Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.CN([C:11](N(C)C)=[N+:12]1[C:16]2C=CC(Cl)=C[C:15]=2[N+:14]([O-])=N1)C.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34](=[O:61])[C:35]1[CH:40]=[CH:39][C:38]([CH2:41][N:42]([CH2:55][CH2:56][CH2:57][N:58]([CH3:60])[CH3:59])[C:43]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]([OH:54])=O)=[CH:48][CH:47]=2)=[O:44])=[CH:37][CH:36]=1.[CH3:62]NN(NC)CCN.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34](=[O:61])[C:35]1[CH:36]=[CH:37][C:38]([CH2:41][N:42]([CH2:55][CH2:56][CH2:57][N:58]([CH3:60])[CH3:59])[C:43]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]([NH:14][CH2:15][CH2:16][N:12]([CH3:11])[CH3:62])=[O:54])=[CH:48][CH:47]=2)=[O:44])=[CH:39][CH:40]=1
Reactant: CNN(CCN)NC
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2cc(Cl)ccc21
Reactant: CN(C)CCCN(Cc1ccc(C(=O)Nc2ccccc2N)cc1)C(=O)Nc1ccc(C(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCCN(Cc1ccc(C(=O)Nc2ccccc2N)cc1)C(=O)Nc1ccc(C(=O)NCCN(C)C)cc1
Yield: 57 %

Procedure:
1-[Bis(dimethylamino)methylene]-5-chloro-1H-benzo triazolium 3-oxide hexafluorophosphate (49 mg, 0.067 mmol) was added to a suspension of N-(2-aminophenyl)-4-[3-(4-carboxyphenyl)-1-(3-dimethylaminopropyl)ureidomethyl]benzamide (Compound No. 4-1, 33 mg, 0.067 mmol), N,N-dimethylaminoethylenediamine (0.30 mL, 2.8 mmol) and N,N-diisopropylethylamine (0.023 mL, 0.13 mmol) in DMF (5.0 mL), and then the mixture was stirred at room temperature for 80 minutes. Saturated aqueous sodium hydrogen carbonate solution (30 mL) was added thereto, the whole was extracted with ethyl acetate (20 mL) twice, and then the organic layer was washed with brine (30 mL) twice. The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to give 21 mg of the title compound as colorless oil. (Yield 57%)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[BH4-].[Na+].O>C(O)C>[CH2:22]([NH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:13]1[CH2:12][CH2:11][CH:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:15][CH2:14]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCCCN)CC1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC1CCN(CCCCCNCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
A solution (150 ml) of 5-(4-tert-butoxycarbonylaminomethylpiperidin-1-yl)pentylamine (5.0 g) and benzaldehyde (2.0 g) in ethanol was stirred at 70° C. for 3 hr. After cooling, sodium borohydride (1.40 g) was added, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 3.7 g of N-benzyl-5-(4-tert-butoxycarbonylaminomethylpiperidin-1-yl)pentylamine.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:20]1([C:26]2[N:27]=[C:28]([NH:31][C:32](=[O:37])[CH2:33][C:34]([OH:36])=O)[S:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.Cl.Cl.[N:51]1([C:57]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]([F:68])([F:67])[F:66])=[O:58])[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1>CN(C=O)C.O>[O:36]=[C:34]([N:54]1[CH2:55][CH2:56][N:51]([C:57](=[O:58])[C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]([F:68])([F:66])[F:67])[CH2:52][CH2:53]1)[CH2:33][C:32]([NH:31][C:28]1[S:29][CH:30]=[C:26]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:27]=1)=[O:37]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: O=C(O)CC(=O)Nc1nc(-c2ccccc2)cs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)Nc1nc(-c2ccccc2)cs1
Temperature: 10 °C
Reaction time: 8 h
Yield: 14.4 %

Procedure:
HOBt (38 mg, 0.29 mmol) and DIEA (111 mg, 0.85 mmol) were added to a stirred solution of N-(4-phenyl-thiazol-2-yl)-malonamic acid (75 mg, 0.29 mmol) in DMF (1.5 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (66 mg, 0.34 mmol) followed by piperazin-1-yl-(2-trifluoromethyl-phenyl)-methanone hydrochloride (92 mg, 0.3 mmol) were added. The reaction mixture was stirred at room temperature overnight then diluted with water and the product extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate and brine solution, dried over Na2SO4 and concentrated to afford 21 mg (13%) of 3-Oxo-N-(4-phenyl-thiazol-2-yl)-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionamide. LCMS: 503.13 (M+1)+, 97.4%, 1H NMR: (CDCl3): δ 7.85 (d, 2H), 7.74 (d, 1H), 7.6 (m, 2H), 7.4 (td, 2H), 7.33 (m, 2H), 7.15 (d, 1H), 4.02 (m, 2H), 3.7 (m, 4H), 3.52 (m, 2H), 3.24 (m, 2H).
Reaction SMILES: [OH:1][C:2]([CH:4]([C:6]1[CH:15]=[CH:14][C:9]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:8][CH:7]=1)[CH3:5])=[O:3].[CH2:16]([NH:24][CH2:25][C@@H:26]([C@H:28]([C@@H:30]([C@@H:32]([CH2:34][OH:35])[OH:33])[OH:31])[OH:29])[OH:27])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[CH2:16]([NH:24][CH2:25][C@@H:26]([C@H:28]([C@@H:30]([C@@H:32]([CH2:34][OH:35])[OH:33])[OH:31])[OH:29])[OH:27])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[OH:3][C:2]([C@H:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][CH:11]([CH3:12])[CH3:13])=[CH:14][CH:15]=1)[CH3:5])=[O:1]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Agent: CCCCCCCCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)Cc1ccc([C@H](C)C(=O)O)cc1
Temperature: 25 °C

Procedure:
Racemic ibuprofen (18.03 g, 87.4 mmol), N-octyl-D-glucamine (12.12 g, 41.3 mmol), triethylamine (8.6 g, 88 mmol), water (0.5 mL), and toluene (150 mL) were heated to 80° C., forming a clear solution. The solution was cooled slowly to 25° C. The resulting crystalline precipitate was recovered by filtration, washed with toluene, and dried to give (S)-ibuprofen N-octyl-D-glucamine salt (18.0 g, 82.4% yield, 86.4% ee).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7])#[N:2].[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH2:27])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH:27][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=2)=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)c2cccc(C#N)c2)sc1C(=O)NCc1ccccc1
Yield: 36 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 3-cyanobenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 36% yield; m.p. 207-208° C.; 1H NMR (CDCl3, 300 MHz) δ 8.21 (s, 1H), 8.11 (d, J=7.8 Hz, 1H), 7.87 (d, J=7.8 Hz, 1H) 7.67-7.58 (m, 1H), 7.36-7.32 (m, 5H), 5.99 (t, J=5.6 Hz, 1H), 4.59 (d, J=5.6 Hz, 2H), 2.53 (s, 3H); MS (ES+) m/z 377.2 (M+1).
Reaction SMILES: [N:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([CH2:21][C:22](=[O:26])[NH:23]2)=[CH:19][C:18]=1[CH2:27][CH2:28]Cl.C(=O)([O-])[O-].[K+].[K+].S1(CCCC1)(=O)=O>[I-].[K+].O>[S:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:28][CH2:27][C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][C:17]=3[Cl:16])[NH:23][C:22](=[O:26])[CH2:21]4)[CH2:3][CH2:2]2)=[N:8]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: O=C1Cc2cc(CCCl)c(Cl)cc2N1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: O=C1Cc2cc(CCN3CCN(c4nsc5ccccc45)CC3)c(Cl)cc2N1
Yield: 74.9 %

Procedure:
In a 50 ml 3 necked round bottom flask there were placed 1 gram (4.56 mmol) of 3-piperazinylbenzo[d]isothiazole; 1.25 grams (5.43 mmol) of 6-chloro-5-(2-chloroethyl)indolin-2-one; 50 mg of potassium iodide; 0.82 gram (5.94 mmol) of potassium carbonate and 3 ml of sulfolane. The contents of the flask were heated to 95° C. to 100° C. The reaction was monitored by HPLC. After completion of the reaction, 50 ml of DM water was added to the reaction mixture and stirred. The product was filtered off and washed with water and dried to obtain 1.41 grams (75%) of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one. The crude product was purified by IPA and/or THF. The product matched the spectra of a standard NMR and showed the correct retention time by HPLC with 98.0% assay. The melting point of the compound was found to be 218° C.-220° C., and was found to conform with the melting point of 218°-220° C. as disclosed in U.S. Pat. No. 5,206,366.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[NH:12][C:11]1=[O:21].[H-].[Na+].Cl[CH2:25][O:26][CH2:27][CH3:28]>O1CCCC1>[CH2:27]([O:26][CH2:25][N:12]1[C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][C:15](=[O:16])[N:10]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=2[Cl:9])[C:11]1=[O:21])[CH3:28]
Reactant: CCOCCl
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1c(Cl)cc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCn1c(C(F)(F)F)cc(=O)n(-c2c(Cl)cc(Cl)cc2Cl)c1=O
Yield: 68.9 %

Procedure:
1.50 g of 3-(2,4,6-trichlorophenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione was added to a 10 ml tetrahydrofuran solution of 0.30 g of sodium hydride (purity: 55%) with stirring under ice cooling, and the mixed solution was stirred at room temperature for 15 minutes. Then, after adding 0.70 g of chloromethylethyl ether, the solution was further stirred at room temperature for 3 hours. Then ice was added to the solution to decompose excess sodium hydride. The resulting mixture was extracted with 100 ml of ethyl acetate, and the obtained organic layer was washed thrice with water and dried over magnesium sulfate. Then the solvent was distilled away under reduced pressure to obtain 1.2 g of the objective compound as a viscous oily substance.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.[K]>CN(C)C=O.C(OCC)(=O)C>[Cl:25][C:20]1[CH:19]=[C:18]([C:12]2([C:14]([F:17])([F:15])[F:16])[O:11][N:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:2][N:30]4[C:29](=[O:31])[C:28]5=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]5[C:26]4=[O:36])=[CH:8][CH:7]=3)[CH2:13]2)[CH:23]=[C:22]([Cl:24])[CH:21]=1
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(CCl)cc2)=NO1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.6 %

Procedure:
In a solution of 1.20 g of 3-[4-(chloromethyl)phenyl]-5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole in 20 mL of N,N-dimethylformamide, 0.54 g of potassium phthalimide was added and stirred at room temperature for 20 hours. After the completion of the reaction, the reaction mixture was diluted with 100 mL of ethyl acetate, washed with water (50 mL×3) and then dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous magnesium sulfate in that order, and the solvent was distilled off under reduced pressure to obtain 1.50 g of the aimed product as white crystal.
Reaction SMILES: [H-].[Na+].[C:3](=[N:7][OH:8])([NH2:6])[CH2:4][CH3:5].[C:9]1([C:15]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:16]2[CH2:21][CH:20]([C:22](OC)=O)[CH2:19][N:18]=[CH:17]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[C:32]1([C:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:16]2[CH2:21][CH:20]([C:22]3[O:8][N:7]=[C:3]([CH2:4][CH3:5])[N:6]=3)[CH2:19][N:18]=[CH:17]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCC(N)=NO
Reactant: COC(=O)C1CN=CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1noc(C2CN=CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)n1
Temperature: 0 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
Prepared by a procedure similar to Example 9, where sodium hydride (60% dispersion in mineral oil 56 mg, 1.4 mmol) and propionamidoxime (123 mg, 1.4 mmol) were suspended in dry THF in an oven dried round bottom flask with stirring under nitrogen at 0° C. After 15 minutes stirring the ice bath was removed and the grey suspension refluxed 45 minutes to give a white suspension. 1-Triphenylmethyl-1,4,5,6-tetrahydro-5-methoxycarbonylpyrimidine (540 mg, 1.4 mmol) was added, dissolved in dry THF and reflux continued 18 hours. The solvents were evaporated in vacno and the residue was chromatographed (silica, chloroform/methanol 9:1) to yield 1-triphenylmethyl-1,4,5,6-tetrahydro-5-(3-ethyl-1,2,4-oxadiazol-5-yl)pyrimidine 420 mg (70%). This product was dissolved in trifluoroacetic acid (2 mL), with stirring at room temperature for 24 hours. The yellow solution was then evaporated in vacuo, and the residue recrystallized from methanol/ether to yield 144 mg (49%) white crystals, mp 116°-118° C. identified by 300 MHz nmr.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:14]([NH:15][C:16]2[N:21]=[C:20]([N:22]([CH:32]3[CH2:34][CH2:33]3)CC3C=CC(OC)=CC=3)[C:19]3=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:18]3[N:17]=2)=[CH:13][C:12]([C:40]#[N:41])=[CH:11][C:10]=1[N:42]1[CH2:50][C@H:49]2[C@H:44]([N:45](C(OC(C)(C)C)=O)[CH2:46][CH2:47][CH2:48]2)[CH2:43]1.C1(OC)C=CC=CC=1>ClCCCl>[Cl:8][C:9]1[C:10]([N:42]2[CH2:50][C@H:49]3[C@H:44]([NH:45][CH2:46][CH2:47][CH2:48]3)[CH2:43]2)=[CH:11][C:12]([C:40]#[N:41])=[CH:13][C:14]=1[NH:15][C:16]1[N:21]=[C:20]([NH:22][CH:32]2[CH2:33][CH2:34]2)[C:19]2=[N:35][CH:36]=[C:37]([C:38]#[N:39])[N:18]2[N:17]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4C[C@@H]5CCCN(C(=O)OC(C)(C)C)[C@@H]5C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(N2C[C@@H]3CCCN[C@@H]3C2)c1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 69.9 %

Procedure:
TFA (0.382 mL, 4.96 mmol) was added to a solution of (4aS,7aS)-tert-butyl 6-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate (50 mg, 0.072 mmol) and anisole (0.031 mL, 0.288 mmol) in DCE (1 mL) and the reaction mixture was heated at 60° C. for 1 hour. The solvent was removed in vacuo and the material azeotroped with toluene 3× to remove the excess TFA. 10 ml of 2N NH3 in MeOH was added, and the solution was stirred for 20 min. The solvent was removed in vacuo and the material was triturated with MeOH/Et2O (1:20 ratio). The solid was collected by vacuum filtration to give a yellow solid which was purified by prep-HPLC to give 2-((2-chloro-5-cyano-3-((4aS,7aS)-hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (23.9 mg)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1>C(O)(=O)CC>[OH:1][C:2]1[CH:3]=[C:4]([C:5]2[C:14]3[NH:10][C:11]([C:5]([C:4]4[CH:7]=[CH:8][CH:9]=[C:2]([OH:1])[CH:3]=4)=[C:11]4[N:10]=[C:14]([C:5]([C:4]5[CH:7]=[CH:8][CH:9]=[C:2]([OH:1])[CH:3]=5)=[C:11]5[NH:10][C:14](=[C:5]([C:4]6[CH:7]=[CH:8][CH:9]=[C:2]([OH:1])[CH:3]=6)[C:11]6[CH:12]=[CH:13][C:14]=2[N:10]=6)[CH:13]=[CH:12]5)[CH:13]=[CH:12]4)=[CH:12][CH:13]=3)[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(O)c1
Reactant: c1cc[nH]c1
Solvent: CCC(=O)O
Product: Oc1cccc(-c2c3nc(c(-c4cccc(O)c4)c4ccc([nH]4)c(-c4cccc(O)c4)c4nc(c(-c5cccc(O)c5)c5ccc2[nH]5)C=C4)C=C3)c1
Temperature: 140 °C
Reaction time: 12 h

Procedure:
3-Hydroxybenzaldehyde (0.910 g, 7.45 mmol) is dissolved in propionic acid (50 mL) and heated to 140° C. Pyrrole (0.52 mL, 7.45 mmol) is added in one portion and the mixture heated at reflux for 2 h. Stirring is continued for an additional 12 h at room temperature. Propionic acid is removed in vacuo and the residue dissolved in acetone and purified by chromatography on a column (250 g) of silica which is eluted with toluene containing a continuously increasing proportion of ethyl acetate. The product is eluted with toluene:ethyl acetate (6:1 by vol.). Solvent is removed in vacuo to afford the product as a violet solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:9]([O:11][CH3:12])=[O:10].[Br:13]Br>C(Cl)(Cl)(Cl)Cl>[Br:13][CH:8]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([C:9]([O:11][CH3:12])=[O:10])[C:2]1=[O:1]
Reactant: BrBr
Reactant: COC(=O)C1CCCCCC1=O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C1CCCCC(Br)C1=O
Temperature: 0 °C
Reaction time: 96 h

Procedure:
Methyl 2-oxo-1-cycloheptanecarboxylate (50 g, 294 mmole) was dissolved in carbon tetrachloride (200 mL) and chilled to 0° C. Bromine (46.8 g, 294 mmole) was added via addition funnel over ˜30 minutes. The cooling bath was then removed and the reaction was allowed to warm to rt. The reaction was stirred under nitrogen at room temperature for 4 days. After 4 days the solution was poured into a separatory funnel containing water (1 L). The organic was washed with water and dried over sodium sulfate. Removal of the solvent in vacuo gave (72.4 g, 291 mmole, 99% crude yield). The material was carried on without further purification.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH:5][NH2:6])=[S:4].[CH3:7][C:8]([CH3:15])([CH3:14])[C:9](=O)[C:10](O)=[O:11]>O>[C:8]([C:9]1[C:10](=[O:11])[N:2]([NH2:1])[C:3]([SH:4])=[N:5][N:6]=1)([CH3:15])([CH3:14])[CH3:7]
Reactant: CC(C)(C)C(=O)C(=O)O
Reactant: NNC(=S)NN
Solvent: O
Product: CC(C)(C)c1nnc(S)n(N)c1=O

Procedure:
Analogously to instructions given by A. Dornow and others (Chem. Berichte 97 (1964), page 2173-2178), 53 g (0.5 mole) of thiocarbohydrazide are dissolved in 500 ml of boiling water and 65 g (0.5 mole) of trimethylpyruvic acid are added slowly. A colorless precipitate is deposited, which is filtered off, washed with water and dried in vacuo at 50° C. 6-tert.-butyl-3-mercapto-4-amino-1,2,4-triazin-5(4H)-one is obtained from this reaction in almost quantitative yield.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:9]=[C:8]([C:11]([OH:13])=[O:12])[S:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.C1CCCCC1.ClC(Cl)(Cl)C(=N)O[C:24]([CH3:27])([CH3:26])[CH3:25]>B(F)(F)F.CCOCC.ClCCl>[C:24]([O:12][C:11]([C:8]1[S:7][C:6]2[CH2:5][CH2:4][CH2:3][C:2](=[O:1])[C:10]=2[CH:9]=1)=[O:13])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C(O)c1cc2c(s1)CCCC2=O
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)c1cc2c(s1)CCCC2=O
Reaction time: 1.5 h
Yield: 89.1 %

Procedure:
4-Oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid (Behringer, H.; Falkenberg, K. Chem. Ber., 1966, 99, 3309) (7.69 g, 39.19 mmol) was suspended in 120 mL 2:1 cyclohexane: dichloromethane. Tert-butyl 2,2,2-trichloroacetimidate (17.13 g, 78.38 mmol) was added in one portion, followed by boron trifluoride diethyl etherate (87.8 mg, 6.19 μmol, 0.16 mol %). The resultant slurry was stirred vigorously for 1.5 hours and a further portion of tert-butyl 2,2,2-trichloroacetimidate (8.57 g, 39.19 mmol) was added. Stirring was continued overnight. Further portions of tert-butyl 2,2,2-trichloroacetimidate (8.57 g, 39.19 mmol) were added at 1.5 hours and 3 hours and after a further 3 hours the reaction was quenched by cautious addition of solid NaHCO3 (˜1 g). Silica was added (˜80 mL) and the resulting suspension was concentrated under reduced pressure. The resulting crude mixture was purified by silica gel chromatography (20% EtOAc in hexanes on 1 L of silica) to afford the title compound as a light yellow solid (8.81 g, 89% yield). MS (ES+) 253. δH (CDCl3) 1.5-1.6 (9H, s), 2.2-2.3 (2H, m), 2.5-2.6 (2H, m), 3.0-3.1 (2H, m), 7.9 (1H, s).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[N:19]1([C:25]2[S:26][C:27]3[C:28](=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=3)[N:29]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>O1CCCC1>[OH:34][C:30]1[C:28]2[N:29]=[C:25]([N:19]3[CH2:24][CH2:23][N:22]([C:7]([C:6]4[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=4[O:4][CH:1]([CH3:2])[CH3:3])=[O:9])[CH2:21][CH2:20]3)[S:26][C:27]=2[CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: Oc1cccc2sc(N3CCNCC3)nc12
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nc3c(O)cccc3s2)CC1

Procedure:
Prepared in analogy to example 1.1 b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.2) and 2-Piperazin-1-yl-benzothiazol-4-ol hydrochloride in tetrahydrofuran. The crude material was purified by chromatography (SiO2, heptane/ethyl acetate), and the residue was then triturated in ether to yield the title compound as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].C1(C)C=CC=CC=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21]Cl)=[CH:16][CH:15]=1>O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:1][CH2:2][CH:3]([OH:5])[CH3:4])=[CH:16][CH:15]=1
Reactant: CC(O)CN
Reactant: ClCCc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(O)CNCCc1ccc(Cl)cc1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
In a separate 250-mL round-bottom flask equipped with a magnetic stir bar, a thermocouple, a condenser, and a nitrogen bubbler vented to a caustic scrubber, was charged 1-aminopropan-2-ol (60.1 g, 800 mmol), which was then heated to 85° C. To this was slowly added the toluene solution of 1-chloro-4-(2-chloroethyl)benzene from Step A while maintaining the reaction temperature at <99° C. On completion of the addition, stirring was continued at 90 to 95° C. for 2 h. Toluene (50 mL) and water (25 mL) were added and the mixture was stirred at 70 to 75° C. for 15 minutes before the phases were separated at room temperature. The upper aqueous phase was extracted with toluene (2×25 mL) at 70 to 75° C. Then, the combined organic phases were washed with water (2×25 mL) at 70 to 75° C., and concentrated by distillation under reduced pressure at 60° C. (bath). The residue was diluted with toluene to a total volume of 112.5 mL and the yellow solution was stirred under nitrogen overnight at 50° C. (bath). Karl Fischer titration showed 0.091% water.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:17]([CH3:19])[CH3:18]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([O:9][CH:17]([CH3:19])[CH3:18])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Oc1cc(F)cc(F)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 3,5-difluorophenol (1.0 equiv.) in DMF (0.26 M) was added potassium carbonate (2.2 equiv.) followed by 2-iodopropane (1.1 equiv.) and the reaction was stirred overnight at room temperature. The reaction was poured into a separatory funnel and diluted with a 3:1 (v/v) solution of EtOAc:heptanes. The organic phase was washed with water, then sat'd NaHCO3. The remaining organic phase was dried over MgSO4, filtered and concentrated in vacuo to provide 1,3-difluoro-5-isopropoxybenzene in 88% yield. 1H NMR (400 MHz, <cdcl3>) δ ppm 1.33 (d, J=6.26 Hz, 6H), 4.48 (dt, J=11.93, 6.16 Hz, 1H), 6.31-6.47 (m, 3H).