Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:9]=2[C:10](O)=[O:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[NH2:20][NH2:21]>>[CH:1]1([C:6]2[C:8]3[C:9](=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[C:10](=[O:11])[NH:21][N:20]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C(=O)C2CCCC2)c(C(=O)O)c1
Reactant: NN
Solvent: O
Product: COc1ccc2c(C3CCCC3)n[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting unpurified 2-cyclopentanecarbonyl-5-methoxybenzoic acid with hydrazine hydrate.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.CN(P(N(C)C)(N(C)C)=O)C.O.C(OCC)C>O1CCCC1>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH:6]1[CH2:2][CH2:3][CH2:4][S:5]1
Reactant: ClCCCSCc1ccccn1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Solvent: O
Product: c1ccc(C2CCCS2)nc1
Reaction time: 1 h
Yield: 69.9 %

Procedure:
A solution of pyrid-2-ylmethyl 3-chloropropyl sulphide (330 g) in anhydrous tetrahydrofuran (400 cc) is added dropwise, in the course of 20 minutes, at a temperature of about 25° C., to a solution of potassium tert.-butylate (283 g) in a mixture of anhydrous hexamethylphosphorotriamide (428 cc) and anhydrous tetrahydrofuran (2300 cc). After stirring for 1 hour, the reaction mixture is added to a mixture of distilled water (4200 cc) and diethyl ether (2500 cc). After decantation, the aqueous phase is again extracted with diethyl ether (1700 cc). The combined ether extracts are washed three times with distilled water (12600 cc in total), dried over anhydrous sodium sulphate and concentrated to dryness. 2-(Pyrid-2-yl)-tetrahydrothiophene (189 g) is thus obtained in the form of a brown oil [Rf=0.56; chromatography on a thin layer of silica gel; solvent: ethyl acetate-cyclohexane (50:50 by volume)].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[C:11](=[O:23])[C:10]([O:24][CH3:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.Br[C:27]1[S:28][CH:29]=[CH:30][N:31]=1.Cl>C(O)C>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:12]2[C:11](=[O:23])[C:10]([O:24][CH3:25])=[N:9][N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:27]4[S:28][CH:29]=[CH:30][N:31]=4)[CH:3]=3)[C:13]2=[O:14])=[CH:17][CH:18]=1
Reactant: Brc1nccs1
Reactant: COc1nn(-c2cccc(N)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Agent: Cl
Solvent: CCO
Product: COc1nn(-c2cccc(Nc3nccs3)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Temperature: 100 °C
Yield: 6.5 %

Procedure:
According to Scheme 9 Step 2: To a Solution of 2-(3-Aminophenyl)-4-(4-chlorobenzyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione (125 mg, 0.34 mmol) in ethanol (10 ml) was added bromothiazole (124 μL, 1.4 mmol) and 5 mL of concentrated hydrochloric acid. The reaction mixture was heated to 100° C. for 48 hours. The reaction mixture was quenched and neutralised with sat NaHCO3 and extracted in ethyl acetate (×3). The organic layers were combined and successively washed with water, brine, dried over MgSO4, filtered and concentrated. The crude oily solid was purified by flash chromatography, 10 g prepacked column, cyclohexane/ethyl acetate 70/30 to afford 4-(4-chlorobenzyl)-6-methoxy-2-(3-(thiazol-2-ylamino)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione 4.144 (10 mg (Yield=6.5%) as a white solid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:33]=[C:32]3[C:28]([C:29]([NH:42][C:43](=[O:47])[CH2:44][CH2:45][CH3:46])=[N:30][N:31]3COCC[Si](C)(C)C)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1>[N:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:33]=[C:32]3[C:28]([C:29]([NH:42][C:43](=[O:47])[CH2:44][CH2:45][CH3:46])=[N:30][NH:31]3)=[CH:27][CH:26]=2)=[CH:23][CH:24]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccncc3)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccncc3)ccc12
Temperature: 67 °C

Procedure:
4.1 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 280 mg of N-[6-(4-pyridyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 20 cm3 of tetrahydrofuran, the medium is maintained at 67° C. for 17 hours and is then allowed to return to room temperature to add 50 cm3 of ethyl acetate and 50 cm3 of saturated aqueous sodium hydrogen carbonate solution. The organic phase is washed with 50 cm3 of saturated aqueous sodium chloride solution and then with 50 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 45° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2 cm), eluting with ethyl acetate. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure (2 kPa; 50° C.). The residue is taken up in 10 cm3 of diisopropyl ether, filtered off on a sinter funnel and then washed successively with 5 cm3 of ethyl acetate and with 10 cm3 of diisopropyl ether. After drying (90 Pa; 50° C.), 60 mg of N-[6-(4-pyridyl)-1H-indazol-3-yl]butanamide are obtained in the form of a white solid melting at 200° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH3:7])[CH2:5][NH2:6])[CH3:2].C([N:16]=[C:17]=[S:18])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].S(=O)(=O)(O)O>C(Cl)(Cl)Cl>[CH2:1]([O:3][CH:4]([CH3:7])[CH2:5][NH:6][C:17]([NH2:16])=[S:18])[CH3:2]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CCOC(C)CN
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CCOC(C)CNC(N)=S
Temperature: 75 °C
Yield: 68 %

Procedure:
2-Ethoxy-propylamine (1.50 g, 14.5 mmol) and benzoylisothiocyanate (2.61 g, 16.0 mmol) in chloroform (50 mL) were heated at 75° C. for 1 h. The solvent was removed under reduced pressure and methanol (15 mL) and water (30 mL) were added. Potassium carbonate (2.0 g, 14.5 mmol) was added and the mixture was heated at 75° C. for 2 h. After cooling to room temperature, the mixture was neutralized with 2M sulphuric acid and the solvent was removed under reduced pressure. The crude product was dissolved in methanol and insoluble material was removed by filtration. The solvent was distilled off and the resulting solid was washed with dichloromethane and dissolved in ethanol. Insoluble material was removed by filtration and the solvent was removed under reduced pressure. This gave the title compound as a white solid (1.6 g, 59% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[S:4][C:5]([C:9]([OH:11])=O)=[C:6]([CH3:8])[N:7]=1.CN(C)C1SC(C(Cl)=O)=C(C)N=1.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.[NH2:32][CH:33]([C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)[C:34]#[N:35]>C(N(CC)CC)C>[C:34]([CH:33]([NH:32][C:9]([C:5]1[S:4][C:3]([N:2]([CH3:1])[CH3:12])=[N:7][C:6]=1[CH3:8])=[O:11])[C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)#[N:35]
Reactant: Cc1nc(N(C)C)sc1C(=O)O
Reactant: N#CC(N)c1cccs1
Agent: Cc1nc(N(C)C)sc1C(=O)Cl
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc(N(C)C)sc1C(=O)NC(C#N)c1cccs1
Yield: 33.7 %

Procedure:
1.2g of 2-dimethylamino-4-methyl-thiazole-5-carboxylic acid was converted into 2-dimethylamino-4-methyl-thiazole-5-carboxylic acid chloride using 1.3g of phosphorus pentachloride according to the same procedure as EXAMPLE 1. Then 1.1g of amino-thiophen-2-yl-acetonitrile hydrochloride and 2.5ml of triethylamine were added thereto and the reaction mixture was treated according to the same procedure as EXAMPLE 1 to obtain 0.65g (Yield 36%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[N:16]([CH:17]=2)[C:15]2[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=2[S:13]3)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][Cl:32].O>CN(C=O)C>[Cl:32][CH2:31][CH2:30][O:22][C:20]1[CH:19]=[CH:18][C:15]2[N:16]3[CH:17]=[C:10]([C:7]4[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=4)[N:11]=[C:12]3[S:13][C:14]=2[CH:21]=1
Reactant: ClCCBr
Reactant: O=[N+]([O-])c1ccc(-c2cn3c(n2)sc2cc(O)ccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-c2cn3c(n2)sc2cc(OCCCl)ccc23)cc1

Procedure:
To a stirred solution of 2-(4-nitrophenyl)imidazo[2,2-b]benzothiazol-7-ol (2) (1 equivalent) in anhydrous DMF at rt are added potassium carbonate (2-3 equivalents) and 1-bromo-2-chloroethane (2-3 equivalents), and the mixture is stirred at a temperature between rt and 60° C. until the reaction is substantially complete as monitored by LCMS or TLC. The mixture is added to water and the resulting aqueous mixture is extracted with EtOAc. The organic layer is separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel flash chromatography to afford 7-(2-chloro-ethoxy)-2-(4-nitro-phenyl)-benzo[d]imidazo[2,1-b]thiazole.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:28](=[O:29])[N:7]2[CH:8]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:30])[C:5]1=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=4.[CH:32]1([NH2:36])[CH2:35][CH2:34][CH2:33]1>>[CH:32]1([NH:36][CH2:2][CH2:3][N:4]2[C:28](=[O:29])[N:7]3[CH:8]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=4)[C:9]4[NH:10][C:11]5[C:16]([C:17]=4[CH2:18][C:6]3([CH3:30])[C:5]2=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=5)[CH2:35][CH2:34][CH2:33]1
Reactant: NC1CCC1
Reactant: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCBr)C(=O)N1C3c1cccc(O)c1
Product: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCNC2CCC2)C(=O)N1C3c1cccc(O)c1

Procedure:
The title compound is prepared similarly as described for example 30 using (3aSR,10RS)-2-(2-Bromoethyl)-10-(3-hydroxy-phenyl)-6-methoxy-3a-methyl-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenta[b]-fluorene-1,3-dione (example 24) and cyclobutyl amine as starting materials. MS: m/z (MH+)=475.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[N:10][N:11]3[C:16](O)=[CH:15][C:14]([CH3:18])=[N:13][C:12]=23)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.O=P(Cl)(Cl)[Cl:37].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:37][C:16]1[N:11]2[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:12]2[N:13]=[C:14]([CH3:18])[CH:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Cl)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Temperature: 100 °C

Procedure:
To a slurry of 3-(4-chlorophenyl)-2-(2-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-ol (I-3A-4a; 1.08 g, 2.92 mmol) and diisopropylethylamine (0.763 ml, 4.38 mmol) in toluene (30 ml) at room temperature was added POCl3 (1.36 ml, 14.6 mmol), dropwise. The mixture was heated at 100° C. for 16 hours, cooled to room temperature, then slowly added to a stirred mixture of ice, saturated aqueous sodium bicarbonate and ethyl acetate. The aqueous layer was separated and extracted with additional ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), and then concentrated, in vacuo, to afford the crude product. Purification on a Biotage™ Flash 40M column using 0–10% ethyl acetate in hexanes as eluant afforded I-3A-4b (1.05 g, 92%) as a yellow solid: +ESI MS (M+1) 388.1; 1H NMR (400 MHz, CD2Cl2) δ 7.55–7.35 (m, 6H), 7.26 (d, J=8.7 Hz, 2H), 6.98 (s, 1H), 2.64 (s, 3H).
Reaction SMILES: Cl.[CH2:2]([O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH2:9][NH2:10])[CH2:3][CH3:4].[Cl:16][C:17]1[C:18](=[O:27])[N:19]([CH:24]([CH3:26])[CH3:25])[N:20]=[CH:21][C:22]=1Cl.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[Cl:16][C:17]1[C:18](=[O:27])[N:19]([CH:24]([CH3:25])[CH3:26])[N:20]=[CH:21][C:22]=1[NH:10][CH2:9][C:8]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:6]([O:5][CH2:2][CH2:3][CH3:4])[CH:7]=1
Reactant: CCCOc1cc(CN)ccc1OC
Reactant: CC(C)n1ncc(Cl)c(Cl)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCCOc1cc(CNc2cnn(C(C)C)c(=O)c2Cl)ccc1OC
Reaction time: 8 h

Procedure:
A mixture comprising 1.34 g of 3-n-propoxy-4-methoxybenzylamine hydrochloride, 0.4 g of 4,5-dichloro-2-i-propyl-3(2H)pyridazinone, 1.08 g of potassium carbonate, 6 ml of 1,4-dioxane and 18 ml of water was refluxed under stirring for 8 hours. The solvent was distilled off under reduced pressure, and water was added to the the residue thereby obtained, and then the mixture was extracted with ethyl acetate. The extract was washed successively with diluted hydrochloric acid, water and a saturated sodium chloride aqueous solution, and dried over sodium sulfate, and then the solvent was distilled off. The product was crystallized from ethyl acetate-diethyl ether-n-hexane to obtain 230 mg of the above identified compound having a melting point of from 120° to 122° as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH:9][CH2:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[C:6]([F:8])[CH:7]=1.[Cl:17][CH2:18][C:19]([O-])=O.[Na+].CS(C1C2C(=CN=CC=2)NN=1)(=O)=O>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]2[N:9]([CH2:10][CH2:11][C:12]([F:13])([F:14])[F:15])[C:19]([CH2:18][Cl:17])=[N:16][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)cc(F)c1NCCC(F)(F)F
Reactant: O=C([O-])CCl
Agent: CS(=O)(=O)c1n[nH]c2cnccc12
Agent: [Na+]
Product: Fc1cc(Cl)cc2nc(CCl)n(CCC(F)(F)F)c12

Procedure:
5-Chloro-2-chloromethyl-7-fluoro-1-(3,3,3-trifluoro-propyl)-1H-benzoimidazole was prepared according to the procedure described in Example 2-1 by using 4-chloro-6-fluoro-N-(3,3,3-trifluoropropyl)benzene-1,2-diamine and sodium 2-chloroacetate instead of 5-chloro-2-chloromethyl-1-((S)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-1H-benzoimidazole and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine. MS obsd. (ESI+) [(M+H)+] 315.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:91]=[CH:92][CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([N:71]5[CH2:76][CH2:75][N:74]([CH2:77][C:78]([NH2:80])=[O:79])[CH2:73][CH2:72]5)=[CH:67][CH:66]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:91]=[CH:92][CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([N:71]5[CH2:76][CH2:75][N:74]([CH2:77][C:78]([NH2:80])=[O:79])[CH2:73][CH2:72]5)=[CH:69][CH:70]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(CC(N)=O)CC5)cc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cc2)CC1
Yield: 53 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 2-(4-(4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl) acetamide (25 mg, 0.037 mmol) was hydrolyzed by lithium hydroxide (7 mg, 0.188 mmol) in THF/methanol/water (2/2/2 ml) to afford 10 mg (52.6% yield) of the titled compound after purification by preparative TLC (Silicagel-1000 micron) using 3% methanol in DCM as eluent. MS: m/z=553.2 (M+1). 1H NMR (CD3OD, 400 MHz): δ 8.45-8.44 (d, 1H), 8.32-8.31 (d, 1H), 8.20 (s, 1H), 7.93 (s, 1H), 7.62-7.60 (m, 3H), 7.42-7.34 (q, 1H), 7.13-7.11 (m, 3H), 7.05-7.02 (m, 2H), 5.45 (s, 2H), 3.12 (s, 2H), 2.76 (s, 4H). MS: m/z=510.3 (M+1), HPLC: 92.51% in method A.
Reaction SMILES: C([NH:8][C@@H:9]([C:24]([NH:26][C@@H:27]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[CH3:28])=[O:25])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])(OC(C)(C)C)=O.[ClH:37]>CCOC(C)=O>[ClH:37].[C:14]([NH:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:24]([NH:26][C@@H:27]([C:29]1[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[CH3:28])=[O:25])[NH2:8])([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15]
Reactant: COc1ccc([C@@H](C)NC(=O)[C@@H](CCCNC(=O)OCc2ccccc2)NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc([C@@H](C)NC(=O)[C@H](N)CCCNC(=O)OCc2ccccc2)cc1

Procedure:
(R)-N2 -(Boc)-N5 -(Cbz)-(R)-N-[1-(4-methoxyphenyl)ethyl]ornithine amide (14.0 g; from step (a) above) in EtOAc (300 mL) was treated with EtOAc saturated with hydrogen chloride (HCl/EtOAc; 300 mL) at room temperature for 5 hours. The solution was concentrated to give the crude sub-title compound as a crushable foam (12.9 g) which was used without purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C@H:11]([NH:13][C@@H:14]2[C@@H:19]([OH:20])[C@H:18]([CH2:21][C:22]3[CH:27]=[C:26]([O:28][C@H:29]([CH2:34][O:35][CH3:36])[C:30]([F:33])([F:32])[F:31])[C:25]([N+:37]([O-:39])=[O:38])=[C:24]([F:40])[CH:23]=3)[CH2:17][S:16][CH2:15]2)[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH:41]O>C1COCC1.CC(O)=O.CCOC(C)=O>[C:1]([C:5]1[CH:6]=[C:7]([C@H:11]([NH:13][C@@H:14]2[C@@H:19]([OH:20])[C@H:18]([CH2:21][C:22]3[CH:27]=[C:26]([O:28][C@H:29]([CH2:34][O:35][CH3:36])[C:30]([F:32])([F:31])[F:33])[C:25]([N+:37]([O-:39])=[O:38])=[C:24]([F:40])[CH:23]=3)[CH2:17][S:16](=[O:41])[CH2:15]2)[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: OO
Reactant: COC[C@@H](Oc1cc(C[C@@H]2CSC[C@H](N[C@H](C)c3cccc(C(C)(C)C)c3)[C@H]2O)cc(F)c1[N+](=O)[O-])C(F)(F)F
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC[C@@H](Oc1cc(C[C@@H]2CS(=O)C[C@H](N[C@H](C)c3cccc(C(C)(C)C)c3)[C@H]2O)cc(F)c1[N+](=O)[O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of (3R,4S,5S)-3-[(R)-1-(3-tert-butyl-phenyl)-ethylamino]-5-[3-fluoro-4-nitro-5-((R)-2,2,2-trifluoro-1-methoxymethyl-ethoxy)-benzyl]-tetrahydro-thiopyran-4-ol (0.249 g, 0.423 mmol) in THF (2 mL) and AcOH (1 mL) was treated with 0.22 mL 30% H2O2 and stirred for 18 h at 25° C. The mixture was diluted with EtOAc and washed with aq. Na2S2O3, and brine. The organic layer was dried over Na2SO4 and evaporated to give (3R,4S,5S)-3-[(R)-1-(3-tert-butyl-phenyl)-ethylamino]-5-[3-fluoro-4-nitro-5-((R)-2,2,2-trifluoro-1-methoxymethyl-ethoxy)-benzyl]-1-oxo-hexahydro-1lambda*4*-thiopyran-4-ol as a mixture of sulfoxide diastereomers (HPLC RtH1=2.30, 2.39 min; ESIMS [M+H]+=605), pure enough for further transformation. This product was dissolved in THF-MeOH 4:1 (5 mL) and stirred in the presence of 10% Pd—C (0.1 g) under an atmosphere of hydrogen at 45° C. for 1.5 h. The mixture was filtered over Celite, evaporated and dissolved in 5 mL 3N HCl in MeOH. After 3 d the reaction mixture was concentrated and taken up in 10% aq. Na2CO3 solution and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and evaporated. The title compound was obtained after purification by column chromatography on silica gel (EtOAc/5% MeOH) 70-0% hexane as a colorless foam: HPLC RtH1=2.535 min; ESIMS [M+H]+=575; [α]D=−9.8° (c=0.4, CH2Cl2); 1H NMR (600 MHz, DMSO-d6): δ 7.37 (s, 1H), 7.23-7.20 (m, 2H), 7.13 (m, 1H), 6.69 (s, 1H), 6.61 (d, 1H), 5.10 (m, 1H), 4.82 (s, OH), 4.59-4.55 (NH2), 3.80 (m, 1H), 3.70 (m, 2H), 3.30 (s, 3H), 3.23 (d, 1H), 3.02 (m, 1H), 2.92 (m, 1H), 2.80 (m, 1H), 2.62 (m, 1H), 2.39 (m, 1H), 2.25-2.18 (m, 3H), 1.25 (s, 9H), 1.20 (d, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[O:21]C)[C:5]=2[CH:4]=1.Cl.N1C=CC=CC=1>O>[OH:2][C:3]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[OH:21])[C:5]=2[CH:4]=1
Reactant: COc1ccc2c3ccccc3c3c(OC)cccc3c2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Oc1ccc2c3ccccc3c3c(O)cccc3c2c1
Temperature: 220 °C
Yield: 98.8 %

Procedure:
2,9-dimethoxytriphenylene (49.1 g, 0.170 mol) and pyridine hydrochloride (200 g, 1.70 mol) were placed in a 500 mL round-bottom flask equipped with a stir bar, reflux condenser, and a nitrogen inlet and heated at 220° C. for 90 minutes. The solution was cooled and water was added, resulting in the formation of a white precipitate, which was collected by vacuum filtration, washed with water, and dried in vacuo to yield 43.7 g (96%) of 2,9-dihydroxytriphenylene.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C(N(CC)CC)C.[OH:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20][CH3:21])=O.[CH:25]12[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[C:26]1=O)[CH2:32]2>C1COCC1.O>[OH:14][C:15]1[CH:16]=[C:17]([CH2:18][O:20][CH2:21][C:25]23[CH2:34][CH:29]4[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]4)[CH2:26]2)[CH2:32]3)[CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Oc1cccc(COCC23CC4CC(CC(C4)C2)C3)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
[(3-Hydroxyphenyl)methoxymethyl]adamantane (1a) was prepared as described in my previous application Ser. No. 224,681, filed Jul. 27, 1988. A 500-mL flask was fitted with a reflux condenser, a 125-mL addition funnel, and nitrogen line. The apparatus was dried by means of a hot air gun and nitrogen purging. Dry THF (40 mL) was added and the flask cooled in an ice bath. TiCl3 (1.5 g, 10 mmol) was added rapidly followed by LAH (0.19 g, 5 mmol) in portions with stirring. The cooling bath was removed and the black mixture was allowed to warm to room temperature. Triethylamine (0.7 mL, 5 mmol) was added to the stirred suspension and refluxed for 15 min. After this period, a solution of methyl 3-hydroxybenzoate (152 mg, 1 mmol) and 2-adamantanone (300 mg, 2 mmol) in 20 mL of dry THF was added dropwise to the refluxing mixture over 15 min. Refluxing was continued for an additional 15 min after which the reaction was cooled to room temperature and diluted with 100 mL of distilled water. The aqueous solution was extracted with 3×50 mL portions of ethyl acetate. The combined organic layer was washed with water, dried over MgSO4, and concentrated. Chromatography over silica with 15% ethyl acetate/hexane gave 240 mg (89%) of 1a as a white solid: mp 133°-4° C.; 1H NMR (CDCl3) δ1.64-1.96 (m, 12H), 2.65 (s, 1H), 3.24 (s, 1H), 3.32 (s, 3H), 5.25 (s, 1H, OH exchange with D2O), 6.70-7.30 (m, 4H); 13C NMR (CDCl3) δ28.45, 30.36, 32.36, 37.30, 39.18, 39.33, 57.82, 114.60, 116.16, 122.19, 129.24, 137.24, 155.62; MS m/e (rel intensity) 271 (20, M+1), 270 (100, M), 253 (7.3), 213 (35.1), 121 (41.7), 93 (9.4); Exact mass: calcd 270.1619, found 270.1616. ##STR21##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[CH2:25]([O:28][CH2:29][CH2:30]Cl)[CH2:26]Cl>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:30][CH2:29][O:28][CH2:25][CH2:26]2)=[CH:4][C:3]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)Nc1cc(N)ccc1F
Reactant: ClCCOCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)ccc1F
Temperature: 150 °C
Yield: 35.1 %

Procedure:
To a mixture of tert-butyl (2-fluoro-5-aminophenyl)carbamate (2.02 g, 8.93 mmol), K2CO3 (2.47 g, 17.86 mmoll) and NaI (4.02 g, 26.79 mmol) in DMF (60 mL) was added 2,2′-dichlorodiethyl ether (1.28 g, 8.93 mmol) slowly at 150° C. under N2. The reaction was heated at 150° C. overnight, then cooled to rt, poured into water (200 mL) and extracted with CH2Cl2 (200 mL×2). The combined organic phases were washed with water (200 mL×2) and brine (200 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1) to give the title compound as a yellow solid (0.93 g, 35%).