Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([C:16](=O)[CH2:17]Br)=[C:11]([CH3:20])[CH:10]=2)=[CH:4][CH:3]=1.[NH2:21][C:22]([NH2:24])=[S:23]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([C:16]3[N:21]=[C:22]([NH2:24])[S:23][CH:17]=3)=[C:11]([CH3:20])[CH:10]=2)=[CH:4][CH:3]=1
Reactant: NC(N)=S
Reactant: Cc1cc(Nc2ccc(Br)cc2)cc(C)c1C(=O)CBr
Solvent: CC#N
Product: Cc1cc(Nc2ccc(Br)cc2)cc(C)c1-c1csc(N)n1
Yield: 73.5 %

Procedure:
A solution of 1-(4-(4-bromophenylamino)-2,6-dimethylphenyl)-2-bromoethanone (1.6 g, 4.0 mmol) and thiourea (0.79 g, 7.2 mmol) in acetonitrile (30 mL) was heated at reflux for 90 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (1.0 mL), and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give product (1.1 g), which was used directly for the next step without further purification.
Reaction SMILES: C(OC([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:24]([S:33]([C:36]2[CH:44]=[CH:43][C:39]([C:40]([OH:42])=[O:41])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.[ClH:45].O1CCOCC1>C(OCC)C>[ClH:45].[C:11]1([C@H:9]([NH:8][CH2:21][C@@H:22]2[C@@H:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][N:24]([S:33]([C:36]3[CH:44]=[CH:43][C:39]([C:40]([OH:42])=[O:41])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH2:23]2)[CH3:10])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(S(=O)(=O)c2ccc(C(=O)O)cc2)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: C[C@@H](NC[C@H]1CN(S(=O)(=O)c2ccc(C(=O)O)cc2)C[C@@H]1c1ccccc1)c1cccc2ccccc12

Procedure:
A 320 mg portion of 4-{[(3S,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]sulfonyl}benzoic acid was dissolved at room temperature in 3.0 ml of 4 M hydrogen chloride/1,4-dioxane solution and stirred for 24Hours. The reaction solution was diluted with diethyl ether and then concentrated under a reduced pressure, the thus obtained residue was dissolved in THF and mixed with diisopropyl ether, and the thus precipitated solid was collected by filtration and dried under a reduced pressure to obtain 183 mg of 4-{[(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]sulfonyl}benzoic acid hydrochloride as a colorless solid.
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:6])[CH2:2][C:3]([O-])=[O:4].C(Cl)(=O)C([Cl:18])=O>C(Cl)Cl.CN(C)C=O>[Cl:18][C:3](=[O:4])[CH2:2][C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: O=C([O-])CC(=O)OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of commercially available mono-benzyl malonate (Aldrich Chemical Co., Milwaukee, Wis.) (7.76 g, 40 mmol) in methylene chloride (100 mL) was added oxalyl chloride (14 mL, 160 mmol) followed by 3 drops of dimethylformamide. The reaction mixture was stirred at room temperature for 3 hours and concentrated in vacuo.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([Br:27])[CH:21]=1)[C:9]([NH2:18])=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:35][CH2:36][CH2:37][OH:38]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:35][CH2:36][CH2:37][OH:38])=[C:22]([Br:27])[CH:21]=1)[C:9]([NH2:18])=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: OCCCBr
Reactant: CC(C)(C)OC(=O)N=C(N)N(Cc1ccc(O)c(Br)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N=C(N)N(Cc1ccc(OCCCO)c(Br)c1)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of 1,2-bis(tert-butoxycarbonyl)-1-[3-bromo-4-hydroxybenzyl]-guanidine (for synthesis, see, for example, Purohit et al., International PCT Patent Publication No. WO2008/083056, incorporated herein by reference) (2.0 g, 4.51 mmol) dissolved in anhydrous DMF (45 mL) was added K2CO3 (1.12 g, 8.13 mmol), and 3-bromopropanol (816 mg, 5.87 mmol) and the reaction mixture warmed to 50° C. using an oil bath. After 2 h, the reaction mixture was diluted with water (30 mL), and the aqueous layer separated then extracted with EtOAc (3×100 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to a solid. The crude material was purified using silica gel chromatography (4:1 to 3:2 hexanes:EtOAc) to yield a white solid product (2.00 g, 88% yield). 1H NMR (CDCl3, 600 MHz): δ 9.42 (brs, 1H), 9.27 (brs, 1H), 7.54 (d, J=1.8 Hz, 1H), 7.26 (m, 1H), 6.85 (d, J=2.4 Hz, 1H), 5.08 (brs, 2H), 4.19 (t, J=5.4 Hz, 2H), 3.92 (m, 2H), 2.16 (m, 1H), 2.18 (m, 2H), 1.51 (s, 9H), 1.43 (s, 9H); 13C NMR (CDCl3, 150 MHz): δ 163.8, 160.8, 155.0, 154.3, 144.8, 133.1, 132.6, 127.9, 113.0, 111.7, 84.7, 79.2, 67.8, 60.6, 46.7, 31.9, 28.5, 28.3.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]([C:20]([OH:22])=O)=[CH:14]3)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl-].[Li+].[NH:25]1[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]1>>[O:31]=[S:28]1(=[O:32])[CH2:29][CH2:30][N:25]([C:20]([C:15]2[NH:16][C:17]3[C:13]([CH:14]=2)=[CH:12][C:11]([O:10][CH:7]2[CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8]2)=[CH:19][CH:18]=3)=[O:22])[CH2:26][CH2:27]1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)O)cc3c2)CC1
Reactant: O=S1(=O)CCNCC1
Agent: [Cl-]
Agent: [Li+]
Product: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 1, step 3, the title compound was synthesized from 5-(1-isopropyl-piperidin-4-yloxy)-1H-indole-2-carboxylic acid hydrochloric salt with one equivalent of lithium chloride (example 2, step 1) and thiomorpholine-1,1-dioxide (purchased at Syntec, ref. M1201). The title product was obtained in 75% yield as white solid. MS (m/e): 420.5 (MH+, 100%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][S:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1.S(=O)(=O)(O)O.[CH3:20]O>>[CH3:20][O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:6]([S:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][CH:8]=1
Reactant: COCCSc1ccc(C(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COCCSc1ccc(C(=O)OC)cc1
Yield: 78 %

Procedure:
4-(2-Methoxy-ethylsulfanyl)-benzoic acid was esterified in methanol by adding catalytic amount of sulfuric acid. Subsequent work up afforded 4 g of desired product in 78% yield.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=1[Cl:22])=O)(C)(C)C.[CH3:23][CH:24]([S:26]([C:29]1[CH:30]=[C:31]([C:35]2[N:43]3[C:38]([CH:39]=[N:40][C:41](O)=[N:42]3)=[CH:37][CH:36]=2)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27])[CH3:25]>>[Cl:22][C:16]1[CH:17]=[CH:18][C:19]([NH:21][C:41]2[N:40]=[CH:39][C:38]3=[CH:37][CH:36]=[C:35]([C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([S:26]([CH:24]([CH3:25])[CH3:23])(=[O:28])=[O:27])[CH:30]=4)[N:43]3[N:42]=2)=[CH:20][C:15]=1[O:14][CH2:13][C@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(N)ccc1Cl
Reactant: CC(C)S(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Product: CC(C)S(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(Cl)c(OC[C@H]5CCCN5)c4)nn23)c1

Procedure:
This example was prepared by using (R)-2-(5-Amino-2-chloro-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (J. Med. Chem. 2007, 50, 4353) and 7-[3-(Propane-2-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ol as described in Example 1255c followed by deprotection as described in Example 1223. 1H-NMR (DMSO) δ 9.7 (s, 1H), 9.5 (brs, 1H), 9 (s, 1H), 8.9 (brs, 1H), 8.5 (s, 1H), 8.4 (d, (d, J=7.5 Hz, 1H), 7.8 (m, 2H), 7.5 (d, J=8.7 Hz, 1H), 7.4 (m, 2H), 7.3 (d, J=4.8 Hz, 1H), 7 (d, J=4.8 Hz, 1H), 4.1 (m, 1H), 4.0 (m, 1H), 3.0 (brs, 1H), 3.5 (m, 2H), 3.2 (m, 2H), 2.0 (m, 2H), 1.9 (m, 1H), 1.7 (m, 1H), 1.1 (d, J=6.5 Hz, 6H); LC/MS (ESI+): 526 (M+H).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]#[C:33][CH3:34])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:31]([O:30][C:27]1[CH:28]=[CH:29][C:24]([S:21]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[CH2:10][CH2:11]2)(=[O:22])=[O:23])=[CH:25][CH:26]=1)[C:32]#[C:33][CH3:34]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(OC)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(OC)cc3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperdine-4-carboxylic acid was prepared starting from 4-(4-but-2-ynyloxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperdine-4-carboxylic acid ethyl ester (2.5 g, 5.15 mmol) dissolved in THF:methanol (3:1, 200 ml) and 10 N NaOH (15 ml). The resulting reaction mixture was worked up as outlined in Example 1 (Step 7). Yield 1.26 g (54%); off white solid; mp 223° C.; MS: 458 (M+H)+
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:6]=1[O:7][CH2:8][CH2:9]Br)(=[O:3])[CH3:2].[I-].[K+].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][NH:32][CH3:33])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>CN(C)C=O>[C:1]([NH:4][C:5]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:6]=1[O:7][CH2:8][CH2:9][N:32]([CH2:31][CH2:30][C:24]1[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=1)[CH3:33])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1OCCBr
Reactant: CNCCc1ccc(OC)c(OC)c1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CCN(C)CCOc2ccc([N+](=O)[O-])cc2NC(C)=O)cc1OC
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
A portion (440 mg, 1.46 mmol) of the 1-(2-acetamido-4-nitrophenoxy)-2-bromoethane produced in (2) above was dissolved in dimethylformamide (5 ml) and, thereafter, potassium iodide (267 mg, 1.608 mmol) and 2-(3,4-dimethoxyphenyl)-N-methylethylamine (0.81 ml, 4.36 mmol) were added to the solution, which was stirred at 70° C. for 1.5 h. Thereafter, the solvent was evaporated from the reaction mixture and the residue was subjected to extraction with ethyl acetate. The organic layer was washed with water four times and dried with sodium sulfate, followed by evaporation of the solvent, with the resulting residue being purified by being subjected to column chromatography on silica gel using, as an eluent, chloroform containing methanol (6%) to yield the end compound 1-(2-acetamido-4-nitrophenoxy)-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane (590 ml) as a yellow caramel-like substance.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].Cl[CH2:12][C:13]1[O:17][N:16]=[C:15]([CH2:18][S:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:14]=1>C[O-].[Na+].CO>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([S:19][CH2:18][C:15]2[N:14]=[C:13]([CH2:12][S:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[N:2]([CH3:10])[CH3:1])[O:17][N:16]=2)=[CH:21][CH:22]=1
Reactant: ClCc1nc(CSc2ccc(Cl)cc2)no1
Reactant: CN(C)c1ccccc1S
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN(C)c1ccccc1SCc1nc(CSc2ccc(Cl)cc2)no1

Procedure:
2-Dimethylaminobenzenethiol (1.67 g, 0.011 mol) was dissolved in a solution of sodium methoxide (0.59 g) in methanol (50 ml) and 5-chloromethyl-3-(4-chlorophenylthiomethyl)-1,2,4-oxadiazole (3.0 g 0.011 mol) was added dropwise with stirring. After a further 10 min. stirring the solution was filtered and evaporated to leave a brown oil, which was purified by chromatography on silica gel elution with hexane/ether (3:2) giving 3-(4-chlorophenylthiomethyl)-5-(2-dimethylaminophenylthiomethyl)-1,2,4-oxadiazole as a colourless oil, mass spectrum M+1 392; refractive index 1.6263.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9](=[O:16])[NH:10][O:11][CH2:12][C:13]([OH:15])=O)=[CH:3][CH:2]=1.[NH2:17][C@@H:18]([CH2:42][C:43]([NH:45][C:46]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[C:19]([N:21]([C@@H:33]([CH3:41])[CH:34]([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)=[O:20]>>[CH2:36]([O:35][CH:34]([O:38][CH2:39][CH3:40])[C@@H:33]([N:21]([CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[C:19](=[O:20])[C@@H:18]([NH:17][C:13](=[O:15])[CH2:12][O:11][NH:10][C:9]([NH:8][CH2:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)=[O:16])[CH2:42][C:43](=[O:44])[NH:45][C:46]([C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1)[CH3:41])[CH3:37]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)CONC(=O)NCc1ccncc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CONC(=O)NCc1ccncc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(pyridin-4-ylmethyl)ureidooxy)acetic acid (Compound VI-10) 52 mg (0.23 mmol) was coupled with (S)-2-amino-N1—((S)-1,1-diethoxypropan-2-yl)-N1-(naphthalen-1-ylmethyl)-N4-tritylsuccinamide (Compound IV-19) 100 mg (0.16 mmol) to obtain the title compound.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([I:13])[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[C:8]([I:13])[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1ccc(-n2ccnc2)cc1I
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc(-n4ccnc4)cc3I)c2cc1OC
Temperature: 140 °C
Reaction time: 7.5 h
Yield: 45.2 %

Procedure:
4-(Imidazol-1-yl)-2-iodophenol (123 mg), 4-chloro-6,7-dimethoxyquinoline (288 mg), and 4-dimethylaminopyridine (158 mg) were suspended in o-dichlorobenzene (3 ml), and the suspension was stirred at 140° C. for 7.5 hr. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure. The residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (92 mg, yield 45%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:5]=1.O.[NH2:24][NH2:25]>CO>[CH3:10][C:8]1[CH:7]=[C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:5]=[C:4]([C:3]([NH:24][NH2:25])=[O:2])[CH:9]=1
Reactant: COC(=O)c1cc(C)cc(Oc2cccc(C(F)(F)F)c2)n1
Reactant: NN
Solvent: O
Solvent: CO
Product: Cc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NN)c1

Procedure:
4-methyl-6-[3-(trifluoromethyl)phenoxy] picolinic acid methyl ester (0.507 g, 0.00163 mol) was dissolved in 10 ml of methanol, and then mixed with hydrazine monohydrate (0.816 g, 0.00163×10 mol). The resultant mixture was refluxed for about 3 hours. The obtained reaction solution was concentrated, and the obtained residues were distributed in ethyl acetate-saturated sodium bicarbonate water. The organic phase separated from the solution was washed with water and then dried with anhydrous sodium sulfate. After distilling off the solvent, the obtained residues were purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])C=O)([CH3:4])([CH3:3])[CH3:2].[C:18]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:19][C:20](O)=O.N1CCCCC1>N1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:15])([CH3:17])[CH3:16])[C:12]=1[OH:13])[CH:20]=[CH:19][C:18]([O:24][CH2:25][CH3:26])=[O:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC(=O)O
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CCOC(=O)C=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
Ethyl 3,5-di tert.butyl-4-hydroxycinnamate was prepared by heating a mixture of 33.0 grams of 3,5-di tert.butyl-4-hydroxybenzaldehyde, 55.0 grams of ethyl hydrogen malonate, 50 milliliters of pyridine, and 3 milliliters of piperidine at 90° to 95° C. for 7 hours. The reaction mixture was cooled to room temperature and the solid which precipitated was filtered off, washed with 5 percent hydrochloric acid, and dried. Thirty grams of product was obtained which melted at 149° to 152° C. Working up the filtrate yielded an additional 5.5 grams of product.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:12]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=3[O:10][C:9]=2[CH:18]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>CN(C)C=O.[I-].[K+]>[Cl:17][C:15]1[CH:14]=[CH:13][C:12]2[C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][N:19]4[CH:23]=[CH:22][N:21]=[CH:20]4)=[CH:18][C:9]=3[O:10][C:11]=2[CH:16]=1
Reactant: c1c[nH]cn1
Reactant: ClCCOc1ccc2c(c1)oc1cc(Cl)ccc12
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc2c(c1)oc1cc(OCCn3ccnc3)ccc12
Temperature: 110 °C
Reaction time: 16 h
Yield: 70.3 %

Procedure:
0.5 g of potassium iodide was added to 19.6 g (0.06 mole) of 1-chloro-2-(7-chlorodibenzofuran-3-yloxy)-ethane and 16.4 g (0.24 mole) of imidazole in 50 ml of dimethylformamide, and the mixture was stirred for 16 hours at 110° C., cooled and then evaporated down under reduced pressure. The residue was partitioned between 100 ml of water and 1 liter of methylene chloride, and 20 ml of 50% strength sodium hydroxide solution were added, while cooling with ice. The organic layer was separated off, washed with three times 50 ml of water, dried, and evaporated down under reduced pressure. The solid, colorless residue was left to stand with 15 ml of ether at +5° C. for 1 hour, after which it was filtered off under suction and washed with 20 ml of cold n-pentane. 13.2 g (70.4% of theory) of N-[2-(7-chlorodibenzofuran-3-yloxy)-ethyl]-imidazole of melting point 150°-151° C. were obtained.
Reaction SMILES: C([CH:3]([C:26]([OH:28])=[O:27])[N:4]([C:16](OCC1C=CC=CC=1)=O)[CH2:5][P:6]([CH:12]([CH2:14][CH3:15])[CH3:13])([CH:8]([CH2:10][CH3:11])[CH3:9])=[S:7])C.Br.[CH3:30]COCC>C(O)(=O)C>[CH2:16]([N:4]([CH2:5][P:6]([CH:12]([CH2:14][CH3:15])[CH3:13])([CH:8]([CH2:10][CH3:11])[CH3:9])=[S:7])[CH2:3][C:26]([OH:28])=[O:27])[CH3:30]
Reactant: CCOCC
Reactant: CCC(C(=O)O)N(CP(=S)(C(C)CC)C(C)CC)C(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: CCC(C)P(=S)(CN(CC)CC(=O)O)C(C)CC
Reaction time: 1 h

Procedure:
Ethyl N-carbobenzoxy-N-(di-sec-butylthiophosphinylmethyl)glycine (1 g., 0.0023 mole) was dissolved in 5 ml. of 30% hydrogen bromide in glacial acetic acid at 0° C. The mixture was stirred for one hour. Ether was added and the oily precipitate isolated by decanting the ether layer. The oil was washed twice with ether and then suspended in benzene and treated with propylene oxide. The solution was concentrated in vacuo to yield ethyl N-(di-sec-butylthiophosphinylmethyl)-glycine (0.04 g., 0.001 mole) as an oil, ND25 =1.3450.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8].[N-:15]=[N+]=[N-].[Na+]>CO.C(O)C>[N+:7]1([O-:9])[O:8][N:15]=[C:2]2[S:3][C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][C:6]=12
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(Br)s1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CCOC(=O)c1cc2c(no[n+]2[O-])s1
Temperature: 70 °C
Yield: 33.7 %

Procedure:
A suspension of 25.0 g (90 mmol) of ethyl 2-bromo-3-nitro-5-thiophenecarboxylate (Tetrahedron 21 (1965) 1061) and 29.0 g (450 mmol) of sodium azide in 300 ml of methanol is stirred at room temperature for 4 hours in 300 ml of ethanol. The mixture is poured into 4 l of ice-water, the precipitate is filtered off and the residue is heated at 70° C. for 3 hours in 700 ml of toluene. Subsequent purification by flash chromatography yields 6.5 g (34%) of ethyl thieno[2,3-c][1,2,5]oxadiazole-5-carboxylate-1-oxide and -3-oxide, m.p. 72°-74° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([C:16]2[N:17]=[CH:18][C:19]3[N:24]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[S:22][C:20]=3[N:21]=2)[CH3:15])[CH:11]=[CH:10][C:9]=1[F:29])(C)(C)C.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[NH2:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:15])[C:16]2[N:17]=[CH:18][C:19]3[N:24]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[S:22][C:20]=3[N:21]=2)[CH:11]=[CH:10][C:9]=1[F:29]
Reactant: CC(=O)Nc1nc2cnc(N(C)c3ccc(F)c(NC(=O)OC(C)(C)C)c3)nc2s1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nc2cnc(N(C)c3ccc(F)c(N)c3)nc2s1
Yield: 90 %

Procedure:
A solution of the above-mentioned crude product of tert-butyl(5-{[2-(acetylamino)[1,3]thiazolo[5,4-d]pyrimidin-5-yl](methyl)amino}-2-fluorophenyl)carbamate and anisole (1.5 mL) in trifluoroacetic acid (15 mL) was stirred at 0° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, to the obtained residue was added saturated aqueous sodium hydrogen carbonate solution (50 mL), and the mixture was extracted with ethyl acetate/tetrahydrofuran mixture (1:1, 50 mL, 20 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound (638 mg, 90%) as a gray solid.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[C:11]([C:15]1[CH:16]=[C:17]([C:26]2[N:27]=[C:28]3[N:32]([CH:33]=2)[CH2:31][CH2:30][S:29]3)[CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[C:11]([C:15]1[CH:16]=[C:17]([C:26]2[N:27]=[C:28]3[N:32]([C:33]=2[CH:3]=[O:4])[CH2:31][CH2:30][S:29]3)[CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1cc(-c2cn3c(n2)SCC3)cc(C(C)(C)C)c1O
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(-c2nc3n(c2C=O)CCS3)cc(C(C)(C)C)c1O
Reaction time: 1 h

Procedure:
To a solution of 1.5 ml of dimethylformamide in 10 ml of chloroform was added 1.1 g of phosphorus oxychloride under ice-cooling and the mixture was allowed to stand for one hour. To the reaction mixture was added 1.5 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole and the mixture was refluxed for 4 hours. To the reaction mixture was added 20 ml of an aqueous 10% potassium carbonate solution and the mixture was stirred for 15 minutes. The chloroform layer was dried and concentrated. The crystals thus obtained were recrystallized from ethanol to provide 1.0 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-formyl-2,3-dihydroimidazo[2,1-b]thiazole.