Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][O:2][C:1]2[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=2)=[CH:12][CH:11]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Oc1ccc(OCc2ccc(F)cc2)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 40.9 %

Procedure:
A solution of 10 g of hydroquinone in 90 ml of acetonitrile was treated with 8.58 g of 4-fluorobenzylbromide and 15.7 g of potassium carbonate. The mixture was heated to 90° C. and stirred during 18 h. For the working-up, the reaction mixture was cooled to room temperature and treated with cold water. The solid material that has formed was filtered, washed twice with cold water and dried. For purification and separation from the bis-ether, the crude material was chromatographed on silica gel using a 4:1 mixture of heptane and ethyl acetate as the eluent. There were obtained 4.05 g (27% of theory) of 4-(4-fluoro-benzyloxy)-phenol as a white solid; MS: m/e=218 (M)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([OH:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.[CH2:22]=[C:23]([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([O:16][C:23]([CH3:25])([CH3:24])[CH3:22])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: C=C(C)C
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 98 %

Procedure:
A 100-ml flask was charged with 5 ml of toluene and 2.12 g (10 mmol) of 4′-methyl-2-biphenylcarboxylic acid, and they were vigorously stirred. To this mixture was added dropwise 0.18 ml (2 mmol) of phosphorus oxytrichloride, and isobutene gas (98 mmol) was introduced to the mixture at a flow rate of 1.2 liter/min for 2 minutes. The resulting mixture was stirred at room temperature for 6 hours. After having confirmed that almost all of the peaks ascribed to 4′-methyl-2-biphenylcarboxylic acid disappeared by HPLC, the reaction solution was washed with a 1.5 M aqueous sodium hydroxide. The reaction solution was dried over anhydrous magnesium sulfate, and then the mixture was concentrated by distilling off toluene by using a rotary evaporator, to give 2.63 g of tert-butyl 4′-methyl-2-biphenylcarboxylate as crystals (yield: 98% based on 4′-methyl-2-biphenylcarboxylic acid, purity by HPLC: 99.9%). Incidentally, the obtained compound had the same physical properties as those of the compound obtained in Example II-1.
Reaction SMILES: [CH3:1][C:2]([NH:36][C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])([CH3:35])[CH2:3][C:4]([NH:6][C@@H:7]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[N:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:26]([C:31]([OH:33])=O)=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)[C:8]1=[O:34])=[O:5].[CH2:47]([NH2:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[C:48]1([CH2:47][NH:54][C:31]([C:26]2[C:25]([C:22]3[CH:21]=[CH:20][C:19]([CH2:18][N:9]4[C:10]5[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=5[CH2:12][CH2:13][C@@H:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([NH:36][C:37]([O:39][CH2:40][C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)=[O:38])([CH3:1])[CH3:35])[C:8]4=[O:34])=[CH:24][CH:23]=3)=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:33])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3C(=O)O)cc2)C1=O)NC(=O)OCc1ccccc1
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3C(=O)NCc3ccccc3)cc2)C1=O)NC(=O)OCc1ccccc1

Procedure:
The title compound was prepared from 4'-[[2,3,4,5-tetrahydro-3(R)-[[3-methyl-1-oxo-3-[(benzyloxycarbonyl)amino]butyl]amino-]-2-oxo-1H-1-benzazepin-1yl]methyl][1,1'-biphenyl]-2-carboxylic acid (Example 72, Step B) and benzylamine according to the procedure described in Example 74, Step A. 1H NMR (200 MHz,CDCl3): 1.31 (s,3H), 1.35 (s,3H), 1.75 (m,1H), 2.30-2.65 (m,5H), 4.23 (d,5 Hz,2H), 4.47 (m,1H), 4.83 (d,14 Hz,1H), 5.02 (s,2H), 5.45 (m,1H), 5.60 (s,1H), 6.68 (d,6Hz,1H), 6.90 (m,2H), 7.10-7.50 (m,20H), 7.65 (m,1H). FAB-MS: calculated for C44H44N4O5 708; found 709 (M+H), 731 (M+Na, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([NH:7][CH3:8])=O.[N-:15]=[N+:16]=[N-:17].[Na+].S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.C([O-])(O)=O.[Na+]>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[N:7]([CH3:8])[N:17]=[N:16][N:15]=2)[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1
Reactant: CNC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cn1nnnc1-c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 41.1 %

Procedure:
3-bromo-N-methyl-5-nitrobenzamide (23.20 g, 90 mmol, 1 equiv.) was suspended in 200 ml of acetonitrile at 25° C. under nitrogen then sodium azide (5.82 g, 90 mmol, 1 equiv.) was added. Cooled to 0° C. then very slowly added triflic anhydride (15.07 ml, 90 mmol, 1 equiv.) dropwise via an addition funnel. The reaction became an amber solution. Worked up after 4 hours by adding 200 ml of sat'd NaHCO3 and stirred 10 minutes. Then added ethyl acetate and separated the layers. The ethyl acetate was rinsed twice with sat'd NaHCO3 then once with brine. The ethyl acetate was dried over MgSO4 then stripped in vacuo to give a dark amber oil which was stirred in 25 ml of ethyl acetate. After stirring 5 minutes, solids which precipitated were filtered off, and pumped under high vacuum to give 10.5 g of tan solids. The filtrate was stripped then purified over silica gel in 100% methylene chloride to obtain an additional 9.0 g of solids. By NMR both solids were identical for product and were combined.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:13][CH:14]=2)=[CH:4][CH:3]=1.[N:26]#[C:27][NH2:28].Cl>C(OCC)(=O)C.C(O)C>[NH2:28][C:27]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:25])[S:13][CH:14]=2)=[CH:4][CH:3]=1)=[NH:26]
Reactant: Nc1ccc(CCc2csc(NC(=O)OCc3ccccc3)n2)cc1
Reactant: N#CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: N=C(N)Nc1ccc(CCc2csc(NC(=O)OCc3ccccc3)n2)cc1
Temperature: 100 °C
Reaction time: 72 h
Yield: 53.6 %

Procedure:
A mixture of benzyl 4-[2-(4-aminophenyl)ethyl]-1,3-thiazol-2-ylcarbamate (25 mg), cyanamide (6.0 mg), 4N hydrogen chloride in ethyl acetate (0.018 ml) and ethanol (1 ml) was stirred at 100° C. for 72 hours. The reaction mixture was concentrated in vacuo. To the residue was added ethyl acetate (5 ml) and saturated aqueous sodium hydrogen bicarbonate (5 ml). The precipitated solid was filtered and washed with ethylacetate and water to give benzyl 4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-carbamate (15 mg).
Reaction SMILES: [CH2:1](Cl)[CH2:2][OH:3].[OH:5][C:6]1[C:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14][C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[N:7]=1.[OH-].[Na+]>C(O)(C)(C)C>[OH:3][CH2:2][CH2:1][N:7]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[N:14]=[C:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6]1=[O:5]
Reactant: OCCCl
Reactant: Oc1nc2c(nc1Cc1ccccc1)CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: O=c1c(Cc2ccccc2)nc2c(n1CCO)CCCC2
Temperature: 60 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
Ethylene chlorohydrin (16.10 g, 0.2M) was added to a solution of 2-hydroxy-3-benzyl-5,6,7,8-tetrahydro quinoxaline (9.60 g, 40 mM) in dilute aqueous 5N NaOH (40 ml) and t-butanol (120 ml), and stirred at 60° C. for 3 hours. The t-butanol was distilled off in vacuo. The residue was extracted three times with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 220 g) packed with chloroform, and eluted with chloroform-methanol (200:1) to obtain compound 643 (10.90 g, yield: 83.8%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][C:3]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.[SH:16][C:17]1[S:18][CH:19]=[CH:20][N:21]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:15][C:10]1[C:9]([C:3]2[CH:4]=[C:5]([CH:7]=[O:8])[S:6][C:2]=2[S:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=Cc1cc(-c2cccnc2F)c(Br)s1
Reactant: Sc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=Cc1cc(-c2cccnc2F)c(Sc2nccs2)s1
Yield: 100.1 %

Procedure:
With 5-bromo-4-(2-fluoropyridin-3-yl)thiophene-2-carbaldehyde (250 mg) as a starting material, and using 2-mercaptothiazole (134 mg) and potassium carbonate (193 mg), an operation similar to that of Reference Example 1 was performed to give the title compound as a white powder (yield 282 mg, yield 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10](=[O:31])[C@@H:11]2[C@@H:15]([CH2:16][CH3:17])[CH2:14][CH2:13][N:12]2[CH:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:19]2[CH2:23][CH2:22][CH2:21][NH:20]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH3:35]>CN(C=O)C>[CH3:35][N:9]([CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C:10](=[O:31])[C@@H:11]1[C@@H:15]([CH2:16][CH3:17])[CH2:14][CH2:13][N:12]1[CH:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1
Reactant: CC[C@H]1CCN(C(C(=O)OC(C)(C)C)[C@@H]2CCCN2)[C@@H]1C(=O)NCc1cccc(Cl)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@H]1CCN(C(C(=O)OC(C)(C)C)[C@@H]2CCCN2)[C@@H]1C(=O)N(C)Cc1cccc(Cl)c1
Temperature: 0 °C

Procedure:
N-[(t-Butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-proline-N-(3-chlorophenylmethyl) amide (0.175 g, 0.39 mmol) was dissolved in dry DMF (4 mL) with stirring at 0° C. under Ar, treated with NaH (60% dispersion in mineral oil, 0.023 g, 0.58 mmol), and after 15 minutes treated with iodomethane (0.029 mL, 0.47 mmol). The reaction mixture was stirred at 25° C. for 2 h, then evaporated to dryness and partitioned between EtOAc and aqueous saturated NaHCO3 solution. The organic layer was separated, washed with brine, dried (MgSO4), filtered, and concentrated to dryness to give the title compound.
Reaction SMILES: [CH3:1][CH:2]([NH2:5])[C:3]#[CH:4].Cl.CCN(CC)CC.[Cl:14][C:15]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>C1COCC1>[CH3:1][CH:2]([NH:5][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][CH:22]=[C:23]([C:24]([F:25])([F:26])[F:27])[C:15]=1[Cl:14])[C:3]#[CH:4]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Reactant: C#CC(C)N
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CC(C)NC(=O)c1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the suspension of but-3-yn-2-amine.HCl salt (10 g, 94.7 mmol, 1.0 equiv.) in THF (150 mL), Et3N (27.5 mL, 199 mmol, 2.1 equiv.) and (2-chloro-3-(trifluoromethyl)benzoyl chloride (23.1 g, 94.7 mmol, 1.0 equiv.) were added sequentially at 0° C. The reaction mixture was then stirred at room temperature for 16 hours. The precipitate was filtered off and washed with THF. The filtrate solution was concentrated and re-dissolved in EtOAc. The EtOAc solution was washed with saturated NaHCO3 and brine, dried over Na2SO4, concentrated. Trituration of the crude product from EtOAc/hexanes afforded Intermediate 233: (23 g, 83.8 mmol, 88%) as a white solid. 1H NMR (600 MHz, CDCl3) δ 7.82-7.75 (dd, J=7.9, 1.6 Hz, 1H), 7.73-7.66 (dd, J=7.7, 1.6 Hz, 1H), 7.48-7.41 (dd, J=8.2, 7.3 Hz, 1H), 6.35-6.02 (d, J=7.9 Hz, 1H), 5.09-4.90 (dqd, J=8.1, 6.9, 2.3 Hz, 1H), 2.47-2.20 (m, 1H), 1.58-1.54 (d, J=6.9 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 164.7, 137.9, 132.5, 129.4 (q, JC—F=31.5 Hz), 129.1, 129.0 (q, JC—F=5.2 Hz), 127.1, 122.5 (q, JC—F=273.4 Hz), 83.2, 71.2, 37.8, 22.1. HRMS-ESI (m/z): [M+H]+ calcd for C12H10ClF3NO, 276.0398. found, 276.0390.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[N:11][CH:10]=1.[NH2:23][CH2:24][C:25]([CH3:28])([OH:27])[CH3:26]>ClCCl>[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:23][CH2:24][C:25]([CH3:28])([OH:27])[CH3:26])=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[N:11][CH:10]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)cnc2c1Cl
Reactant: CC(C)(O)CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cc(Br)cnc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
Triethylamine (35.95 mL, 257.9 mmol) was added to a suspension of 7-bromo-4-chloro-3-nitro[1,5]naphthyridine (49.6 g, 172 mmol) in dichloromethane (500 mL). 1-Amino-2-methylpropan-2-ol (16.86 g, 189 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 16 hours and then-concentrated under reduced pressure. The residue was triturated with water and stirred for 1 hour. The precipitated solid was isolated by filtration, washed with water, and dried. This material was suspended in diethyl ether (400 mL), sonicated, isolated by filtration, and then dried in a vacuum oven at 40° C. for 16 hours to provide 58.1 g of 1-[(7-bromo-3-nitro[1,5]naphthyridin-4-yl)amino]-2-methylpropan-2-ol as a yellow solid, mp 189-190° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Li]CCCC.[C:17](=[O:19])=[O:18].O>CCOCC>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:17]([OH:19])=[O:18]
Reactant: Cc1cccc2c1ccn2C
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: Cc1cccc2c1cc(C(=O)O)n2C
Reaction time: 1 h
Yield: 26.4 %

Procedure:
A solution of 1,4-dimethyl-1H-indole (0.9 g, 6.2 mmole) in anhydrous Et2O (20 mL) was treated with 2.5 M n-BuLi in hexanes (5.0 mL, 12 mmole) and the reaction was heated at reflux for 15 hr. The dark reaction mixture was poured into a slurry of excess crushed dry ice in Et2O, and the mixture was allowed to stand for 1 hr. Water (10 mL) was added, the layers separated, and the aqueous layer was filtered through celite®. The clear filtrate was acidified with 2.0 N HCl to pH 2, and the precipitate was collected and dried to afford the title compound (0.29 g, 26.4%) as an off-white solid: MS (ES) m/e 190.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.Cl[S:13]([OH:16])(=[O:15])=[O:14]>ClCCl>[CH3:1][C:2]1([CH3:11])[C:6]2[CH:7]=[C:8]([S:13]([OH:16])(=[O:15])=[O:14])[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: CC1(C)COc2ccccc21
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: CC1(C)COc2ccc(S(=O)(=O)O)cc21
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3,3-dimethyl-2,3-dihydro-benzofuran (160 mg, 1.08 mmol) in dichloromethane (2 mL) at −10° C. was added chlorosulfonic acid (72 μL, 1.08 mmol). The mixture was stirred at −10° C. for 15 minutes, then the solvent was evaporated to give 3,3-dimethyl-2,3-dihydro-benzofuran-5-sulfonic acid [1H-NMR (300 MHz, CDCl3): 1.37 (s, 6H), 4.35 (s, 2H), 6.85 (d, J=8.2 Hz, 1H), 7.67 (d, J=2.1 Hz, 1H), 7.73 (dd, J1=8.5 Hz, J2=2.1 Hz, 1H), 10.12 (br s, 1H)]. The residue was diluted with thionyl chloride (1 mL, 13.71 mmol) and one drop of dimethylformamide was added. After 45 minutes reflux and evaporation of the solvent, the solid compound was washed in a mixture of dichloromethane/hexane to give 3,3-dimethyl-2,3-dihydro-benzofuran-5-sulfonyl chloride [1H-NMR (300 MHz, CDCl3): 1.41 (s, 6H), 4.41 (s, 2H), 6.92 (d, J=8.8 Hz, 1H), 7.74 (d, J=2.3 Hz, 1H), 7.87 (dd, J1=8.5 Hz, J2=2.1 Hz, 1H)]. A solution of methylamine 2.0 M in tetrahydrofuran (0.81 mL, 1.62 mmol) was then slowly added and the mixture was stirred at room temperature for 15 minutes. The solvent was evaporated to afford 215 mg of 3,3-dimethyl-2,3-dihydro-benzofuran-5-sulfonic acid methylamide. 83% yield. 1H-NMR (300 MHz, CDCl3): 1.38 (s, 6H), 2.66 (d, J=5.3 Hz, 3H), 4.21 (m, 1H), 4.34 (s, 2H), 6.86 (d, J=8.5 Hz, 1H), 7.60 (d, J=2.1 Hz, 1H), 7.66 (dd, J1=8.5 Hz, J2=1.8 Hz, 1H).
Reaction SMILES: [C:1]([O:7][OH:8])([CH2:4][CH2:5][CH3:6])([CH3:3])[CH3:2].[C:9](OC)([CH2:12][CH2:13][CH3:14])([CH3:11])[CH3:10]>>[C:1]([O:7][O:8][C:9]([CH2:12][CH2:13][CH3:14])([CH3:11])[CH3:10])([CH2:4][CH2:5][CH3:6])([CH3:3])[CH3:2]
Reactant: CCCC(C)(C)OO
Reactant: CCCC(C)(C)OC
Product: CCCC(C)(C)OOC(C)(C)CCC

Procedure:
In similar manner, although optimal conditions may vary, hydrogen peroxide may be reacted with methyl t-amyl ether to provide t-amyl hydroperoxide or di-t-amyl peroxide; with methyl t-hexyl ether to provide t-hexyl hydroperoxide or di-t-hexyl peroxide; with ethyl t-butyl ether to provide t-butyl hydroperoxide or di-t-butyl peroxide; with ethyl t-amyl ether to provide t-amyl hydroperoxide or di-t-amyl peroxide; with ethyl t-hexyl ether to provide t-hexyl hydroperoxide or di-t-hexyl peroxide; with n-propyl t-butyl ether to provide t-butyl hydroperoxide or di-t-butyl peroxide; with n-propyl t-amyl ether to provide t-amyl hydroperoxide or di t-amyl peroxide; or with n-propyl t-hexyl ether to provide t-hexyl hydroperoxide or di-t-hexyl peroxide. Illustrative of reactions employing hydroperoxide reactants are the reaction of t-butyl hydroperoxide with methyl t-butyl ether to provide di-t-butyl peroxide; the reaction of t-hexyl hydroperoxide with methyl t-hexyl ether to provide di-t-hexyl peroxide; the reaction of t-butyl hydroperoxide with methyl t-amyl ether to provide t-butyl t-amyl peroxide; the reaction of t-butyl hydroperoxide with methyl t-hexyl ether to provide t-butyl t-hexyl peroxide; and the reaction of t-amyl hydroperoxide with ethyl t-hexyl ether to provide t-amyl t-hexyl peroxide.
Reaction SMILES: [OH:1][C@:2]([C:32]1[CH:36]=[C:35]([CH3:37])[O:34][N:33]=1)([CH3:31])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]2[O:14][CH2:13][CH2:12][N:11]3[C:15]([C:21]([NH:23][CH:24]4CCOCC4)=[O:22])=[C:16]([C:18]([NH2:20])=[O:19])[N:17]=[C:10]3[C:9]=2[CH:30]=1.CN[C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1>>[OH:1][C@:2]([C:32]1[CH:36]=[C:35]([CH3:37])[O:34][N:33]=1)([CH3:31])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]2[O:14][CH2:13][CH2:12][N:11]3[C:15]([C:21]([NH:23][CH2:24][C:40]4[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=4)=[O:22])=[C:16]([C:18]([NH2:20])=[O:19])[N:17]=[C:10]3[C:9]=2[CH:30]=1
Reactant: CNc1cccnc1
Reactant: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NC4CCOCC4)n2CCO3)no1
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NCc4cccnc4)n2CCO3)no1

Procedure:
Prepared as described for (R)-10-(3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-yn-1-yl)-N3-(tetrahydro-2H-pyran-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide replacing oxan-4-amine hydrochloride with 3-(methylamino)pyridine. off-white solid (26.4 mg, 9%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([O:13][CH:14]([O:17][CH2:18][CH3:19])[CH:15]=[CH2:16])[CH3:12].C(O)(=O)C>C(#N)C>[CH2:11]([O:13][CH:14]([O:17][CH2:18][CH3:19])[CH2:15][CH2:16][SH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[CH3:1])[CH3:12]
Reactant: C=CC(OCC)OCC
Reactant: Cc1nc2ccccc2s1
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(CC[SH]1C(C)=Nc2ccccc21)OCC

Procedure:
1-(3,3-Diethoxypropyl)-2-methyl-benzothiazole was prepared by reaction of 2-methylbenzothiazole (125 mg, 0.84 mmol) with acrolein diethyl acetal (1.64 g, 12.6 mmol) and acetic acid (100 μl) in acetonitrile (4 ml) by a method analogous to that described in Section 1.2. The product was purified by HPLC on a Rainin Dynamax C18, 8 μm using a 0–100% gradient elution of water/acetonitrile (containing 0.1% TFA) over 60 minutes at 20 ml/min. The product was obtained as a colourless oil (220 mg, 95%); m/z (FAB−): 280.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH2:11])=[S:10].Br[CH:13]([CH:19]([CH3:21])[CH3:20])[C:14](OCC)=[O:15]>>[CH:19]([CH:13]1[S:10][C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[N:11][C:14]1=[O:15])([CH3:21])[CH3:20]
Reactant: Cc1ccccc1NC(N)=S
Reactant: CCOC(=O)C(Br)C(C)C
Product: Cc1ccccc1NC1=NC(=O)C(C(C)C)S1

Procedure:
Synthesis was performed from N-(2-methylphenyl)thiourea and ethyl 2-bromo-3-methylbutanoate according to Method C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]2)=[C:4]([F:28])[CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.[O:44]1[CH2:48][CH2:47][C@H:46]([C:49](O)=[O:50])[CH2:45]1>ClCCCl>[CH2:20]([N:17]([CH2:18][CH3:19])[C:15]([CH:14]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:49]([C@H:46]3[CH2:47][CH2:48][O:44][CH2:45]3)=[O:50])=[CH:3][C:4]=2[F:28])[CH2:9][CH2:10]1)=[O:16])[CH3:21]
Reactant: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc(N)cc2F)CC1
Reactant: O=C(O)[C@H]1CCOC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCCl
Product: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)[C@H]3CCOC3)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
A mixture of 2-[4-(4-amino-2-fluoro-phenyl)-piperazin-1-yl]-N,N-diethyl-2-phenyl-acetamide (0.30 mmol) and DCC (1.0 mmol) in DCE (10 mL) was stirred at rt for 1 h, then was treated with (S)-tetrahydro-furan-3-carboxylic acid (1.0 mmol), and was stirred at rt for 16 h. The mixture was concentrated, and the residue was purified by PTLC to provide the title compound (74 mg, 51%). MS (ESI): mass calcd. for C27H35FN4O3, 482.27. m/z found, 483.4 [M+H]+. 1H NMR (CDCl3): 7.75-7.60 (m, 1H), 7.55-7.26 (m, 5H), 7.10-7.00 (m, 1H), 6.84 (t, J=9.0, 1H), 4.21 (s, 1H), 4.05-3.72 (m, 4H), 3.50-3.10 (m, 4H), 3.10-2.95 (m, 5H), 2.73-2.60 (m, 4H), 2.28-2.18 (m, 2H), 1.14-1.02 (m, 6H).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][S:17][C:11]=2[N:10]=[C:9]1[CH2:19][CH:20]([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:28]Br.CCOC(C)=O>C(O)(=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][S:17][C:11]=2[N:10]=[C:9]1[CH:19]([Br:28])[CH:20]([CH3:22])[CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: Cc1nsc2nc(CC(C)C)n(Cc3ccccc3)c(=O)c12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1nsc2nc(C(Br)C(C)C)n(Cc3ccccc3)c(=O)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
To a solution of 5-benzyl-6-isobutyl-3-methyl-5H-isothiazolo[5,4-d]pyrimidin-4-one (method 27) (5.81 g, 18.5 mmol) and sodium acetate (10 g) in acetic acid (100 ml) at 100° C., a solution of the bromine (6 g, 38 mmol) in acetic acid (60 ml) was added dropwise over a period of 20 minutes. The reaction mixture was stirred at that temperature for 30 min and cooled and the TLC (eluent 10% EtOAc in hexanes) and MS showed the complete disappearance of the SM and only the product. The reaction mixture was poured into ice water and extracted with EtOAc (3×60 ml) and the organic layers were combined and washed with 2% sodium thiosulfate solution (60 ml), water (100 ml), brine (100 ml) and dried over Na2SO4. Concentration of the organic layer provided 5-benzyl-6-(1-bromo-2-methyl-propyl)-3-methyl-5H-isothiazolo[5,4-d]pyrimidin-4-one (7.27 g, 99%) as white crystalline solid. 1H NMR (300 MHz) δ 0.54 (d, 3H), 1.11 (d, 3H), 2.62-2.76 (m, 1H), 2.83 (s, 3H), 4.42 (d, 1H), 4.80 (d, 1H), 6.22 (d, 1H), 7.12-7.42 (m, 5H).