Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:8]([NH:10]C(=O)CCC)[CH:9]=1)([O-:3])=[O:2].CC(C)([O-])C.[K+].O>CN1CCCC1=O>[N+:1]([C:4]1[CH:9]=[C:8]2[C:7]([CH:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCC(=O)Nc1cc([N+](=O)[O-])ccc1C#Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc2cc(-c3ccccc3)[nH]c2c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 39.1 %

Procedure:
To a solution of N-(5-nitro-2-(phenylethynyl)phenyl)butyramide (580 mg, 1.88 mmol) in 1-Methyl-2-pyrrolidinone (20 mL) under nitrogen was added potassium tert-butoxide (243 mg, 2.16 mmol). The resulting solution was heated at 70° C. for 6 h, and then left at room temperature for 16 h. Water was added and the aqueous layer was extracted several times with ethyl acetate. The combined organic layers were washed 10 times with water, 3 times with brine, dried over anhydrous MgSO4 and evaporated. The resulting material was purified by column chromatography eluting with ethyl acetate/hexanes 15:85 v/v to afford 175 mg (39%) of the title compound.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:33]([OH:35])[CH3:34])[C@@H:3]1[O:5][C@H:4]1[CH2:6][C@@H:7]1[C@@H:12]([OH:13])[C@@H:11]([OH:14])[C@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:19])[O:9][CH2:8]1.[O-2:36].[Ca+2:37]>O>[CH3:1][C@H:2]([C@H:3]1[C@H:4]([CH2:6][C@H:7]2[CH2:8][O:9][C@@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O-:31])=[O:30])=[O:19])[C@H:11]([OH:14])[C@@H:12]2[OH:13])[O:5]1)[C@H:33]([CH3:34])[OH:35].[CH3:1][C@H:2]([C@H:3]1[C@H:4]([CH2:6][C@H:7]2[CH2:8][O:9][C@@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O-:31])=[O:30])=[O:19])[C@H:11]([OH:14])[C@@H:12]2[OH:13])[O:5]1)[C@H:33]([CH3:34])[OH:35].[OH2:36].[OH2:5].[Ca+2:37]
Reactant: [O-2]
Reactant: C/C(=C\C(=O)OCCCCCCCCC(=O)O)C[C@@H]1OC[C@H](C[C@@H]2O[C@H]2[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Agent: [Ca+2]
Solvent: O
Product: C/C(=C\C(=O)OCCCCCCCCC(=O)[O-])C[C@@H]1OC[C@H](C[C@@H]2O[C@H]2[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Temperature: 5 °C
Reaction time: 1 h
Yield: 131.3 %

Procedure:
Pseudomonic acid (10 g) was suspended in water (26 ml). Calcium oxide (0.58 g) was added to the suspension. The mixture was stirred for one hour, and filtered. The mixture was cooled to 5° C. After standing for 15 h, the crystalline product was filtered and washed with cooled water (10 ml) and dried in an air circulated oven at room temperature. Mupirocin calcium dihydrate (9.4 g, 87%) was obtained.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[C:24]1([C:34](O)=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][N:25]=2)=[O:35])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1nccc2ccccc12
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2nccc3ccccc23)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with Isoquinoline-1-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].O.NN.C([O-])(=O)C.[Na+].Br[CH:22]([CH3:24])[CH3:23]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:22]([CH3:24])[CH3:23])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]
Reactant: CC(C)Br
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Agent: CC(=O)[O-]
Agent: NN
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 12 %

Procedure:
To a solution of 4-bromo-3-fluorobenzene-1-sulfonyl chloride (5.40 mL, 36.5 mmol) in THF (150 mL) at 0° C. was added hydrazine monohydrate (6.20 mL, 63.9 mmol) dropwise under a nitrogen atmosphere. The reaction mixture was stirred for 1.5 hours. The solvent was removed in vacuo and replaced with heptanes (150 mL) and the resulting precipitate was collected by filtration. The solid was dissolved in industrial methylated spirit (150 mL) and to this solution was added sodium acetate (17.9 g, 218 mmol) and 2-bromopropane (17.2 mL, 183 mmol). The resultant reaction mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and quenched with water (300 mL) before being extracted with CH2Cl2 (3×300 mL). The combined organic extracts were washed with brine (300 mL), dried over MgSO4, filtered and evaporated in vacuo. The crude material was purified by silica gel column chromatography eluting with EtOAc:heptanes 20/80 to afford title compound as a colourless solid in 12% yield, 1.19 g.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3C(OCC3C=CC=CC=3)=O)=[N:9][C:10]=2Br)[CH:5]=[CH:6][N:7]=1.[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[NH:32][C:33](=[O:43])[C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:16][CH2:15][CH2:14][NH:13]3)=[N:9][C:10]=2[C:37]2[CH:38]=[CH:39][C:34]([C:33]([NH:32][C:28]3[S:27][CH:31]=[CH:30][N:29]=3)=[O:43])=[CH:35][CH:36]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c([C@@H]3CCCN3C(=O)OCc3ccccc3)nc(Br)c12
Reactant: O=C(Nc1nccs1)c1ccc(B(O)O)cc1
Product: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4nccs4)cc3)c12
Yield: 73.1 %

Procedure:
This intermediate was prepared, in an analogous manner as described for intermediate 2, from (S)-benzyl 2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (Intermediate 1e) and commercially available N-2-thiazolyl 4-boronobenzamide to afford the title compound (229 mg, 73.1%).
Reaction SMILES: [C:1]1([C@H:7]([CH3:11])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:15])=O>>[C:1]1([C@H:7]([CH3:11])[C:8]([Cl:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](C(=O)O)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Product: C[C@H](C(=O)Cl)c1ccccc1

Procedure:
Stir a solution of (S)-2-phenylpropanoic acid (300 mg, 2.0 mmol) in 5 mL of oxalyl chloride for 3 hours at room temperature. After removal of solvent under vacuum, (S)-2-phenylpropanoyl chloride is obtained as pole yellow oil. Dissolve the oil in 10 mL of CH2Cl2. Add (1S,2R,3R,5R)-2-((dimethylamino)methyl)-3-(3-hydroxyphenyl)bicyclo[3.2.1]octan-3-ol (400 mg, 1.45 mmol) and Et3N (293 mg, 2.9 mmol) to the solution. Stir the resultant mixture at room temperature for additional 3 hours. After addition of 20 mL of water, basify the mixture with K2CO3 to pH=10, and extract the aqueous mixture with EtOAc (20 mL×3). The combined organic layers are washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purify the residue by silica gel chromatography (CH2Cl2:MeOH=30:1) to afford (S)-3-((1S,2R,3R,5R)-2-((dimethylamino)methyl)-3-hydroxybicyclo[3.2.1]octan-3-yl)phenyl 2-phenylpropanoate (500 mg, 84.7%; MS (m/z): 408 (M+1)) as yellow oil. Stir (S)-3-((1S,2R,3R,5R)-2-((dimethylamino)methyl)-3-hydroxybicyclo[3.2.1]octan-3-yl)phenyl 2-phenylpropanoate (250 mg, 0.61 mmol) with H2O (11 mg, 0.61 mmol) and TMSCl (66 mg, 0.61 mmol) in 2-butanone (5 mL) for 3 hours. Collect the precipitate by filtration to afford (S)-3-((1S,2R,3R,5R)-2-((dimethylamino)methyl)-3-hydroxybicyclo[3.2.1]octan-3-yl)phenyl 2-phenylpropanoate hydrochlorid (215 mg, Yield: 79.3%) as white solid. The absolute configuration of its hydrochloride salt form was confirmed by x-ray analysis. 1H NMR (400 MHz, DMSO) δ 9.81 (br, 1H), 7.31-7.41 (m, 7H), 7.14 (s, 1H), 6.87-6.90 (m, 1H), 5.01 (s, 1H), 4.08-4.10 (m, 1H), 3.02-3.08 (m, 1H), 2.42-2.58 (m, 4H), 2.12-2.26 (m, 6H), 1.90-1.99 (m, 2H), 1.75-1.80 (m, 2H), 1.51-1.59 (m, 6H).
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([CH2:34][NH2:35])=[N:23][C:24]=2[NH:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)(=O)C.[S:36]([C:40]1[CH:48]=[CH:47][C:43]([C:44](O)=[O:45])=[CH:42][CH:41]=1)([OH:39])(=[O:38])=[O:37].CN(C)CCCN=C=NCC>CN(C)C=O.O>[OH:4][C@@H:5]1[C@H:9]([OH:10])[C@@H:8]([CH2:14][OH:15])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([CH2:34][NH:35][C:44]([C:43]1[CH:42]=[CH:41][C:40]([S:36]([OH:39])(=[O:38])=[O:37])=[CH:48][CH:47]=1)=[O:45])=[N:23][C:24]=2[NH:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C(O)c1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)nc(CN)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1nc(NC2CCCC2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)c1ccc(S(=O)(=O)O)cc1
Reaction time: 4 h
Yield: 47.4 %

Procedure:
To a solution of (2R,3R,4R,5R)-4-acetyloxy-5-(acetyloxymethyl)-2-[2-(aminomethyl)-6-(cyclopentylamino)purin-9-yl]oxolan-3-yl acetate (55 mg, 0.15 mmol) in a mixture of N,N-dimethylformamide (5 ml) and water (10 ml) was added 4-sulfobenzoic acid (37 mg, 0.153 mmol) and 1(3-dimethylaminopropyl)-3-ethylcarbodiimide (28 mg, 0.147 mmol), and the mixture was stirred for 4 hours. Solvent was removed under reduced pressure, and the residue was purified by HPLC, to provide 4-[N-({9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}methyl)carbamoyl]benzenesulfonic acid (39 mg). MS MH+548.57.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([CH:7]1[CH2:9][CH2:8]1)=O.O.[NH2:12][NH2:13]>C(O)(=O)C>[CH:7]1([C:5]2[CH2:4][C:3](=[O:2])[NH:12][N:13]=2)[CH2:9][CH2:8]1
Reactant: NN
Reactant: COC(=O)CC(=O)C1CC1
Solvent: O
Solvent: CC(=O)O
Product: O=C1CC(C2CC2)=NN1
Temperature: 100 °C
Yield: 147 %

Procedure:
To a solution of methyl-3-cyclopropyl-3-oxopropionate (10 g) and acetic acid (28 mL) in a round bottom flask under argon was added hydrazine hydrate (2.25 g). The mixture was immersed into an oil bath and heated to 100° C. overnight. The reaction vessel was then cooled and the acetic acid was evaporated in vacuo and the remaining solid was added to 1 N aqueous sodium hydroxide solution. The resulting precipitate was collected by filtration and washed with water and cold ether to afford the desired 5-cyclopropyl-2,4-dihydro-pyrazol-3-one (8.2 g) as a beige solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:6]=1[OH:14])([CH3:4])([CH3:3])[CH3:2]>[C].[Pd].C(O)C>[NH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:6]=1[OH:14]
Reactant: CC(C)(C)c1cccc([N+](=O)[O-])c1O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1cccc(N)c1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.1 %

Procedure:
A 10% palladium carbon catalyst (250 mg) was added to a solution of the nitrophenol (316 mg, 1.62 mmol) in ethanol (20 ml) and stirred under hydrogen atmosphere at room temperature for 12 hours. The reaction solution was filtered off through celite and the filtrate was evaporated in vacuo to provide 260 mg (yield 97%) of 2-amino-6-tert-butylphenol as red crystals. Potassium O-ethyl dithiocarbonate (242 mg, 1.51 mmol) was added to a solution of the aminophenol (227 mg, 1.37 mmol) in ethanol (10 ml) followed by heating to reflux for eight hours. After allowing to cool, the solvent was evaporated in vacuo and the resulting residue was dissolved in water, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over an hydrous sodium sulfate and the solvent was evaporated therefrom. The residue was purified by a silica gel column chromatography (20 g of silica gel; developing solvent, hexane:acetone=4:1) to provide 124 mg (yield 44%) of 7-tert-butyl-2-mercaptobenzooxazole as colorless crystals.
Reaction SMILES: Br[CH:2]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[NH2:21][C:22]([NH2:24])=[S:23].C([O-])(=O)C.[Na+]>>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:21]=[C:22]([NH2:24])[S:23][C:2]=2[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)C(Br)CCc2ccccc2)cc1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Product: COc1ccc(-c2nc(N)sc2CCc2ccccc2)cc1
Yield: 85.9 %

Procedure:
A procedure similar to step 5 of Example 6 was used. 2-bromo-1-(4-methoxy-phenyl)-4-phenyl-butan-1-one prepared in the step 3, thiourea and anhydrous sodium acetate were used as starting materials, refluxed for 3 hours, followed by post-treatment to give a crude product, which was recrystallized with anhydrous ethanol to obtain a product as a white solid in a yield of 85.9%, mp: 143-144 └. 1H-NMR (CDCl3, 400 MHz) δ: 2.90 (2H, t, J=7.60 Hz, CH2), 3.05 (2H, t, J=7.60 Hz, CH2), 3.82 (3H, s, OCH3), 4.99 (2H, br, NH2), 6.89 (2H, d, J=8.40 Hz, ArH), 7.12˜7.30 (5H, m, ArH), 7.35 (2H, d, J=8.40 Hz, ArH); EI-MS m/e (%): 310.1 (M+, 23), 219.1 (100), 177.1 (39); HREI-MS Calcd. for C18H18N2OS: 310.1140. found: 310.1140. Anal. Calcd. for C18H18N2OS: C, 69.65; H, 5.84; N, 9.02. found: C, 69.74; H, 5.86; N, 9.03.
Reaction SMILES: C(O[C:4](=[O:11])[CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH3:10])C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:22]1([NH:27][C:28]2[C:33]([CH:34]=O)=[CH:32][N:31]=[C:30]([S:36][CH3:37])[N:29]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1>[CH:22]1([N:27]2[C:28]3[N:29]=[C:30]([S:36][CH3:37])[N:31]=[CH:32][C:33]=3[CH:34]=[C:5]([CH2:6][CH2:7][O:8][CH2:9][CH3:10])[C:4]2=[O:11])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CCOCCCC(=O)OCC
Reactant: CSc1ncc(C=O)c(NC2CCCC2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOCCc1cc2cnc(SC)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a cooled (−78° C.) solution of 4-ethoxy-butyric acid ethyl ester (9.85 g, 61.47 mmol) in THF (25 ml) was added lithium bis(trimethylsilyl)amide (77.0 ml, 76.85 mmol, 1 M solution in THF). The reaction mixture was stirred for 10 minutes to form the anion. 4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde was then added and the reaction allowed to warm to RT and stirred overnight. The reaction mixture was quenched with 10% aqueous HCl (100 ml). The aqueous layer was extracted with ethylacetate (150 ml total) and the organic layers were combined and concentrated to give a yellow oil. Chromatographic purification on silica gel (chloroform/ethyl acetate gradient) gave 8-cyclopentyl-6-(2-ethoxy-ethyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (3.22 g, 9.65 mmol). MS (APCI+) 334 (M+1, 100); 1H NMR δ (400 MHz, DMSO-d6) 8.54 (s, 1H), 7.47–7.46 (m, 1H), 5.99–5.90 (m, 1H), 3.69 (t, J=6.25 Hz, 2H), 3.49 (q, J=7.03 Hz, 2H), 2.84 (t, J=6.25 Hz, 2H), 2.59 (s, 3H), 2.34–2.29 (m, 2H), 2.08–2.02 (m, 2H), 1.88–1.83 (m, 2H), 1.69–1.65 (m, 3H), 1.17 (t, J=7.04 Hz, 3H).
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:6]1([CH3:20])[N:10]2[C:11](=[O:18])[C:12]3[C:17]([C:9]2=[N:8][C:7]1=[O:19])=[CH:16][CH:15]=[CH:14][CH:13]=3)([CH3:5])[CH3:4].Cl>C(O)C.O1CCCC1>[CH:3]([C:6]1([CH3:20])[N:10]2[C:11](=[O:18])[C:12]3[C:17]([CH:9]2[NH:8][C:7]1=[O:19])=[CH:16][CH:15]=[CH:14][CH:13]=3)([CH3:5])[CH3:4]
Reactant: CC(C)C1(C)C(=O)N=C2c3ccccc3C(=O)N21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)C1(C)C(=O)NC2c3ccccc3C(=O)N21
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
To a stirred suspension of 10.4 g (0.274 mole) sodium borohydride in 164 ml absolute ethanol under nitrogen was added dropwise at 5° C a solution of 133.9 g (0.548 mole) of 2,5-dihydro-3-isopropyl-3-methyl-3H-imidazo[2,1-a]isoindole-2,5-dione in 155 ml tetrahydrofuran. After the addition, the mixture is stirred a further 3 hours at room temperature and then poured over 1070 g ice with stirring. The mixture is acidified with concentrated HCl and after stirring for 1.5 hours, the precipitate removed by filtration, washed with water and air-dried to give 118.7 g of 1,9b-dihydro-3-isopropyl-3-methyl-5H-imidazo[2,1-a]isoindole-2(3H),5-dione, melting point 178°-200° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21](Br)([F:23])[F:22].[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[F:22][C:21]([F:23])=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1ccccc1
Reactant: FC(F)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)=Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
5.25 g (0.02 mol) of triphenyl phosphine was dissolved in 20 ml of dichloromethane, and the mixture was cooled to 0° C. 2.1 g (0.01 mol) of dibromodifluoromethane was added to the mixture using an injector, and the reaction mixture was stirred for 30 minutes at room temperature. 1.06 g (0.01 mol) of benzaldehyde was added thereto and the mixture was refluxed for 4 hours. The resulting mixture was distilled under a reduced pressure at 40° C./1 mmHg using a distilling apparatus to obtain the title compound (0.81 g, 57.5%).
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:17]([NH:20][C:21]4[CH:42]=[CH:41][C:24]([C:25]([NH:27][C@H:28]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:26])=[CH:23][CH:22]=4)(=[O:19])=[O:18])[CH:15]=[CH:16][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1>COCCOCCOC.[Pd]>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:17]([NH:20][C:21]4[CH:22]=[CH:23][C:24]([C:25]([NH:27][C@H:28]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:26])=[CH:41][CH:42]=4)(=[O:19])=[O:18])[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(NS(=O)(=O)c2ccc3c(c2)-c2c(nc(C)[nH]c2=O)CC3)cc1)C(=O)OCC
Agent: [Pd]
Solvent: COCCOCCOC
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(NS(=O)(=O)c2ccc3ccc4nc(C)[nH]c(=O)c4c3c2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
A solution of diethyl N-(4-((1,2,5,6-tetrahydro-3-methyl-1-oxo-benzo-[f]quinazolin-9-yl) sulfonamido)benzoyl)-L-glutamate (0.50 g, 0.84 mmol) in diglyme (10 ml) was stirred with 10% palladium on carbon (0.25 g) (Aldrich) under nitrogen at reflux for 3 hours. The solution was diluted with diglyme (20 ml), filtered hot through celite, and concentrated under high vacuum. The resulting solid was suspended in hot methanol (50 ml), stirred overnight at room temperature, filtered, and dried under high vacuum to give diethyl N-(4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)sulfonamido)benzoyl)-L-glutamate as a white solid (0.25 g). 1H NMR (DMSO-d6, 200 MHz) δ: 1.10 (t, J=7 Hz, 3H, ester CH3), 1.12 (t, J=7 Hz, 3H, ester CH3), 1.78-2.15 (m, 2H, glu CH2), 2.35 (t, J=7 Hz, 2H, glu CH2), 2.4 3 (s, 3H, C3 --CH3), 3.98 (q, J=7 Hz, 2H, ester CH2), 4.04 (q, J=7 Hz, 2H, ester CH2), 2.35-4.39 (m, 1H, glu CH), 7.21 (d, J=9 Hz, 2H, Ar), 7.69 (d, J=9 Hz, 2H, Ar), 7.76 (d, J=9 Hz, 1H, Ar), 7.91 (dd, J=9,2 Hz, 1H, Ar), 8.19 (d, J=9 Hz, 1H, Ar), 8.29 (d, J 9 Hz, 1H, Ar), 8.51 (d, J=7 Hz, 1H, glu NH), 10.44 (d, J=2 Hz, 1H, Ar), 10.88 (br s, 1H, SO2NH), 12.75 (br s, 1H, N2H). Mass spectrum (CI-CH4): 595 (M+1, 24.1%). Anal. Calculated for C29H30N4O8S: C, 58.58; H, 5.08; N, 9.42; S, 5.39. Found: C, 58.46; H, 5.10; N, 9.34; S, 5.41.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH2:5]([O:7][C:8](=[O:11])[NH:9][NH2:10])[CH3:6]>CCOCC>[C:8]([NH:9][NH:10][C:1]([Cl:4])=[O:2])([O:7][CH2:5][CH3:6])=[O:11]
Reactant: O=C(Cl)Cl
Reactant: CCOC(=O)NN
Solvent: CCOCC
Product: CCOC(=O)NNC(=O)Cl
Reaction time: 8 h

Procedure:
A one-liter flask is fitted with a gas-dispersion tube, a 500 ml dropping funnel, a stirrer and a condenser fitted with a drying tube. The gas-dispersion tube is connected to a laboratory tank of phosgene on a pan balance. Dry ether, 200 ml, is placed in the flask. The flask is cooled with an ice bath. Phosgene, 115 g (1.2M) is run into the ether. Ethylcarbazate, 24 g (0.24M), is added to 500 ml of ether and placed in the dropping funnel. The solution of ethylcarbazate is added slowly and when addition is complete, the reaction is allowed to stir overnight. The solution is filtered and the solvent and excess phosgene removed with a vacuum pump fitted with a dry-ice trap. The trapped phosgene is destroyed by addition to a mixture of NaHCO3 solution and ice. The product is a white powder which is redissolved in ether and filtered. The ether is evaporated resulting in a crystalline white solid weighing 38 g, mp 77°-80°.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([F:22])[CH:20]=3)[N:15]=[CH:14][C:13]2=[O:23])[CH2:6][CH2:5]1.[O:24]=[C:25]1[CH2:30][S:29][C:28]2[CH:31]=[CH:32][C:33]([CH:35]=O)=[N:34][C:27]=2[NH:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CO.O.C(N(CC)CC)C.C(Cl)(Cl)Cl>[ClH:1].[ClH:1].[F:22][C:19]1[CH:20]=[C:21]2[C:16]([N:15]=[CH:14][C:13](=[O:23])[N:12]2[CH2:11][CH2:10][N:7]2[CH2:6][CH2:5][CH:4]([NH:3][CH2:35][C:33]3[CH:32]=[CH:31][C:28]4[S:29][CH2:30][C:25](=[O:24])[NH:26][C:27]=4[N:34]=3)[CH2:9][CH2:8]2)=[CH:17][CH:18]=1
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: O=C1CSc2ccc(CNC3CCN(CCn4c(=O)cnc5ccc(F)cc54)CC3)nc2N1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
A solution of 1-[2-(4-amino-1-piperidinyl)ethyl]-7-fluoro-2(1H)-quinoxalinone dihydrochloride (60 mg; 0.166 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde (for a synthesis, see WO2004058144, Example 7(d)) (32 mg, 0.166 mmol) in MeOH (3 ml), chloroform (3 ml) and triethylamine (0.06 ml) was stirred at rt for 1 h then heated at 70° C. overnight. It was cooled and sodium triacetoxyborohydride (0.106 g; 0.5 mmol) was added and the mixture was stirred at rt for 5 h. More 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (4 mg) was added and the mixture was stirred for 3 h at rt. Sodium triacetoxyborohydride (53 mg) was added and the mixture was stirred at rt for 72 h. Water and sodium carbonate solution were added and the mixture was extracted (3×) with 10% MeOH-DCM, dried (sodium sulphate), evaporated, and chromatographed on silica gel, eluting with 0-15% MeOH-DCM to give the free base of the title compound.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6]1[C:14]2[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[N:11][C:10]=2[CH:9]=[C:8]([C:21]([F:24])([F:23])[F:22])[CH:7]=1.CN1CC[N:30]([C:33](=O)[CH:34]=[CH:35]C2C3N(C4C=CC=CC=4)C=NC=3C=C(C(F)(F)F)C=2)CC1>>[C:15]1([N:13]2[C:14]3[C:6]([CH:5]=[CH:4][C:3]([NH:30][CH2:33][CH2:34][CH3:35])=[O:2])=[CH:7][C:8]([C:21]([F:22])([F:23])[F:24])=[CH:9][C:10]=3[N:11]=[CH:12]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Reactant: CN1CCN(C(=O)C=Cc2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)CC1
Product: CCCNC(=O)C=Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12

Procedure:
This was prepared from 3-(3-phenyl-6-trifluoromethyl-3H-benzoimidazol-4-yl)acrylic acid methyl ester in a similar manner to 1-(4-methylpiperazin-1-yl)-3-(3-phenyl-6-trifluoromethyl-3H-benzimidazol-4-yl)prop-2-en-1-one. The oily residue was purified by preparative LCMS to afford, after removal of the solvent, the title compound as a white solid (16 mg, 6%), m/z 374.0 (M+H)+.