Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)[N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][C:3]=12.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=1>>[O:9]1[CH:10]=[CH:11][N:12]=[C:8]1[C:6]1[N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][C:3]2=[C:2]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:21][CH:22]=2)[CH:7]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: Clc1cc(-c2ncco2)nc2c1CCC2
Product: CCOC(=O)Cc1ccc(Nc2cc(-c3ncco3)nc3c2CCC3)cc1
Yield: 71.9 %

Procedure:
Following general procedure B1, 2-(4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)oxazole (0.040 g, 0.18 mmol) was reacted with ethyl 2-(4-aminophenyl)acetate (0.039 g, 0.22 mmol) to afford the title compound (0.047 g, 71%) as a white foam. MW=363.41. 1H NMR (CDCl3, 500 MHz) δ 7.72 (s, 1H), 7.66 (s, 1H), 7.31 (d, J=8.5 Hz, 2H), 7.22-7.17 (m, 3H), 5.80 (s, 1H), 4.18 (q, J=7.0 Hz, 2H), 3.61 (s, 2H), 3.11 (t, J=7.5 Hz, 2H), 2.84 (t, J=7.5 Hz, 2H), 2.22 (quin, J=7.5 Hz, 2H), 1.28 (t, J=7.0 Hz, 3H); APCI MS m/z 364 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:12])[C:6]=1[CH2:7][CH2:8][C:9]([OH:11])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:12])[C:6]=1[CH2:7][CH2:8][C:9]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:11]
Reactant: Cc1c[nH]c(C)c1CCC(=O)O
Reactant: C1COCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c[nH]c(C)c1CCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
To a suspension of 3-(2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid (10 g, 60.8 mmol) in 60 ml of dichloromethane was added 1,1′-carbonyldiimidazole (11.6 g, 71.8 mmol) followed morpholine (5.5 ml, 60.8 mmol) and N,N-diisopropylethylamine (Hunig's base, 10 ml, 60.8 mmol). The dark red reaction mixture was stirred at room temperature overnight and poured into ice water. The organic layer was washed with brine until the wash had a pH of about 6, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified on a silica gel column eluting with dichloromethane-methanol (98:2) to give 13.84 g (96%) of 3-(2,4-dimethyl-1H-pyrrol-3-yl)-1-morpholin-4-yl-propan-1-one.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][CH:8]([NH:11][C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:9][OH:10])(C)(C)C.[CH2:19](O)[CH:20]([CH3:22])[CH3:21]>>[CH2:15]([O:14][C:12](=[O:13])[NH:11][CH:8]1[CH2:7][C:6](=[O:5])[O:18][CH:9]1[O:10][CH2:19][CH:20]([CH3:22])[CH3:21])[CH:16]=[CH2:17]
Reactant: C=CCOC(=O)NC(CO)CC(=O)OC(C)(C)C
Reactant: CC(C)CO
Product: C=CCOC(=O)NC1CC(=O)OC1OCC(C)C
Yield: 7.3 %

Procedure:
Prepared from 3-allyloxycarbonylamino-4-hydroxy-butyric acid tert-butyl ester as described for 40 using isobutanol to afford 190 mg (yield 7.3%) of the title compound as an anti diastereomer and 290 mg (yield 11%) of the syn diastereomer. 1H-NMR (500 MHz, CDCl3) for anti diastereomer: δ (higher Rf) 0.85-1.05 (m, 6H), 1.82-1.98 (m, H), 2.37-2.42 (d, H), 2.98-3.04 (m, H), 3.31-3.35 (m, H), 3.55-3.58 (m, H), 4.20-4.30 (t, H), 4.58 (br, 2H), 5.07 (br, H), 5.22-5.43 (m, 3H), 5.84-5.96 (m, H), for syn diastereomer (lower Rf) 0.85-1.05 (m, 6H), 1.88-1.95 (m, H), 2.40-2.51 (m, H), 2.83-2.90 (m, H), 3.33-3.36 (m, H), 3.61-3.65 (m, H), 3.87-3.88 (d, H), 4.40-4.68 (m, 3H), 5.20-5.40 (m, 2H), 5.42-5.43 (d, H), 5.80-5.97 (m, H); LC-MS: m/z=258 (M+H+) for both of diastereomers.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][NH:9]2)[CH:5]=[CH:4][C:3]=1[C:14]1[O:15][C:16]2[C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.[CH:26](=O)[CH2:27][CH3:28]>CO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[CH2:26][CH2:27][CH3:28])[CH:5]=[CH:4][C:3]=1[C:14]1[O:15][C:16]2[C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1
Reactant: CCC=O
Reactant: NC(=O)c1cccc2nc(-c3ccc(C4CCCCN4)cc3F)oc12
Agent: [Pd]
Solvent: CO
Product: CCCN1CCCCC1c1ccc(-c2nc3cccc(C(N)=O)c3o2)c(F)c1
Yield: 56 %

Procedure:
A solution of 2-(2-fluoro-4-(piperidin-2-yl)phenyl)benzo[d]oxazole-7-carboxamide (200 mg, 0.44 mmol), 10% Pd/C (100 mg) and propanal (10 ml, 4 mmol) in methanol (10 ml) was hydrogenated at room temperature for two days. The solution was filtered off and concentrated; the residue was purified by prep-HPLC to give 2-(2-fluoro-4-(1-propylpiperidin-2-yl)phenyl)benzo[d]oxazole-7-carboxamide (94 mg, yield 43%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 0.80 (s, 3H), 1.60-1.77 (m, 3H), 1.97-2.13 (m, 5H), 2.86 (s, 2H), 3.18 (s, 1H), 3.78-3.80 (m, 1H), 4.39-4.413 (m, 1H), 7.302-7.43 (m, 1H), 7.50-7.70 (m, 3H), 7.92-7.93 (m, 2H), 8.39 (s, 1H); LC-MS (ESI) m/z: 382 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH2:14]([O:16][C:17](=[O:25])[CH2:18]N1CCNCC1)[CH3:15].O.Cl>CN(C)C=O>[CH2:14]([O:16][C:17]([CH2:18][CH:9]1[CH2:5][CH2:4][N:3]([C:2]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)[CH2:2][CH2:10]1)=[O:25])[CH3:15]
Reactant: O=C(O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CN1CCNCC1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCN(c2ncc(C(=O)O)cc2[N+](=O)[O-])CC1
Temperature: 130 °C
Yield: 162.2 %

Procedure:
A mixture of 2.00 g (9.87 mmol) of 6-chloro-5-nitro-nicotinic acid and 2.03 g (11.8 mmol) of piperazin-1-yl-acetic acid ethyl ester in N,N-dimethylformamide (10 mL) are heated to 130° C. in a microwave reactor for 1 hour. The resulting dark mixture is poured into water which forms a precipitate. The pH of the mixture is adjusted to approximately pH 2 by adding concentrated hydrochloric acid. The precipitated solid is collected by filtration, washed with water, and dried under reduced pressure to give 2.70 g (81.1%) of 4-ethoxycarbonylmethyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid as a yellow solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][C:12]([C:14]3[C:19]([O:20]CC=C)=[CH:18][C:17]([CH3:24])=[CH:16][C:15]=3[O:25][C@@H:26]3[O:34][C@H:33]([CH2:35][O:36][C:37]([O:39][CH3:40])=[O:38])[C@@H:31]([OH:32])[C@H:29]([OH:30])[C@H:27]3[OH:28])=[O:13])[CH:8]=[CH:9][C:2]1=2.C([O-])=O.[NH4+]>C(#N)C.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>[O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][C:12]([C:14]3[C:19]([OH:20])=[CH:18][C:17]([CH3:24])=[CH:16][C:15]=3[O:25][C@@H:26]3[O:34][C@H:33]([CH2:35][O:36][C:37]([O:39][CH3:40])=[O:38])[C@@H:31]([OH:32])[C@H:29]([OH:30])[C@H:27]3[OH:28])=[O:13])[CH:8]=[CH:9][C:2]1=2
Reactant: C=CCOc1cc(C)cc(O[C@@H]2O[C@H](COC(=O)OC)[C@@H](O)[C@H](O)[C@H]2O)c1C(=O)CCc1ccc2occc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC#N
Product: COC(=O)OC[C@H]1O[C@@H](Oc2cc(C)cc(O)c2C(=O)CCc2ccc3occc3c2)[C@H](O)[C@@H](O)[C@@H]1O
Yield: 84.8 %

Procedure:
3-(5-Benzo[b]furanyl)-2'-(6-O-methoxycarbonyl-β-D-glucopyranosyloxy)-6'-allyloxy-4'-methylpropiophenone (470 mg) is dissolved in acetonitrile (7 ml), and thereto are added dichlorobis(triphenylphosphine)-palladium (II) (17.7 mg,) and ammonium formate (319 mg), and the mixture is heated under reflux overnight. After cooling, the insoluble materials are removed by filtration, and the filtrate is concentrated. To the residue are added ethyl acetate and water, and the mixture is shaken. The organic layer is separated, washed with water, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give 3-(5-benzo[b]furanyl)-2'-(6-O-methoxycarbonyl-β-D-glucopyranosyloxy)-6'-hydroxy-4'-methylpropiophenone (370 mg).
Reaction SMILES: C(OC([C:6]1[N:7]([NH:11][C:12]([NH:14][C:15](=[O:22])C2C=CC=CC=2)=[S:13])[CH:8]=[CH:9][CH:10]=1)=O)C.[OH-].[Na+].C(O)C.C(O)(=O)C>O.CCOCC>[S:13]=[C:12]1[NH:14][C:15](=[O:22])[C:8]2=[CH:9][CH:10]=[CH:6][N:7]2[NH:11]1
Reactant: CCOC(=O)c1cccn1NC(=S)NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: O=c1[nH]c(=S)[nH]n2cccc12
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
Into a 1000 mL beaker was added 1-(3-Benzoyl-thioureido)-1H-pyrrole-2-carboxylic acid ethyl ester (55.47 g, 0.1748 mol) and 2M of Sodium hydroxide in Water (350 mL). The mixture was heated at 85° C. for 75 minutes. After cooling to room temperature, the solid was dissolved with Ethanol (100 mL). Acetic acid (41.7 mL, 0.734 mol) was added at 0° C. and stirred for 30 minutes. The solid was filtered and washed with cold EtOH (50 mL) to afforded a white solid. The white solid was stirred in Ether (300 mL) for 20 minutes. The solid was filtered and washed with Ether (200 mL) to give a white solid. Because a large amount of desired product was water soluble, the water filtrate was reduced and the product was triturated with water to afford an additional amount of desired product. After drying under vacuum overnight, 43 grams of 2-Thioxo-2,3-dihydro-1H-pyrrolo[2,1-f][1,2,4]triazin-4-one was isolated as a white powder. Note. The product contained a significant amount of water but was carried on without further drying. 1H NMR (400 MHz, DMSO, d6) δ 9.91 (s, 1H), 7.09 (m, 1H), 6.53 (m, 1H), 6.21 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[NH2:35][CH2:36][C:37]1[CH:61]=[CH:60][C:40]([CH2:41][NH:42][C:43](=[O:59])[C:44]2[CH:49]=[C:48](F)[CH:47]=[N:46][C:45]=2[O:51][C:52]2[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=2)=[CH:39][CH:38]=1.CN1CCOCC1>CN(C)C=O>[F:58][C:55]1[CH:54]=[CH:53][C:52]([O:51][C:45]2[N:46]=[CH:47][CH:48]=[CH:49][C:44]=2[C:43]([NH:42][CH2:41][C:40]2[CH:60]=[CH:61][C:37]([CH2:36][NH:35][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=3[OH:1])=[CH:38][CH:39]=2)=[O:59])=[CH:57][CH:56]=1
Reactant: NCc1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)cc1
Reactant: Cc1cccc(C(=O)O)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)NCc2ccc(CNC(=O)c3cccnc3Oc3ccc(F)cc3)cc2)c1O
Yield: 21.3 %

Procedure:
A solution of 2-Hydroxy-3-methylbenzoic acid (118 mg, 0.773 mmol), 1-hydroxybenzotriazole (157 mg, 1.16 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (193 mg, 1.01 mmol), N-(4-aminomethyl-benzyl)-5-fluoro-2-(4-fluoro-phenoxy)-nicotinamide hydrochloride (300 mg, 0.773 mmol) (see Preparation 3) and N-methyl morpholine (0.17 ml, 1.55 mmol) in N,N-dimethylformamide (6 ml) was stirred under nitrogen at room temperature for 18 hours. The mixture was then partitioned between ethyl acetate (10 ml) and water (10 ml). The organic phase was separated, washed with a saturated aqueous solution of sodium chloride (10 ml) and dried over anhydrous magnesium sulphate. The solvent was then removed in vacuo and the residue was triturated with diethylether (3-fold 10 ml) giving 2-(4-fluoro-phenoxy)-N-{4-[(2-hydroxy-3-methyl-benzoylamino)-methyl]-benzyl}-nicotinamide (80 mg) as an off-white foam.
Reaction SMILES: COC(=O)[CH2:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.[CH2:73]([O:75][C:76](=[O:80])[CH2:77]CN)[CH3:74]>CN(C)C=O>[CH2:73]([O:75][C:76](=[O:80])[CH2:77][CH2:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:34][CH2:35]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36])[CH3:74]
Reactant: CCOC(=O)CCN
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 85 %

Procedure:
To a solution of 0.18 g (0.37 mmol) 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) in 2 mL N,N-dimethylformamide were added 0.148 g (0.39 mmol) O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1) and 0.25 mL (1.49 mmol) N,N-diisopropylethylamine. To the light brown solution 0.060 g (0.39 mmol) beta-alanine ethylester hydrochloride (commercially available, CAS RN 4244-84-2) was added and the solution was stirred at room temperature for 3.5 hours. The solution was poured on water and extracted three times with ethyl acetate. The combined organic layers were washed twice with water and brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The resulting powder was purified by silica gel chromatography using a MPLC system (10 g silica gel column, CombiFlash Companion, Isco Inc.) with a gradient of n-heptane:ethyl acetate (100:0 to 0:100) to afford 0.185 g (85%) of the title compound as a light brown foam. MS (ESI): m/z=583.15 [M+H]+.
Reaction SMILES: [CH2:1]([NH2:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[S:16](N)([NH2:19])(=[O:18])=[O:17]>>[CH2:1]([NH:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCN
Reactant: NS(N)(=O)=O
Product: CCCCCCCCCCCCCCNS(N)(=O)=O
Yield: 63 %

Procedure:
The title compound was prepared following the procedure previously described in Example 1, using 0.43 g (2.0 mmol) of N-tetradecylamine and 0.2 g (2.0 mmol) of sulfamide as starting reagent. 0.37 g of a white solid were obtained. Yield 63%; m.p. 99-101° C.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH:17]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH2:18][C:19]([OH:21])=[O:20])[C:13](=[O:28])[C:12]2=[O:29])=[CH:5][CH:4]=1)#[N:2].S(Cl)(Cl)=O.[CH2:36](O)[CH3:37]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH:17]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH2:18][C:19]([O:21][CH2:36][CH3:37])=[O:20])[C:13](=[O:28])[C:12]2=[O:29])=[CH:30][CH:31]=1)#[N:2]
Reactant: CCO
Reactant: N#Cc1ccc(OCCCN2CCN(C(CC(=O)O)c3cccnc3)C(=O)C2=O)cc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CC(c1cccnc1)N1CCN(CCCOc2ccc(C#N)cc2)C(=O)C1=O

Procedure:
In 14 ml of ethanol was suspended 0.70 g of (-)-3-[4-[3-(4-cyanophenoxy)propyl]-2,3-dioxopiperazin-1-yl]-3-(pyridin-3-yl)propionic acid, followed by adding thereto 0.15 ml of thionyl chloride under ice-cooling, and the resulting mixture was heated under reflux for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure and 10 ml of ethyl acetate and 10 ml of water were added to the resulting residue, and the pH was adjusted to 7.5 with a saturated aqueous sodium hydrogencarbonate solution. The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate. The combined organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure to obtain 0.5 g of ethyl (-)-3-[4-[3-(4-cyanophenoxy)propyl]-2,3-dioxopiperazin-1-yl]-3-(pyridin-3-yl)propionate as colorless crystals having a melting point of 110.5-112° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][C:10]=2[O:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:5][CH:4]=1)=O.C(O)(=O)C.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[CH3:27][O:26][CH2:25][CH2:24][CH2:23][O:22][C:10]1[CH:11]=[C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:13]=[CH:14][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([CH2:1][N:36]2[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]2)=[CH:8][CH:7]=1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(C=O)cc2)c(OCCCOC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)CCc1ccc(-c2ccc(CN3CCN(C)CC3)cc2)c(OCCCOC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
Ethyl 3-[4′-formyl-2-(3-methoxypropoxy)biphenyl-4-yl]propanoate (1 g, 2.7 mmol) was dissolved in dichloroethane (20 mL). At 0° C., acetic acid (0.02 mL, 0.4 mmol) was added, followed, by N-methylpiperazine (0.3 g, 3 mmol) and sodium triacetoxyborohydride (0.86 g, 4 mmol) portionwise. The mixture was stirred at room temperature overnight. At 0° C., saturated aqueous sodium bicarbonate was added. The aqueous layer was extracted three times with dichloromethane. The combined organic layers were washed with brine and water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield 0.98 g (80%) of the desired product as a brown oil used in the following step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][CH:11]2[CH:18]3[CH:14]([N:15](C(OC(C)(C)C)=O)[CH2:16][CH2:17]3)[CH2:13][CH2:12]2)=[O:9])[CH:5]=[N:6][CH:7]=1.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>ClCCl>[CH3:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH:3]=1)[C:8]([NH:10][CH:11]1[CH:18]2[CH:14]([NH:15][CH2:16][CH2:17]2)[CH2:13][CH2:12]1)=[O:9].[C:28]([OH:30])([C:27]([F:32])([F:31])[F:26])=[O:29]
Reactant: Cc1cncc(C(=O)NC2CCC3C2CCN3C(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cncc(C(=O)NC2CCC3NCCC32)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 50 mL round bottom flask was charged with a magnetic stirbar, Compound 12 (1.5 g, 6.11 mmol) and dichloromethane (25 mL). Trifluoroacetic acid (2.1 g, 18.3 mmol) was added and the reaction mixture was allowed to stir at room temperature for 4 hours. Solvent and volatiles were removed in vacuo overnight to yield Compound 13 as its TFA salt.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH:16]=[O:17])=[CH:6][NH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15].C1OCCOCCOCCOCCOC1.Cl.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([S:40](Cl)(=[O:42])=[O:41])[CH:35]=1>O1CCCC1.O>[Cl:3][C:4]1[C:5]([CH:16]=[O:17])=[CH:6][N:7]([S:40]([C:36]2[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=2)(=[O:42])=[O:41])[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: O=Cc1c[nH]c(-c2ccccc2F)c1Cl
Agent: C1COCCOCCOCCOCCO1
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cn(S(=O)(=O)c2cccnc2)c(-c2ccccc2F)c1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.5 %

Procedure:
A suspension of sodium hydride (60% in oil, 216 mg) in tetrahydrofuran (5 mL) was cooled to 0° C., a solution of 4-chloro-5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (335 mg) in tetrahydrofuran (5 mL), 15-crown-5 (991 mg), and pyridine-3-sulfonyl chloride hydrochloride (482 mg) were added at 10° C. or below. After stirring for 15 min, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1→2:1) to give the title compound as a yellow powder (yield 429 mg, 78%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.C[Si](CC(N)=O)(C)C.[NH2:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:24][O:25][CH3:26])[C:21]([OH:23])=O)[N:19]=1.[NH2:27][CH:28]1[C:53](=[O:54])[N:30]2[CH:31]([C:40]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][CH:45]=3)=[O:41])[C:32](=[CH:35][O:36][C:37](=[O:39])[CH3:38])[CH2:33][S:34][C@H:29]12.C(=O)(O)[O-].[Na+]>O1CCCC1.O.C(OCC)(=O)C.CN(C)C=O>[NH2:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:24][O:25][CH3:26])[C:21]([NH:27][CH:28]2[C:53](=[O:54])[N:30]3[CH:31]([C:40]([O:42][CH2:43][C:44]4[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][CH:45]=4)=[O:41])[C:32](=[CH:35][O:36][C:37](=[O:39])[CH3:38])[CH2:33][S:34][C@H:29]23)=[O:23])[N:19]=1
Reactant: CC(=O)OC=C1CS[C@@H]2C(N)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CON=C(C(=O)O)c1csc(N)n1
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=COC(C)=O)CS[C@H]12)c1csc(N)n1
Yield: 64.2 %

Procedure:
Phosphorus oxychloride (1.7 g.), trimethylsilylacetamide (1 g.) and N,N-dimethylformamide (0.73 g.) were added to a suspension of 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 1.8 g.) in tetrahydrofuran (20 ml.) at 5° C. Thus obtained solution was added all at once to a solution of 4-nitrobenzyl 7-amino-3-acetoxymethylenecepham-4-carboxylate (2.9 g.) and trimethylsilylacetamide (5.4 g.) in tetrahydrofuran (30 ml) at -20° C., and the mixed solution was stirred at -10° to -15° C. for an hour. After adding water (10 ml.) at -30° C., the resultant mixture was poured into a solution of ethyl acetate (200 ml) and water (200 ml.), and adjusted to pH 7.5 with sodium bicarbonate. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride and treated with activated charcoal. After concentrating the solution under reduced pressure, the residue was pulverized with diisopropyl ether and collected by filtration to give 4-nitrobenzyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-acetoxymethylenecepham-4-carboxylate (syn isomer, 2.7 g.).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)=[O:8])=[C:5]([CH3:20])[CH:4]=1.[CH3:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:39][CH:38]=2)=[CH:32][CH:31]=1>>[CH3:21][N:2]([CH3:1])[C:3]1[CH:19]=[CH:18][C:6]([C:7]2([N:36]([C:37]3[CH:38]=[CH:39][C:40]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:41][CH:42]=3)[C:33]3[CH:32]=[CH:31][C:30]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])=[CH:35][CH:34]=3)[C:9]3[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:11](=[O:13])[O:8]2)=[C:5]([CH3:20])[CH:4]=1
Reactant: CCCCCCCCc1ccc(Nc2ccc(CCCCCCCC)cc2)cc1
Reactant: Cc1cc(N(C)C)ccc1C(=O)c1ccccc1C(=O)O
Product: CCCCCCCCc1ccc(N(c2ccc(CCCCCCCC)cc2)C2(c3ccc(N(C)C)cc3C)OC(=O)c3ccccc32)cc1
Yield: 46.8 %

Procedure:
Following a procedure similar to that described in Example 1 but employing 5.7 g of 2-[4-(dimethylamino)-2-methylbenzoyl]benzoic acid and 8.0 g of 4,4'-dioctyldiphenylamine there was obtained 6.2 g of 3-[4-(dimethylamino)-2-methylphenyl]-3-[bis(4-octylphenyl)amino]phthalide, m.p. 172°-174° C. A toluene solution of the product contacted with acidic clay or phenolic resin developed a red-colored image.