Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([CH3:19])[CH:4]=1)=O.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][NH2:29])=[CH:23][CH:22]=1.[BH4-].[Na+]>CO>[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][NH:29][CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=3)=[C:5]([CH3:19])[CH:4]=2)=[CH:23][CH:22]=1
Reactant: NCCc1ccc(F)cc1
Reactant: Cc1cc(C=O)ccc1Oc1cnc(C(N)=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(CNCCc2ccc(F)cc2)ccc1Oc1cnc(C(N)=O)cn1
Reaction time: 8 h
Yield: 53.9 %

Procedure:
Place 5-(4-formyl-2-methylphenoxy)pyrazine-2-carboxamide (Example 404, part D) (0.600 g, 2.33 mmol), 2-(4-fluorophenyl)ethylamine (0.325 g, 2.33 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (11.7 mL), cap and stir overnight. Add NaBH4 (0.088 g, 2.33 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 5% to 20% (2.0 M NH3 in methanol) in ethyl acetate. Concentrate the fraction containing the product, then take it up in EtOAc (100 mL). Wash the organic solution with 1.0 N NaOH (2×25 mL), dry it over Na2SO4 and concentrate it to give the title compound (0.478 g, 54.0%): TOF MS ES+ 381.2 (M+H)+, HRMS calcd for C21H22N4O2F 381.1727 (M+H)+, found 381.1729, time 0.39 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=11.3 min, 97.8% purity.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29]([C:33]([OH:35])=[O:34])=[CH:28][CH:27]=[CH:26]2.[OH-].[K+].O>CS(C)=O>[CH2:15]([O:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([O:22][C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[C:29]([C:33]([OH:35])=[O:34])=[CH:28][CH:27]=[CH:26]4)=[CH:3][CH:4]=[N:5]2)=[CH:10][C:9]=1[O:12][CH3:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1cccc2cc(O)ccc12
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2c(Oc3ccc4c(C(=O)O)cccc4c3)ccnc2cc1OCc1ccccc1
Temperature: 130 °C
Yield: 62 %

Procedure:
4-Chloro-7-benzyloxy-6-methoxy-quinoline (3 g) was mixed with 6-Hydroxy-1-naphthoic acid (2 g) and KOH (2.5 g) in DMSO (11 ml). The mixture was heated at 130° C. for 5 hours and cooled to RT. The reaction was then poured into a stirred water (60 ml) solution slowly to give a precipitate that was filtered to give 6-(7-(benzyloxy)-6-methoxyquinolin-4-yloxy)-1-naphthoic acid (2.8 g). This product was mixed with MeNH2—HCl (2 g), EDC (3.3 g), HOBt (2 g) and DIPEA (4 ml) in DCM (80 ml). The reaction was stirred at RT overnight and washed with NaHCO3 solution, dried. The solution was evaporated and purified with silica gel column to give 6-(7-(benzyloxy)-6-methoxyquinolin-4-yloxy)-N-methyl-1-naphthamide. The title compound then was prepared according to the same procedures described in Method A.
Reaction SMILES: O1C2C=CC=CC=2C=C1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=O)[CH:17]=2)[N:12]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[N:11]=1.Cl.CN(C)[CH2:31][CH2:32][CH2:33]N=C=NCC.[CH:40]([NH2:43])([CH3:42])[CH3:41]>CN(C)C=O>[O:23]1[C:22]2[CH:27]=[CH:26][CH:33]=[CH:32][C:31]=2[CH:25]=[C:24]1[CH:27]1[CH2:26][CH2:25][CH2:24][O:23][CH:22]1[N:12]1[C:13]2[C:18](=[CH:17][C:16]([C:19]([NH:43][CH:40]([CH3:42])[CH3:41])=[O:21])=[CH:15][CH:14]=2)[CH:10]=[N:11]1
Reactant: O=C(O)c1ccc2c(c1)c(-c1cc3ccccc3o1)nn2C1CCCCO1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)N
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1ccc2c(cnn2C2OCCCC2c2cc3ccccc3o2)c1
Reaction time: 48 h
Yield: 199.2 %

Procedure:
To solution of 3-benzo[d]furan-2-yl-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxylic acid (190 mg, 0.52 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (109.3 mg, 0.57 mmol) in dimethylformamide was added isopropylamine (48 μL, 0.57 mmol) and the mixture allowed to stir under a nitrogen atmosphere for two days. An additional 2 equivalents of isopropylamine was added to the reaction and allowed to stir for another day. Solvent was removed and the reaction was extracted with ethyl acetate. The crude material was purified by preparative HPLC to yield the title compound (209 mg, 81% yield). ES-MS (m/z) 404 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:16])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[H-].[Na+].Cl[CH2:20][C:21]1[N:22]=[CH:23][S:24][CH:25]=1>O1CCCC1.O>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([O:16][CH2:20][C:21]1[N:22]=[CH:23][S:24][CH:25]=1)[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: ClCc1cscn1
Reactant: OC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cl
Product: Clc1ccc(C(Cn2ccnc2)OCc2cscn2)c(Cl)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 92.6 %

Procedure:
A solution of 1-(2,4-dichloro-phenyl)-2-(1-imidazolyl) ethanol (2.4 g, 9.4 mmole) in dry tetrahydrofuran (20 ml) was added to sodium hydride (0.62 g, as an 80% dispersion in oil, 0.02 mole) and warmed at 70° C for 90 minutes. The solution was cooled to 0° C and 4-chloromethylthiazole (1.5 g, 11.2 mmole), dissolved in a little dry tetrahydrofuran, was added. The mixture was stirred at 0° C for 1 hour and at room temperature for 6 hours. Further 4-chloromethylthiazole (0.25 g) was added and the stirring continued for 36 hours. The reaction mixture was then diluted with water (70 ml) and extracted several times with ether. The ether extracts were combined, dried over MgSO4 and evaporated. The oily residue was taken up in dry ether (50 ml) and treated with a solution of HCl in ether. The solid precipitate was collected and recrystallized from a mixture of methanol and di-isopropyl ether to give 1-[2,4-dichloro-β-(4-thiazolylmethoxy) phenethyl]imidazole hydrochloride (1.7 g, 46%) m.p. 183°-184°. (Found: C, 46.3; H, 3.7; N, 10.7. C15H13N3Cl2OS.HCl requires C, 46.1; H, 3.6; N, 10.7%).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH2:24][C@@H:25]([N:27]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[C:46]2[N:50]([C:51]([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[N:49]=[N:48][N:47]=2)=[CH:36][CH:35]=1)[C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[CH3:26].O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH3:26][C@H:25]([N:27]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[C:46]2[N:50]([C:51]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)([C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)[C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)[N:49]=[N:48][N:47]=2)=[CH:38][CH:39]=1)[C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[CH:24]=[O:23]
Reactant: CCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)[C@@H](C)CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)[C@@H](C)C=O
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
Dess-Martin periodinane (971 mg, 2.3 mmol) was added to a solution of intermediate (5b) (474 mg, 0.8 mmol) in DCM (20 mL) at room temperature. After 30 minutes, water (20 mL) and saturated aqueous sodium thiosulfate (20 mL) was added. The mixture was extracted with DCM (3×30 mL), washed with saturated aqueous NaCl (20 mL), dried over MgSO4, and concentrated in vacuo. Silica gel chromatography gave intermediate (5c) as a white solid (411 mg).
Reaction SMILES: C[O:2][C:3]1[CH:10]=[C:9]([O:11]C)[C:8]([N+:13]([O-:15])=[O:14])=[CH:7][C:4]=1[CH:5]=[O:6].C[S-].[Na+]>CN(C)C(=O)C.O>[OH:2][C:3]1[CH:10]=[C:9]([OH:11])[C:8]([N+:13]([O-:15])=[O:14])=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: COc1cc(OC)c([N+](=O)[O-])cc1C=O
Agent: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=Cc1cc([N+](=O)[O-])c(O)cc1O
Temperature: 80 °C

Procedure:
2,4-dimethoxy-5-nitro-benzaldehyde (135 mg, 0.638 mmol) and sodium methanethiolate (125 mg, 1.78 mmol) are dissolved in 4 ml of N,N-dimethylacetamide and heated at 80° C. for 26 h. The reaction mixture is diluted to 50 ml with water and extracted with dichloromethane. The aqueous layer is then acidified with 5% HCl and extracted again with dichloromethane. All of the organic layers are dried over Na2SO41 concentrated, and purified using silica gel chromatography (100% dichloromethane to 30% acetone in dichloromethane) to yield 2,4-dihydroxy-5-nitro-benzaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[C:10](O)(=O)[CH2:11][SH:12].[OH-:15].[K+]>C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:10][C:11]([OH:15])=[S:12])[CH:7]=[CH:8][CH:9]=1
Reactant: BrCc1cccc(Br)c1
Reactant: O=C(O)CS
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: OC(=S)CCc1cccc(Br)c1
Yield: 92 %

Procedure:
To a solution of 3-bromobenzyl bromide (23.75 g, 90 mmol) and thioglycolic acid (11.42 g, 120 mmol) in ethanol (150 mL) was added potassium hydroxide (14.24 g, 250 mmol) in water (50 mL). The reaction was heated at reflux for 3.5 h, cooled and the ethanol was evaporated. The residue was quenched with water (100 mL) and the mixture was extracted with ether (50 mL). The aqueous layer was acidified to pH 1 with concentrated hydrochloric acid, extracted with ethyl acetate (2×100 mL) and the organic phase was dried. Evaporation of the solvent followed by washing of the residue with hexane afforded 3-bromophenylmethylthioacetic acid as a white solid (92%), mp 90°-91 ° C.: 1H NMR (CDCl3) δ3.10 (s, 2H), 3.82 (s, 2H), 7.20-7.29 (m, 2H), 7.39-7.42 (dd, 1H), 7.52 (d, 1H); IR (KBr) 1706 cm-1 ; Mass spectrum m/z 280 (M+NH4); Anal. calcd. for C9H9O2SBr: C 41,39, H 3.47, S 12.28; Found C 41.43, H 3.49, S 12.10.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[N+](C1C=CC([C:16]2[C:24]([CH2:25][C@H:26]3[C@@H:31]([OH:32])[C:30]4[CH:33]=[C:34]([O:37][CH2:38][C:39]5[S:40][C:41]6[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:42]=6[N:43]=5)[CH:35]=[CH:36][C:29]=4[O:28][CH2:27]3)=[CH:23][CH:22]=[CH:21][C:17]=2[C:18]([O-])=[O:19])=CC=1)([O-])=O>>[F:48][C:45]1[CH:46]=[CH:47][C:41]2[S:40][C:39]([CH2:38][O:37][C:34]3[CH:35]=[CH:36][C:29]4[O:28][CH2:27][C@@H:26]([CH2:25][C:24]5[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=5)[C:18]([NH:1][C:2]5[S:3][CH:4]=[CH:5][N:6]=5)=[O:19])[C@@H:31]([OH:32])[C:30]=4[CH:33]=3)=[N:43][C:42]=2[CH:44]=1
Reactant: O=C([O-])c1cccc(C[C@@H]2COc3ccc(OCc4nc5cc(F)ccc5s4)cc3[C@@H]2O)c1-c1ccc([N+](=O)[O-])cc1
Reactant: Nc1nccs1
Product: O=C(Nc1nccs1)c1cccc(C[C@@H]2COc3ccc(OCc4nc5cc(F)ccc5s4)cc3[C@@H]2O)c1
Yield: 13.3 %

Procedure:
Synthesis was carried out as in example 1, but using 1.43 grams 2-aminothiazole instead of methane sulfonamide, and using 1.17 grams cis-4-nitrophenyl-3-[[6-[(5-fluoro-2-benzothiazolyl)methoxy]-3,4-dihydro-4-hydroxy-2H-1-benzopyran-3-yl]methyl]benzoate. There was obtained 145 milligrams of product, m.p. 120° C.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].C[O-].[Na+].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1>CO>[CH2:1]([C:5]1[N:6]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCc1nc(Cl)c(C=O)n1-c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 29.8 %

Procedure:
2-n-Butyl-4-chloroimidazole-5-carboxaldehyde (10.00 g, 53.6 mmol, 1 eq.) was dissolved in a freshly prepared solution of sodium methoxide (1.23 g Na, 53.6 mmol, 1 eq.) in methanol (175 mL). The methanol was removed in vacuo and replaced with DMF (100 mL). 4-Fluoro-1-nitrobenzene (11.37 mL, 107.0 mmol, 2 eq.) was then added. The mixture was heated at 100° C. for 36 h. Two more equivalents of 4-fluoro-1-nitrobenzene were then added and the mixture heated at 100° C. for an additional 48 hours. The DMF was removed in vacuo and the residue partitioned between ethyl acetate and water. The aqueous phase was extracted twice more with ethyl acetate, the organic layers combined, dried (MgSO4) and the solvent removed in vacuo. Flash chromatography of the residue over silica gel in 9:1 toluene/ethyl acetate yielded 4.92 g (30%) of an amber oil. NMR (CDCl3): δ 9.74 (s, 1); 8.42 (d, 2H, J=9Hz); 7.46 (d, 2H, J=9Hz); 2.51 (t, 2H, J=7Hz); 1.67 (t of t, 2H, J=7,7Hz); 1.30 (t of q, 2H, J=7,7Hz); 0.84 (t, 3H, J=7Hz). Anal. calcd. for C14H14ClN3O3 : C, 54.64; H, 4.59; Cl, 11.52, N, 13.65. Found: C, 54.91; H, 4.67; Cl, 11.20; N, 13.62.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[OH-].[Na+].C[SH-][C:13]([SH-]C)=[N:14][C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1>CN(C=O)C.O>[S:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[NH:14][C:13]1[O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1ccccc1O
Reactant: C[SH-]C(=Nc1nc2ccccc2s1)[SH-]C
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2oc(Nc3nc4ccccc4s3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
2-aminophenol (21.8 g (0.20 mol)) was dissolved in 944 g of DMF, thereto was added 40 mL of 5 mol/L aqueous sodium hydroxide solution (equivalent to 0.20 mol of sodium hydroxide), the resulting mixture was stirred at room temperature for 30 minutes, and then thereto was added a solution obtained by dissolving 50.9 g (0.20 mol) of the obtained S,S′-dimethyl-N-(2-benzothiazolyl)carbonimidodithioate in 1416 g of DMF. The resulting mixture was then heated to 153° C., refluxed under a nitrogen atmosphere for 6 hours, and then cooled to room temperature, and the reaction liquid was added dropwise in 2000 g of water. A precipitate was filtered off, washed with water, and dried to obtain 30.0 g of 2-(2-benzothiazolylamino)benzoxazole (L5: see Table 1 below). The yield was 56.1% based on 2-aminophenol.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([N:15]2[C:19]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=4)[N:22]([CH3:30])[CH:21]=3)=[N:18][NH:17][C:16]2=[O:31])=[CH:6]1.[NH2:32][C:33]([NH2:35])=[S:34]>C(O)C>[BrH:1].[F:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][CH2:3][CH2:2][S:34][C:33](=[NH:32])[NH2:35])[CH:6]=[C:7]2[N:15]1[C:16](=[O:31])[NH:17][N:18]=[C:19]1[C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=2)[N:22]([CH3:30])[CH:21]=1
Reactant: NC(N)=S
Reactant: Cn1cc(-c2n[nH]c(=O)n2-c2cn(CCCBr)c3ccc(F)cc23)c2cc(F)ccc21
Solvent: CCO
Product: Br
Product: Cn1cc(-c2n[nH]c(=O)n2-c2cn(CCCSC(=N)N)c3ccc(F)cc23)c2cc(F)ccc21
Temperature: 75 °C
Reaction time: 4 h
Yield: 83.4 %

Procedure:
In a vial was added the compound obtained in Example 18 (0.064 g, 0.13 mmol), thiourea (0.030 g, 0.39 mmol) and ethanol (99.5%, 1.5 mL). The vial was sealed and heated with stirring at 75° C. for 4 hours. The solvent was evaporated and the residue was purified on silica (dichloromethane-methanol, 95:5 to 90:10), giving 0.061 g (82%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH2:4].[CH2:10]([N:12]([CH2:15][CH2:16]Cl)[CH2:13][CH3:14])[CH3:11].Cl[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21].C(COC)OC>C(N(CC)CC)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[N:4]([CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21])[CH2:11][CH2:10][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14]
Reactant: Nc1cc(Cl)ccc1Cl
Reactant: O=C(CCl)c1ccccc1
Reactant: CCN(CC)CCCl
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CCN(CC)CCN(CC(=O)c1ccccc1)c1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 0.05 mole of N-(2,5-dichlorophenyl)-N',N'-diethylethylenediamine obtained by alkylating 2,5-dichloroaniline with N,N-diethyl-β-chloroethylamine, and 0.05 mole of 2-chloroacetophenone in dimethoxyethane containing 0.05 mole of triethylamine was stirred at room temperature for 24 hours under a nitrogen atmosphere after which the solvent was removed at reduced pressure. The residue was dissolved in 200 ml of chloroform and washed with 5% aqueous sodium carbonate, dried over sodium sulfate and evaporated to dryness to give 2-[N-(2,5-dichlorophenyl)-N-(β-diethylaminoethyl)amino]acetophenone.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[C:7]2[C:12]([C:13]=1[C:14](=[O:25])[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=1)=[CH:11][CH:10]=[C:9]([O:26][CH3:27])[CH:8]=2)=O.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[F:24][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[F:23])[CH2:16][NH:15][C:14]([C:13]1[C:12]2[C:7](=[CH:8][C:9]([O:26][CH3:27])=[CH:10][CH:11]=2)[N:6]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[C:5]=1[CH:3]=[O:2])=[O:25]
Reactant: COC(=O)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OC)cc2n1Cc1ccccn1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: COc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C=O)n(Cc3ccccn3)c2c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
General Procedure O. To a solution of methyl3-(3,4-difluorobenzylcarbamoyl)-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylate (Compound 93, 515 mg, 1.11 mmol) in CH2Cl2 (20 ml) at −78° C. was added DIBAL (1 M in CH2Cl2, 4.4 ml, 4.44 mmol) slowly. The reaction was stirred at −78° C. for 2 h, quenched with H2O, diluted with EtOAc, washed with NaOH and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound as a beige solid.
Reaction SMILES: CI.[C:3]([O:6][CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18](=[S:25])[NH:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][CH:9]=1)(=[O:5])[CH3:4].[CH3:26]C(C)([O-])C.[K+]>C1COCC1.COC(C)(C)C>[C:3]([O:6][CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](/[C:18](/[S:25][CH3:26])=[N:19]/[CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][CH:9]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)OCc1ccc(C(=S)NC[Si](C)(C)C)c2ccccc12
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Solvent: COC(C)(C)C
Product: CS/C(=N\C[Si](C)(C)C)c1ccc(COC(C)=O)c2ccccc12
Reaction time: 0.33 h
Yield: 88.1 %

Procedure:
To a mixed solution of methyl iodide (0.60 g) and (4{[(trimethylsilyl)methyl]carbamothioyl}naphthalen-1-yl)methyl acetate (1.2 g) in THF (30 ml) was added potassium t-butoxide (0.45 g) gradually, and the mixture was stirred for 20 minutes at the same temperature. The mixture was diluted with t-butyl methyl ether and washed with water and a saturated aqueous brine, subsequently dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, to obtain {4-[(Z)-(methylsulfanyl){[(trimethylsilyl)methyl]imino}methyl]naphthalen-1-yl}methyl acetate (1.1 g).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:15]([OH:17])=O)[N:13]=1)=[O:7].[CH3:30][N+:31]([CH3:34])=[CH:32][Cl:33].[Cl-].C[Si](CC(N)=O)(C)C.[NH2:44][CH:45]1[C:63](=[O:64])[N:47]2[C:48]([C:60]([OH:62])=[O:61])=[C:49]([CH2:52][S:53][C:54]3[N:58]([CH3:59])[N:57]=[N:56][N:55]=3)[CH2:50][S:51][C@H:46]12>C(OCC)(=O)C.O.CN(C)C=O>[CH3:30][N+:31]([CH3:34])=[CH:32][Cl:33].[Cl-:3].[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:15]([NH:44][CH:45]2[C:63](=[O:64])[N:47]3[C:48]([C:60]([OH:62])=[O:61])=[C:49]([CH2:52][S:53][C:54]4[N:58]([CH3:59])[N:57]=[N:56][N:55]=4)[CH2:50][S:51][C@H:46]23)=[O:17])[N:13]=1)=[O:7]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)NCCON=C(C(=O)O)c1csc(NC=O)n1
Agent: C[N+](C)=CCl
Agent: C[Si](C)(C)CC(N)=O
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCNC(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Vilsmeier reagent was prepared from N,N-dimethylformamide (0.45 g.) and phosphoryl chloride (1.03 g.) in a usual manner. 2-(2-Formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetic acid (syn isomer, 2.0 g.) was added to the stirred suspension of the Vilsmeier reagent in ethyl acetate (40 ml.) under ice cooling and stirred at the same temperature for 30 minutes [Solution A]. Trimethylsilylacetamide (5.9 g.) was added to a stirred suspension of 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.8 g.) in ethyl acetate (30 ml.), and the mixture was stirred at the room temperature for 30 minutes. To the solution was added the solution A all at once at -30° C., and the resultant solution was stirred at -10° to -40° C. for an hour. Water and ethyl acetate (100 ml.) were added to reaction mixture at -10° C. and, the ethyl acetate layer was separated. Water (100 ml.) was added to the ethyl acetate solution, and adjusted to pH 7.0 with a saturated sodium bicarbonate aqueous solution. After the aqueous layer was separated, ethyl acetate was added thereto. The mixture was adjusted to pH 3.0 with 10% hydrochloric acid under ice-cooling. The ethyl acetate layer was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate and evaporated in vacuo. The residue was pulverized with diisopropyl ether, collected by filtration to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 2.8 g.).
Reaction SMILES: C1C(/C=C/C(C2C=CC(O)=CC=2O)=O)=CC=C(O)C=1.C1C([C@H]2OC3C=C(O)C=CC=3C(=O)C2)=CC=C(O)C=1.[CH:39]1[C:44]([C@H:45]2[O:55][C:54]3[CH:53]=[C:52]([OH:56])[CH:51]=[C:50]([OH:57])[C:49]=3[C:47](=[O:48])[CH2:46]2)=[CH:43][CH:42]=[C:41]([OH:58])[CH:40]=1.C1C(C2C(=O)C3C(O)=CC(O)=CC=3OC=2)=CC=C(O)C=1>>[CH:39]1[C:44](/[CH:45]=[CH:46]/[C:47]([C:49]2[C:50]([OH:57])=[CH:51][C:52]([OH:56])=[CH:53][C:54]=2[OH:55])=[O:48])=[CH:43][CH:42]=[C:41]([OH:58])[CH:40]=1
Reactant: O=C1C[C@@H](c2ccc(O)cc2)Oc2cc(O)cc(O)c21
Agent: O=C(/C=C/c1ccc(O)cc1)c1ccc(O)cc1O
Agent: O=C1C[C@@H](c2ccc(O)cc2)Oc2cc(O)ccc21
Agent: O=c1c(-c2ccc(O)cc2)coc2cc(O)cc(O)c12
Product: O=C(/C=C/c1ccc(O)cc1)c1c(O)cc(O)cc1O

Procedure:
Isoliquiritigenin, liquiritigenin, naringenin and genistein were purchased from Indofine Chemical Co. (Hillsborough, N.J.). Naringenin chalcone was prepared from naringenin as previously described (Shimokoriyama, 1957).
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:23][CH2:22]3)[CH2:17][CH2:16]2)=[C:7]([F:24])[CH:6]=1)C.[OH-].[Na+]>O1CCOCC1>[CH:21]1([N:18]2[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][CH2:12][O:11][C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:25])=[O:3])=[CH:6][C:7]=3[F:24])[CH2:20][CH2:19]2)[CH2:23][CH2:22]1
Reactant: CCOC(=O)c1ccc(OCCCN2CCN(C3CC3)CC2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(OCCCN2CCN(C3CC3)CC2)c(F)c1
Temperature: 60 °C
Yield: 100 %

Procedure:
4-[3-(4-Cyclopropyl-piperazin-1-yl)-propoxy]-3-fluoro-benzoic acid ethyl ester from Example E48.2 (1.0 g, 2.9 mmol) was dissolved in dioxan (10 ml) and 2N NaOH solution (3 ml, 6.0 mmol) was added. The mixture was heated at 60° C. for 18 h then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 1% 35% ammonia:19% methanol:80% dichloro-methane) to yield the title compound (920 mg, 100%).