])=[C:18]([CH2:21][O:22][CH3:23])[CH2:19][S:20][C@H:15]12>>[C:1]1([S:7]([CH2:9][C:10]([NH:13][CH:14]2[C:27](=[O:28])[N:16]3[C:17]([C:24]([OH:26])=[O:25])=[C:18]([CH2:21][O:22][CH3:23])[CH2:19][S:20][C@H:15]23)=[O:12])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CS(=O)c1ccccc1
Reactant: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Product: COCC1=C(C(=O)O)N2C(=O)C(NC(=O)CS(=O)c3ccccc3)[C@H]2SC1

Procedure:
368 mg. of phenylsulfinylacetic acid and 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 320 mg. of 7-(phenylsulfinylacetamido)-3-methoxymethyl-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:34]([O:41][C@H:42]1[C@H:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@@H:46]([CH2:56][O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[O:45][C@H:44]([CH2:65][P:66]([O:71][CH2:72][CH3:73])(=[O:70])[O:67][CH2:68][CH3:69])[C@@H:43]1O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.P([N:91]=[N+:92]=[N-:93])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>C1COCC1>[N:91]([C@H:43]1[C@@H:42]([O:41][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@@H:46]([CH2:56][O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[O:45][C@@H:44]1[CH2:65][P:66]([O:71][CH2:72][CH3:73])(=[O:70])[O:67][CH2:68][CH3:69])=[N+:92]=[N-:93]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CCOP(=O)(C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1O)OCC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOP(=O)(C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1N=[N+]=[N-])OCC
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
DIAD (2.4 mL, 12.4 mmol) was added dropwise to a cooled (−5° C.) solution of Ph3P (3.1 g, 11.7 mmol) in THF (50 mL). After 30 min, a solution of 2 (5.57 g, 9.5 mmol) in THF (20 mL) was added. After an additional 10 min, diphenyl phosphorazidate (DPPA; 2.4 mL, 11.31 mmol) was added and the reaction mixture was allowed to attain rt. After stirring overnight, the solvent was evaporated and the residue was purified by silica gel chromatography to give 3 (5.0 g, 8.2 mmol, 86%) as a colorless oil. 13C-NMR (CDCl3) 138.17, 137.92, 137.38, 128.6-127.7, 78.2, 74.3, 73.9, 73.7, 73.5, 72.4, 69.5, 68.8, 62.2, 62.1, 62.0, 61.9, 61.0, 60.9, 27.9 (d, J=141 Hz), 16.5, 16.4; 31P-NMR (CDCl3) 27.9.
Reaction SMILES: [OH-].[C:2]12([N+:12]([CH3:15])([CH3:14])[CH3:13])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.C12(N(C)C)CC3CC(CC(C3)C1)C2.[C:29](=[O:34])([O:32]C)[O:30][CH3:31]>>[CH3:31][O:30][C:29](=[O:32])[O-:34].[C:2]12([N+:12]([CH3:15])([CH3:14])[CH3:13])[CH2:9][CH:8]3[CH2:7][CH:6]([CH2:5][CH:4]([CH2:10]3)[CH2:3]1)[CH2:11]2
Reactant: COC(=O)OC
Agent: CN(C)C12CC3CC(CC(C3)C1)C2
Agent: C[N+](C)(C)C12CC3CC(CC(C3)C1)C2
Agent: [OH-]
Product: COC(=O)[O-]

Procedure:
The invention is a method for preparing 1-adamantyltrimethylammonium hydroxide. The method comprises reacting 1-adamantyldimethylamine with dimethyl carbonate to produce 1-adamantyltrimethylammonium methylcarbonate, which is then reacted with calcium hydroxide or magnesium hydroxide in the presence of water to produce 1-adamantyltrimethylammonium hydroxide.
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([OH:19])=[C:15]([CH2:16][CH2:17][CH3:18])[C:10]=3[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH2:21][CH2:22][CH2:23]Br.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:19][CH2:23][CH2:22][CH2:21][Br:20])=[C:15]([CH2:16][CH2:17][CH3:18])[C:10]=3[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCc1c(O)ccc2c(-c3ccccc3)noc12
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCBr)ccc2c(-c3ccccc3)noc12

Procedure:
To a mixture of 3-phenyl-7-propyl-6-hydroxy-benz-[4,5]-isoxazole (1.0 g; 3.95 mmol, Prepared in Example 16 Step C), 1,3-dibromopropane (3.98g, 19.5 mmol) and potassium carbonate (0.573g, 4.15 mmol) in 4.0 mL of methyl ethyl ketone was warmed to reflux for 16 hours. Filtered, concentrated and chromatographed (silica gel, 30% ethyl acetate in hexane) to yeild 1.025 g of the title compound as a white solid. NMR (CDCl3): δ 7.95 (d,2H); 7.69 (d,1H); 7.55 (m,3H); 7.03 (d,1H); 4.25 (t,2H); 3.68 (t,2H); 2.95 (t,2H); 2.41 (m,2H); 1.76 (m,2H); 1.01 (t,3H)
Reaction SMILES: N1C2C(=C(C3N=[C:12]([N:22]4[CH2:27][CH2:26]OCC4)[C:13]4SC(COC)=[CH:16][C:14]=4N=3)C=CC=2)C=N1.[Cl:28][C:29]1[N:30]=[C:31]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[C:32]2[S:37][C:36]([CH2:38][OH:39])=[CH:35][C:33]=2[N:34]=1.N1C=CC(CCl)=CC=1>CN(C=O)C.[H-].[Na+]>[Cl:28][C:29]1[N:30]=[C:31]([N:40]2[CH2:41][CH2:42][O:43][CH2:44][CH2:45]2)[C:32]2[S:37][C:36]([CH2:38][O:39][CH2:16][C:14]3[CH:13]=[CH:12][N:22]=[CH:27][CH:26]=3)=[CH:35][C:33]=2[N:34]=1
Reactant: OCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: COCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Agent: ClCc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1nc(N2CCOCC2)c2sc(COCc3ccncc3)cc2n1

Procedure:
Following the procedures for compound 314, (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol in DMF and sodium hydride was alkylated with 4-picolyl chloride to give 4-(2-chloro-6-((pyridin-4-ylmethoxy)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine. Suzuki coupling of 4-(2-chloro-6-((pyridin-4-ylmethoxy)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine and 7 was carried out via General Procedure A. Purification using column chromatography gave 320. NMR: CDCl3: 3.90-3.94 (4 H, m, CH2), 4.08-4.13 (4 H, m, CH2), 4.68 (2 H, s, CH2), 4.92 (2 H, s, CH2), 7.30 (2 H, d, J 5.81, Ar), 7.46 (1 H, s, Ar), 7.51 (1 H, t, J 8.14, Ar), 7.60 (1 H, d, J 8.20, Ar), 8.28 (1 H, d, J 7.32, Ar), 8.61 (2 H, d, J 5.27, Ar), 9.01 (1 H, s, Ar) and 10.14 (1 H, s, NH). MS: (ESI+): MH+ 459.17
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:28][CH2:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:38][CH3:39])=[C:35]([OH:37])[CH:36]=1>>[CH3:39][O:38][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][CH2:29][NH:28][C:23]2[N:22]=[C:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([NH:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:16]=3)[CH:26]=[CH:25][N:24]=2)=[CH:36][C:35]=1[OH:37]
Reactant: COc1ccc(CCN)cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc(-c3ccnc(Cl)n3)c2)CC1
Product: COc1ccc(CCNc2nccc(-c3cccc(NC4CCNCC4)c3)n2)cc1O

Procedure:
Intermediate 7 was coupled with 5-(2-Amino-ethyl)-2-methoxy-phenol following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 420. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.3 (d, 1H) 7.0-7.6 (m, 8H) 4.95 (m, 1H) 3.89 (m, 1H) 3.7 (m, 1H) 3.4 (m, 2H) 2.9-3.3 (m, 5H) 2.2-2.3 (m, 2H) 1.95 (m, 2H) 1.6-1.8 (m, 2H).
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]3[C:15]([C:18]([OH:20])=O)=[CH:16][N:17]=[C:11]3[CH:10]=2)[CH2:4][O:3]1.C(Cl)(=O)C(Cl)=O.[CH2:28]([N:35]1[C:43]2[CH:42]=[CH:41][CH:40]=[C:39]([NH2:44])[C:38]=2[CH:37]=[N:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[CH2:28]([N:35]1[C:43]2[C:38](=[C:39]([NH:44][C:18]([C:15]3[N:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH:5]([OH:6])[CH2:4][OH:3])=[CH:10][C:11]4=[N:17][CH:16]=3)=[O:20])[CH:40]=[CH:41][CH:42]=2)[CH:37]=[N:36]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC1(C)OCC(COc2ccn3c(C(=O)O)cnc3c2)O1
Reactant: Nc1cccc2c1cnn2Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc2c1cnn2Cc1ccccc1)c1cnc2cc(OCC(O)CO)ccn12
Reaction time: 8 h
Yield: 14.7 %

Procedure:
A DCM solution of 7-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (Example 58, Steps A-C, 109.7 mg, 0.375 mmol) was treated at ambient temperature with oxalyl chloride (1.1 equivalents) and a drop of DMF. After gas evolution ceased, 1-benzyl-1H-indazol-4-amine (83.8 mg, 0.375 mmol) and Hunig's base (1.2 equivalents) were added, and stirring continued overnight. The resulting mixture was concentrated, and triturated with diethyl ether, followed by chromatographic purification on silica with 10% MeOH/DCM as eluent to provide 25.2 mg of the desired product. MS (ES+APCI) m/z=458 (M+H) detected.
Reaction SMILES: C(OC(C1C=CC=CC=1O[C:9]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:22][C:12]2[NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[N:15][C:11]=2[CH:10]=1)=O)C.[CH3:39][O:40][N:41]([CH3:49])[C:42](=[O:48])[C@H:43]1[CH2:47][CH2:46][CH2:45][NH:44]1>>[CH3:39][O:40][N:41]([CH3:49])[C:42]([C@H:43]1[CH2:47][CH2:46][CH2:45][N:44]1[C:9]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:22][C:12]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[NH:15][C:11]=2[CH:10]=1)=[O:48]
Reactant: CON(C)C(=O)[C@H]1CCCN1
Reactant: CCOC(=O)c1ccccc1Oc1cc2nc(-c3ccccn3)[nH]c2cc1Oc1ccc(S(C)(=O)=O)cc1
Product: CON(C)C(=O)[C@H]1CCCN1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1

Procedure:
The entitled compound was obtained in the same method as in Example 15 or in accordance with the method or by combining it with an ordinary method but using 5-fluoro-4-(4-methanesulfonyl-phenoxy)-2-nitro-phenylamine obtained in Example 14, and (R)—N-methoxy-N-methylprolinamide.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])=[CH:12][CH:11]=1
Reactant: N[C@@H](CO)C(=O)O
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(CN[C@@H](CO)C(=O)O)cc1

Procedure:
The title compound was prepared from serine (29.6 g, 0.3 mmol) and p-methoxybenzaldehyde (68.0 mL, 0.6 mmol) according to Method W and was obtained as a white solid (36.2 g, 59%) that was used crude. δH (DMSO-d6) 7.37 (2H, dd, J 8.7 and 1.9 Hz), 6.93 (2H, dd, J 8.7 and 1.9 Hz), 3.99 (2H, s), 3.55 (3H, s), 3.73 (3H, m), 3.15 (1H, t, J 4.7 Hz). Not all exchangeable protons were observed.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[OH:13][CH2:14][CH2:15][C:16]1[N:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:19][C:20]=1[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:48]1[CH:49]=[C:50]([C:54](=[O:56])[CH3:55])[CH:51]=[CH:52][CH:53]=1.Cl>C1COCC1.O>[CH3:21][C:20]1[O:19][C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:17][C:16]=1[CH2:15][CH2:14][O:13][C:53]1[CH:52]=[CH:51][C:50]([C:54](=[O:56])[CH3:55])=[CH:49][CH:48]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Reactant: CC(=O)c1cccc(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Reaction time: 48 h
Yield: 77.2 %

Procedure:
Diethylazodicarboxylate (20.7 mL, 131.6 mmol) in THF (35 mL) was added dropwise in to a cold (0° C.) solution of 4-(2'-hydroxy-ethyl)-5-methyl-2-phenyloxazole (25.0 g, 123.0 mmol), triphenylphosphine (34.5 g, 131.6 mmol), and 3'-hydroxyacetophenone (18.0 g, 131.6 mmol) and THF (180 mL). The mixture was allowed to come to room temperature and stirred for 48 hours. Then, it was poured into H2O, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on silica gel (hexane/EtOAc 5/1) gave a white solid (30.5 g, 77% yield, m.p. 70°-71° C.). Analysis for: C20H19NO3Calc'd: C, 74.75; H, 5.96; N, 4.36 Found: C, 74.70; }I, 6.15; N, 4.28
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:61][CH:62]=[CH:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=1[CH3:70].FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:61][CH:62]=[CH:63][C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=3[CH3:70])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: Cc1ccccc1C=CCOC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC=Cc4ccccc4C)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (50 mg in 1.5 ml 33% methylene chloride in cyclohexane), 2-methylcinnamyl trichloroacetimidate (28 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (3 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 20 minutes the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×10 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate: hexane (1:2)+1% methanol) gave the title compound (9 mg).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH2:21]([C@@H:28]1[CH2:33][C@@H:32]([N:34]([CH2:41][C:42]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:45]=[CH:44][CH:43]=2)[C:35](=[O:40])[C:36]([F:39])([F:38])[F:37])[CH2:31][CH2:30][NH:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N>C(Cl)Cl.CO>[CH2:21]([C@@H:28]1[CH2:33][C@@H:32]([N:34]([CH2:41][C:42]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:45]=[CH:44][CH:43]=2)[C:35](=[O:40])[C:36]([F:38])([F:39])[F:37])[CH2:31][CH2:30][N:29]1[C:8](=[O:10])[CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: O=S(Cl)Cl
Product: O=C(C(c1ccccc1)c1ccccc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1

Procedure:
248 mg (1.17 mmol) of diphenylacetic acid are reacted in analogy to Example 2j first with 128 μl (1.76 mmol) of thionyl chloride and subsequently with 200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine to give the product. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.45, FD-MS: M+ =621.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)([O-:3])=[O:2].[CH2:18]([NH2:20])[CH3:19]>O>[N+:1]([CH:4]=[C:5]([NH:20][CH2:18][CH3:19])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)([O-:3])=[O:2]
Reactant: CCN
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1nccs1
Solvent: O
Product: CCNC(=C[N+](=O)[O-])NCCSCc1nccs1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-(2-thiazolylmethylthio)ethylamino]ethylene (see Example 55(ii)) with ethylamine by the procedure of Example 8(ii) gives the title product, m.p. 115°-116° (from water).
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14]C(=O)OC(C)(C)C.[ClH:22]>C(OCC)(=O)C>[ClH:22].[I:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: CC(C)(C)OC(=O)NCCCCCCCCCCCCI
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCCCCCCCCCCCI
Reaction time: 0.5 h

Procedure:
To a solution of 0.33 g of tert-butyl N-(12-iodododecyl)carbamate in 25 ml of ethyl acetate was added 2.6 ml of hydrochloric acid and the mixture was stirred for 0.5 hour. The reaction solution was distilled off under reduced pressure. The residue was dissolved in chloroform, washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Crystallization from ethyl acetate and hexane afforded 0.17 g of the title compound.
Reaction SMILES: OC[C@@H](N)CC(C)C.COC(=O)[C@H](CC(C)C)N.[N+:19]([C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([NH2:32])=[CH:24][CH:23]=1)([O-:21])=[O:20].[N+]([C:36]1[C:45]2[C:40](=CC=C[CH:44]=2)[C:39]([N:46]=[C:47]=[S:48])=[CH:38]C=1)([O-])=O>>[N+:19]([C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([N:32]=[C:47]2[NH:46][C@@H:39]([CH2:40][CH:45]([CH3:36])[CH3:44])[CH2:38][S:48]2)=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(N=C=S)c2ccccc12
Reactant: Nc1ccc([N+](=O)[O-])c2ccccc12
Agent: CC(C)C[C@H](N)CO
Agent: COC(=O)[C@@H](N)CC(C)C
Product: CC(C)C[C@H]1CSC(=Nc2ccc([N+](=O)[O-])c3ccccc23)N1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. 4-Nitro-1-naphthylamine was converted to 4-nitro-1-naphthyl isothiocyanate according to Method A2b. 4-Nitro-1-naphthyl isothiocyanate was reacted with (1S)-1-(hydroxymethyl)-3-methylbutylamine to Method C2a to give (4S)-2-(4-nitro-1-naphthylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-nitro-1-naphthylimino)-3,4-diisobutyl-1,3-thiazolidine.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[C:25]([CH3:26])=[CH:24][S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]2[C:25]([CH3:26])=[CH:24][S:23][C:13]=2[N:14]=1
Reactant: Cc1csc2nc(-c3ccccn3)nc(Cl)c12
Reactant: NCCc1ccccc1
Product: Cc1csc2nc(-c3ccccn3)nc(NCCc3ccccc3)c12

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-2-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-phenethylamino-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([NH:16][C@H:17]1[C@@H:24]2[C@@H:20]([CH2:21][N:22]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[CH2:23]2)[CH2:19][CH2:18]1)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=O)(C)(C)C.Cl>CCOCC>[F:34][C:32]([F:33])([F:35])[C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][N:22]1[CH2:23][C@H:24]2[C@@H:17]([NH:16][C:14](=[O:15])[C@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[NH2:8])[CH2:18][CH2:19][C@H:20]2[CH2:21]1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H]1CC[C@@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@@H]21
Agent: Cl
Solvent: CCOCC
Product: CC(C)C[C@H](N)C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N2-(tert-butyloxycarbonyl)-N1-{(3aR*,4R*,6aS*)-2-[3-(trifluoromethyl)benzyl]octahydrocyclopenta[c]pyrrol-4-yl}-L-leucinamide (140 mg, 0.281 mmol) from Example 137 and 2 N HCl (2.5 mL, 5.00 mmol) were combined in ether (0.5 mL), and the reaction was stirred at room temperature overnight. The solids were collected and dried to give the title compound as the hydrochloride salt: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.59 (s, 0.5H), 8.48 (s, 0.5H), 7.89 (s, 0.5H), 7.83 (s, 0.5H), 7.69 (t, J=6.8, 1H), 7.60 (d, J=7.8, 1H), 7.50-7.44 (m, 1H), 4.96 (br s, 2H), 4.57-4.48 (m, 1H), 3.73 (d, J=13.2, 0.5H), 3.67 (s, 1H), 3.64 (d, J=13.2, 1H), 3.39 (d, J=13.1, 0.5H), 3.35 (d, J=13.2, 0.5H), 2.81-2.70 (m, 2H), 2.45 (dd, J=7.5, 15.3, 1H), 2.39-2.31 (m, 1H), 2.27-2.14 (m, 2H), 1.95-1.79 (m, 2.5H), 1.72-1.56 (m, 2H), 1.53-1.46 (m, 0.5H), 1.33-1.23 (m, 1.5H), 0.90 (dt, J=6.2, 14.1, 6H); MS (ESI+) m/z 398 (M+H)+.