Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[Si](C)(C)C.[O:6]=[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+].[Br:32]N1C(=O)CCC1=O>C1COCC1.CCCCCC.CN(C=O)C>[Br:32][CH:12]1[C:7](=[O:6])[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
Chlorotrimethylsilane (5.6 ml, 44 mmol) was added slowly to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (commercial, 8 g, 40 mmol), triethylamine (12.3 ml, 88 mmol) and DMF (40 ml) at room temperature. The resultant solution was heated to 75° C. and stirred overnight under nitrogen. The reaction mixture was cooled to room temperature and then in an ice bath. Cold hexane (250 ml) was added slowly to the reaction mixture followed by cold (saturated) aqueous sodium bicarbonate (50 ml). The organic phase was separated and washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude silyl enolether was dissolved in THF (15 ml) and cooled to 0° C. N-Bromosuccinimide (7.1 g, 40 mmol) was dissolved in THF (120 ml) and added slowly (45 min.) to the reaction mixture. The resultant mixture was allowed to slowly warm to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by flash chromatography (hexanes/ethyl acetate, 5:1) to provide the title compound as a white solid (11 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([N:13]([CH3:15])[CH3:14])[CH2:10][C@H:9]1[CH2:16][O:17][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([N:13]([CH3:14])[CH3:15])[CH2:10][C@H:9]1[CH2:16][OH:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)[C@@H]1C[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)N(C(=O)OC(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C)[C@@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 108.3 %

Procedure:
To a stirred solution of trans-1-tert-butoxycarbonyl(2S)-(tert-butyldiphenylsilyloxy)methyl-4-dimethylaminopyrrolidine (330 mg, 0.68 mmol) in THF (5 ml) was added TBAF (1.0 M solution in THF, 1.0 ml, 1.0 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 hr. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with MeOH—CH2Cl2 (3:97 to 20:80, v/v) as eluent to give trans-1-tert-butoxycarbonyl-4-dimethylamino-(2S)-hydroxymethylpyrrolidine (180 mg, quant) as a pale yellow oil. 1H-NMR (CDCl3) δ1.47 (s, 9H), 2.23 (s, 6H), 1.65-1.75 (m, 2H), 2.75-4.10 (m, 4H), 3.61 (d, J=5.6 Hz, 2H).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:3]#[N:4].[C:11]([CH2:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16])(=O)[CH3:12]>C(O)C>[NH2:4][C:3]1[C:14]([C:15](=[O:16])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:11]([CH3:12])[NH:1][C:2]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)CC(=O)Nc1ccccc1
Reactant: N#CC(N)c1ccccc1
Solvent: CCO
Product: Cc1[nH]c(-c2ccccc2)c(N)c1C(=O)Nc1ccccc1

Procedure:
This compound is prepared starting from 2-amino-2-phenylacetonitrile and α-acetyl-N-phenyl-acetamide, and is obtained with a 73% overall yield, m.p. 271°-273° C. (from ethanol).
Reaction SMILES: [NH2:1][N:2]1[C:6]([NH:7][CH3:8])=[N:5][NH:4][C:3]1=[O:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:21](OCC)(OCC)[O:22][CH2:23][CH3:24]>>[CH2:23]([O:22][CH:21]=[N:1][N:2]1[C:6]([NH:7][CH3:8])=[N:5][NH:4][C:3]1=[O:9])[CH3:24]
Reactant: CNc1n[nH]c(=O)n1N
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC=Nn1c(NC)n[nH]c1=O
Yield: 54 %

Procedure:
12.9 g (0.1 mol) of 4-amino-5-methylamino-2,4-dihydro-3H-1,2,4-triazol-3-one are refluxed for 4 hours with 100 ml of triethyl orthoformate and 100 mg of p-toluenesulphonic acid. The mixture is then concentrated and crystallized with diethyl ether. Recrystallization from ethanol gives 10.0 g (54% of theory) of 4-ethoxymethyleneamino-5-methylamino-2,4-dihydro-3H-1,2,4-triazol-3-one of melting point 169° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]([CH3:13])[CH3:12])[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:16]=3[CH3:25])[C:6]=2[CH:5]=[C:4]([N+:26]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl.Cl.C(=O)([O-])[O-].[Na+].[Na+]>CO>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]([CH3:13])[CH3:12])[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[C:16]=3[CH3:25])[C:6]=2[CH:5]=[C:4]([NH2:26])[CH:3]=1
Reactant: Cc1c(Cn2c(C(C)C)nc3c(Br)cc([N+](=O)[O-])cc32)cccc1C(F)(F)F
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: O
Product: Cc1c(Cn2c(C(C)C)nc3c(Br)cc(N)cc32)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
To a 250 mL round-bottom flask containing MeOH (100 mL) was added crude 4-bromo-2-isopropyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-nitro-1H-benzo[d]imidazole (7.1 g, 15.56 mmol), tin(II) chloride dihydrate (10.53 g, 46.7 mmol) and hydrochloric acid (6.48 mL, 78 mmol). The resultant suspension was heated to 60° C. and monitored by LC/MS. By LC/MS the reaction was complete in 30 minutes. After the reaction had cooled to rt, the majority of the MeOH was removed in-vacuo and sodium carbonate (150 mL, 150 mmol) was added slowly to adjust the pH to about 10 and the mixture was extracted with Et2O (150 mL) and the organic was washed with H2O and brine and dried over MgSO4 and filtered. The solvent was removed in-vacuo leaving the desired product (4.7 g, 11.03 mmol, 70.9% yield) as crude brown solid that by LC/MS was sufficiently pure to use in the next step. MS (ES+) m/e: 425.1, 426.0 [M+H]+
Reaction SMILES: CCC1OC2C=C(O)C=CC=2C=1C(C1C=C(Br)C(O)=C(Br)C=1)=O.[C:24]([C:27]1[O:28][C:29]2[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:30]=2[CH:31]=1)(=O)[CH3:25].NN>>[CH2:24]([C:27]1[O:28][C:29]2[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:30]=2[CH:31]=1)[CH3:25]
Reactant: COc1ccc2cc(C(C)=O)oc2c1
Agent: CCc1oc2cc(O)ccc2c1C(=O)c1cc(Br)c(O)c(Br)c1
Agent: NN
Product: CCc1cc2ccc(OC)cc2o1

Procedure:
As for preferred example of producing 6-hydroxybenzbromarone according to the present invention, it can be produced as follows. That is, for example, 2-acetyl-6-methoxy-benzofuran is reduced using hydrazine to obtain 2-ethyl-6-methoxy-benzofuran, which is then reacted with acid chloride of 4-methoxy-benzoic acid under the presence of tin tetrachloride to yield 2-ethyl-6-methoxy-3-(p-methoxy-benzoyl)-benzofuran. And then methoxy group of benzoyl group is selectively deprotected under the presence of ethane thiol sodium salt to yield 2-ethyl-6-methoxy-3-(p-hydroxy-benzoyl)-benzofuran, which is then brominated by sodium-N-bromosuccinimide under the presence of dimethyl sulfide to obtain 2-ethyl-6-methoxy-3-(3′,5′-dibromo-4′-hydroxy-benzoyl)-benzofuran, and then methoxy group at sixth place is deprotected under the presence of aluminum chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[NH:35][C:36]([C:38]1[C:46]2[N:45]=[C:44]([C:47](=[O:50])[NH:48][CH3:49])[N:43](CC3C=CC(OC)=CC=3)[C:42]=2[CH:41]=[CH:40][CH:39]=1)=[O:37])[C:6]([N:8]([CH3:31])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](N1CCN(C)CC1)=[O:23])=[O:7].F[C:61](F)(F)[C:62](O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[NH:35][C:36]([C:38]1[C:46]2[N:45]=[C:44]([C:47](=[O:50])[NH:48][CH3:49])[NH:43][C:42]=2[CH:41]=[CH:40][CH:39]=1)=[O:37])[C:6]([N:8]([CH3:31])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](=[C:22]=[O:23])[N:45]1[CH2:62][CH2:61][N:43]([CH3:44])[CH2:42][CH2:46]1)=[O:7]
Reactant: O=C(O)C(F)(F)F
Reactant: CNC(=O)c1nc2c(C(=O)Nc3ccc(C(=O)N(C)c4ccc(C)cc4OCCCCCC(=O)N4CCN(C)CC4)cc3OC)cccc2n1Cc1ccc(OC)cc1
Product: CNC(=O)c1nc2c(C(=O)Nc3ccc(C(=O)N(C)c4ccc(C)cc4OCCCCC(=C=O)N4CCN(C)CC4)cc3OC)cccc2[nH]1

Procedure:
A solution of 3-methoxy-4-[1-(4-methoxybenzyl)-2-(N-methylcarbamoyl)-1 H-benzimidazol-4-yl]carbonylamino-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (130 mg) in trifluoroacetic acid (3 ml) was stirred at 60° C. for 8 hours. The reaction mixture was concentrated in vacuo and the residue was diluted with a mixture of chloroform and saturated aqueous sodium bicarbonate solution. The organic layer was separated and washed with water and brine. The solution was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform-methanol=10:1) to give 3-methoxy-N-methyl-4-[2-(N-methylcarbamoyl)-1 H-benzimidazol-4-yl]carbonylamino-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)-carbonylpent-1-yloxy]phenyl]benzamide (45 mg) as a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11](C(OCC)C)[CH:12]=2)[C:5]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=2)=[C:4]([CH:26]([NH2:28])[CH3:27])[CH:3]=1.Br[C:30]1[N:38]=[CH:37][N:36]=[C:35]2[C:31]=1[N:32]=[CH:33][N:34]2C1CCCCO1.C(N(CC)C(C)C)(C)C.Cl.O>C(O)C.CO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:12]=[N:11][NH:10][CH:9]=2)[C:5]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=2)=[C:4]([CH:26]([NH:28][C:30]2[N:38]=[CH:37][N:36]=[C:35]3[C:31]=2[N:32]=[CH:33][NH:34]3)[CH3:27])[CH:3]=1
Reactant: Brc1ncnc2c1ncn2C1CCCCO1
Reactant: CCOC(C)n1cc(-c2cc(Cl)cc(C(C)N)c2-c2cc(F)cc(F)c2)cn1
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: O
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)cc(-c2cn[nH]c2)c1-c1cc(F)cc(F)c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 42.8 %

Procedure:
A solution of 1-{4-chloro-6-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-3′,5′-difluorobiphenyl-2-yl}ethanamine (60 mg, 0.15 mmol), 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (63 mg, 0.22 mmol, from Example 108, Step 1), and N,N-diisopropylethylamine (77 μL, 0.44 mmol) in ethanol (2.8 mL) was heated in the microwave at 130° C. for 30 minutes. Alternatively, this reaction can be heated at 90° C. overnight on the benchtop. The reaction mixture was cooled to room temperature, treated with 6 M Hydrogen chloride in water (0.49 mL, 3.0 mmol), and stirred for 30 minutes. The reaction mixture was diluted slightly with methanol, filtered, and directly purified via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (29 mg, 43%). LCMS for C22H17ClF2N7 (M+H)+: m/z=452.1. Found: 452.0; 1H NMR (300 MHz, DMSO-d6): δ 12.8 (br s, 1H), 8.32-8.23 (m, 1H), 8.11 (s, 1H), 8.06 (s, 1H), 7.65 (s, 1H), 7.46 (s, 1H), 7.36-7.23 (m, 3H), 7.09-7.01 (m, 1H), 6.96 (d, J=8.5 Hz, 1H), 5.09-4.96 (m, 1H), 1.34 (d, J=6.7 Hz, 3H).
Reaction SMILES: [C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1[N:31]=[C:32]=[S:33]>ClCCl>[C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:32](=[S:33])[NH:31][C:25]5[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]=5[CH3:23])[CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2CC(c3csc(C4CCNCC4)n3)=NO2)cc1
Reactant: Cc1ccc(C)c(N=C=S)c1
Solvent: ClCCl
Product: Cc1ccc(C)c(NC(=S)N2CCC(c3nc(C4=NOC(c5ccccc5)C4)cs3)CC2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]piperidine (i.e. the product of Step B) (1.0 g, 3.2 mmol) in dichloromethane (10 mL) was added a solution of 2,5-dimethylphenyl isothiocyanate (0.52 g, 3.2 mmol) and dichloromethane (5 mL) over 1 minute. The reaction mixture was stirred at room temperature for 20 minutes, concentrated, dissolved in methyl acetate (4 mL), held at 0° C. overnight and filtered to give the title compound as a white powder (1.35 g) melting at 120-123° C.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.O[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20](=[O:25])[CH2:21][CH:22]([CH3:24])[CH3:23])=[N:18][CH:19]=1.C1(P([N:40]=[N+:41]=[N-:42])(C2C=CC=CC=2)=O)C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O.O>[N:40]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20](=[O:25])[CH2:21][CH:22]([CH3:24])[CH3:23])=[N:18][CH:19]=1)=[N+:41]=[N-:42]
Reactant: CC(C)CC(=O)c1ccc(CO)cn1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)CC(=O)c1ccc(CN=[N+]=[N-])cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 106.6 %

Procedure:
Add DBU (240 mg, 1.55 mmol) to a solution of 5-hydroxymethyl-2-(3-methyl-butyryl)-pyridine (250 mg, 1.29 mmol) and diphenylphosphorylazide (430 mg, 1.55 mmol) in anhydrous toluene (10 mL) at 0° C. Stir at 0° C. for 30 min, warm to room temperature and stir for 4 h. Dilute with EtOAc and water. Extract the aqueous phase twice with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (9:1) to provide the desired intermediate (300 mg, 99%). MS (ES+) m/z: 219 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:7]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[C:5]([NH2:15])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1NC1CCOCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Br)cc1NC1CCOCC1
Temperature: 60 °C

Procedure:
To a solution of N-(5-bromo-2-nitrophenyl)tetrahydro-2H-pyran-4-amine (2.5 g, 8.333 mmol) in EtOH/H2O (1:1) (50 mL) was added iron powder (2.8 g, 50 mmol) and NH4Cl (2.65 g, 50 mmol). The reaction mixture was heated at 60° C. for 12 h. After filtering the reaction mixture, the resulting filtrate was extracted with DCM with the separated organic layer dried over sodium sulfate, filtered and concentrated to obtain crude product which was used in next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([CH:13]=1)[C:7]([NH:9][CH:10]([CH3:12])[CH3:11])=[O:8].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([CH:13]=1)[C:7]([NH:9][CH:10]([CH3:11])[CH3:12])=[O:8])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)NC(=O)c1cc(N)ccc1F
Reactant: O=Cc1ccccc1
Product: CC(C)NC(=O)c1cc(NCc2ccccc2)ccc1F

Procedure:
5-Benzylamino-2-fluoro-N-isopropyl-benzamide was synthesized from 5-amino-2-fluoro-N-isopropyl-benzamide and benzaldehyde according to the method described in Example 1
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[C:21]2[C:16]([CH2:17][CH2:18][CH:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:20]2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)P(N(C)C)(N(C)C)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].I[CH2:50][CH3:51]>C1COCC1>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[C:21]2[C:16]([CH2:17][CH2:18][C:19]([CH2:50][CH3:51])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:20]2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCc2ccc(OCCCOCc3ccccc3)cc2O1
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C1(CC)CCc2ccc(OCCCOCc3ccccc3)cc2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a 85 ml anhydrous THF solution of ethyl 7-(3-benzyloxypropoxy)-chromane-2-carboxylate (5.0 g, 13.5 mmol) and hexamethylphosphoramide (3.1 ml, 17.8 mmol) was added sodium bis(trimethylsilyl) amide 1.0M/THF solution (16.2 ml, 16.2 mmol) was added upon cooling in a dry ice-acetone bath. After stirring for 30 min at that temperature, to it was added iodoethane (3.3 ml, 41.3 mmol). The cooling bath was removed allowing the reaction mixture to warm to rt overnight. The solvent was removed under reduced pressure. The residue was diluted with AcOEt and sat. NH4Claq. The organic layer was separated, and the aqueous layer was extracted twice with AcOEt. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and chromatographed on silica gel eluting with 10% methyl-tert-butyl ether/hexanes to give the title compound as a clear oil 3.76 g (70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[N:7]3[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[C:8]3[S:9][C:5]=2[CH:4]=1>C(Cl)Cl.CN(C=O)C.O=[Mn]=O>[CH:13]([C:11]1[N:10]=[C:8]2[N:7]([CH:12]=1)[C:6]1[CH:15]=[CH:16][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[S:9]2)=[O:14]
Reactant: COc1ccc2c(c1)sc1nc(CO)cn12
Agent: O=[Mn]=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2c(c1)sc1nc(C=O)cn12

Procedure:
2-Formyl-7-methoxyimidazo[2,1-b]-benzthiazole was prepared according to the procedure outlined in Example 1, (Step 3). Starting from 7-methoxy imidazo[2,1-b]-benzthiazole-2-methanol (4.0 g 17 mmol) in methylene chloride/DMF(300 mL: 50 mL) and active MnO2 (12 g, excess), 822 mg (21% Yield) of the aldehyde derivative was isolated as brown solid. (M+H) 233.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]1[C:9]([CH2:10][OH:11])=[CH:8][CH:7]=[CH:6][N:5]=1>C1(C)C=CC=CC=1.O=[Mn]=O>[CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]1[C:9]([CH:10]=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: COC(OC)c1ncccc1CO
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: COC(OC)c1ncccc1C=O
Temperature: 25 °C
Yield: 85.5 %

Procedure:
A mixture of 321 mg (1.75 mmol) of (2-dimethoxymethyl-pyridin-3-yl)-methanol and 763 mg (8.77 mmol) of MnO2 in 10 mL of toluene is refluxed for 1.5 hours. The reaction mixture is cooled to room temperature and filtered. The filtrate is evaporated to yield 271 mg of 2-dimethoxymethyl-pyridine-3-carbaldehyde. 1H NMR (CDCl3) δ 10.30 (s, 1H), 8.30 (d, 1H), 8.10 (d, 1H), 7.30 (m, 1H), 5.40 (s, 2H), 4.40 (s, 6H). Step 5:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH:8]([CH3:12])[CH2:7][C:5]=2[N:6]=1.[CH3:13][C:14](OC(C)=O)=[O:15]>>[CH3:12][CH:8]1[CH2:7][C:5]2[N:6]=[C:2]([NH:1][C:14](=[O:15])[CH3:13])[S:3][C:4]=2[C:10](=[O:11])[CH2:9]1
Reactant: CC1CC(=O)c2sc(N)nc2C1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1nc2c(s1)C(=O)CC(C)C2
Temperature: 25 °C

Procedure:
A solution of 2-amino-5-methyl-5,6-dihydro-4H-benzothiazol-7-one (25.0 g, 0.137 mol) in Ac2O (300 mL) is heated at reflux temperature for 3 h. The reaction mixture is then cooled to RT and the precipitate is filtered off to afford N-(5-methyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide. Yield: 26 g.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:24]=[CH:23][C:9]2[N:10]([CH3:22])[C:11]([NH:13][C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])=[N:12][C:8]=2[CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[F:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([F:20])[C:14]=1[NH:13][C:11]1[N:10]([CH3:22])[C:9]2[CH:23]=[CH:24][C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8]=2[N:12]=1
Reactant: CCOC(=O)c1ccc2c(c1)nc(Nc1c(F)cccc1F)n2C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(Nc2c(F)cccc2F)nc2cc(C(=O)O)ccc21

Procedure:
Prepared analogously to example 3b from 2-(2,6-difluoro-phenylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid ethyl ester and NaOH in ethanol.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][CH2:9][CH3:10])[C:5](Cl)=[O:6])[CH2:2][CH3:3].[CH3:11][S:12]([C:15]1[N:19]=[CH:18][NH:17][N:16]=1)(=[O:14])=[O:13].C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:4]([CH2:8][CH2:9][CH3:10])[C:5]([N:17]1[CH:18]=[N:19][C:15]([S:12]([CH3:11])(=[O:14])=[O:13])=[N:16]1)=[O:6])[CH2:2][CH3:3]
Reactant: CCCN(CCC)C(=O)Cl
Reactant: CS(=O)(=O)c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)n1cnc(S(C)(=O)=O)n1

Procedure:
Dipropylcarbamoyl chloride (5.5 g.) was added to a solution of 4.4 g. 3-methylsulphonyl-1,2,4-triazole and 6 ml. dry triethylamine in 25 ml. dry tetrahydrofuran and the resulting mixture refluxed for 2.5 hours under anhydrous conditions. The cooled reaction mixture was filtered to remove triethylamine hydrochloride and the filtrate poured with stirring into 150 ml. ice-cold 0.1N aqueous sodium hydroxide. The precipitated product was collected by filtration, washed with ice-cold water, dried, and crystallized twice from toluene to give 1-dipropylcarbamoyl-3-methylsulphonyl-1,2,4-triazole, m.p. 94° C. Elemental analysis satisfactory.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:9])[C:7]=1[NH2:8].[C:11](O)(=O)[CH3:12]>>[CH3:11][C:12]1[NH:1][C:2]2[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:9])[C:7]=2[N:8]=1
Reactant: Cc1cc(O)cc(N)c1N
Reactant: CC(=O)O
Product: Cc1nc2c(C)cc(O)cc2[nH]1

Procedure:
0.553 g (4.00 mml) 3,4-diamino-5-methyl-phenol in 5.00 mL glacial acetic acid were boiled for 3 h. Then the reaction mixture was evaporated down and dried under HV.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>O>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1ccc(N2CCNC2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(N2CCNC2=O)cc1

Procedure:
A mixture of 10 g of 1-(p-acetamidophenyl)-2-imidazolidinone (see Example 1), 10 g of sodium hydroxide and 100 ml of water is heated under reflux for four hours. The product that crystallizes on cooling is collected and recrystallized from ethanol to yield 1-(4-aminophenyl)-2-imidazolidinone, m.p. 170°-2°.
Reaction SMILES: N.CC(C)([O-:5])C.[K+].[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16].C(OO)(C)(C)C>C1COCC1>[Cl:8][C:9]1[C:10]([N+:15]([O-:17])=[O:16])=[CH:11][N:12]=[C:13]([OH:5])[CH:14]=1
Reactant: CC(C)(C)[O-]
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: CC(C)(C)OO
Agent: N
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc(O)cc1Cl
Temperature: -35 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
THF (500 mL) was cooled to −78° C. and anhydrous NH3 (˜200 mL) was condensed into the THF. Potassium t-butoxide (71.0 g, 630 mmol) was added and the mixture was allowed to warm to ˜−35° C. The product from Step 1 (40.0 g, 250 mmol) was cooled to 0° C. in THF (200 mL) and a solution of t-BuOOH (5 M in decane, 50 mL, 250 mmol) was added over 5 min. This solution was then added dropwise to the KOt-Bu solution prepared above over 1 h, then stirred for 2 h at −35° C. and then carefully quenched with ˜50 mL of sat. NH4Cl solution. The mixture was allowed to vent and warm to rt overnight, then the organics were concentrated and the residue made acidic with NH4Cl solution and filtered. The solid was washed with cold H2O and dried to give the title compound as a dark brown solid (35 g, 80%).