Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1>>[F:30][C:31]1[CH:36]=[CH:35][C:34]([O:29][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:33][CH:32]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(F)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(F)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-fluorophenol: ESMS m/e: 493.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][O:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[C:6]=2[CH:17]=1.[CH3:18][N:19](C)C=O.C(Cl)(Cl)Cl.[C-]#N.[Na+]>O>[O:16]=[C:7]1[C:6]2[CH:17]=[C:2]([C:18]#[N:19])[CH:3]=[CH:4][C:5]=2[CH2:11][O:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]1=2
Reactant: CN(C)C=O
Reactant: O=C1c2cc(Br)ccc2COc2ccccc21
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc2c(c1)C(=O)c1ccccc1OC2

Procedure:
Reflux a mixture of 9.13 gm. (0.0316 mole) of 9-bromo-6,11-dihydro-11-oxodibenz[b,e]oxepin, 6.03 gm. (0.0673 mole) of cuprous cyanide and 32 ml. of dimethylformamide for 4 hours with vigorous stirring. Cool the reaction mixture and shake with a mixture of 45 ml. of chloroform, 32 ml. of saturated sodium cyanide solution and 32 ml. of water until all solids have dissolved. Separate the organic layer and wash with aqueous sodium cyanide solution and water. Dry over anhydrous magnesium dulfate. Remove the solvent to obtain the title product (yield 7.43 gm., m.p. 116°-127° C.).
Reaction SMILES: [Cl:1]C1C=CC([C:8](=[N:19][NH:20][C:21](OC(C)(C)C)=O)[C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[N:15][N:14]([CH3:17])[C:13]=3[CH:18]=2)=CC=1.[ClH:28].O>O1CCCC1>[ClH:1].[Cl:28][C:9]1[CH:10]=[CH:11][C:21]([NH:20][NH:19][CH2:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[N:15][N:14]([CH3:17])[C:13]=3[CH:18]=2)=[CH:13][CH:18]=1
Reactant: Cn1nnc2ccc(C(=NNC(=O)OC(C)(C)C)c3ccc(Cl)cc3)cc21
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cn1nnc2ccc(CNNc3ccc(Cl)cc3)cc21
Temperature: 22 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 10 g of intermediate 1-b in 60 ml of tetrahydrofuran under a nitrogen atmosphere were added dropwise over 15 minutes 26 ml of a borane tetrahydrofuran complex in tetrahydrofuran (1M). After stirring for 15 minutes at ±22° C. there were added 13 ml of hydrochloric acid (6N). The whole was heated to reflux and refluxed for 1.5 hours. The mixture was cooled to room temperature and 50 ml of water were added. After stirring for 1 hour, the reaction mixture was filtered. The filtrate was mixed with 75 ml of methylbenzene. The layers were separated and the aqueous layer was basified (pH 7.5-8) with NH4OH. The product was extracted with dichloromethane and the extract was dried, filtered and evaporated. The residue was converted into the hydrochloride salt in 2-propanol by adding 3ml of a mixture of hydrochloric acid in 2-propanol (4.8N). After stirring for 2 hours the product was filtered off, washed with 2-propanol and dried in vacuo at 50° C., yielding 2.1 g of (±)-6-[(4-chlorophenyl)hydrazinomethyl]-1-methyl-1H-benzotriazole monohydrochloride (interm. 2-e).
Reaction SMILES: Br[CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([S:21][C:18]1[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:7]
Reactant: Fc1ccc(S)cc1
Reactant: CCCCCCC(Br)C(=O)OCC
Product: CCCCCCC(Sc1ccc(F)cc1)C(=O)OCC

Procedure:
2-(4-Fluoro-phenylsulfanyl)-octanoic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from ethyl 2-bromooctanoate (6.47 g, 24.7 mmol) and 4-fluorothiophenol (3 g, 23.4 mmol). Yield: 6.31 g (90%); clear oil; MS: 299 (M+H)+.
Reaction SMILES: [CH3:1]C1CCCN(C)C1(C)C.C([Li])CCC.[CH:16]1([CH2:19][CH:20]=[CH:21][CH2:22][CH:23]2[CH2:25][O:24]2)[CH2:18][CH2:17]1>CC(OC)(C)C>[CH:16]1([CH2:19][CH:20]2[CH:22]3[CH:21]2[CH2:1][CH2:25][CH:23]3[OH:24])[CH2:18][CH2:17]1
Reactant: CC1CCCN(C)C1(C)C
Reactant: C(=CCC1CO1)CC1CC1
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Product: OC1CCC2C(CC3CC3)C12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of tetramethylpiperidine (0.624 ml, 3.7 mmol) in MTBE (5 mL) was added n-butyllithium 2.5M hexanes (1.5 ml, 3.7 mmol) at −78° C. The solution was slowly warmed to approx 0° C. and was added via cannula to a solution of 2-(4-cyclopropyl-but-2-enyl)-oxirane (0.288 g, 1.898 mmol) in MTBE (2 mL) over 10 min at 0° C. The mixture was allowed to warm to rt, stirred overnight, washed with 1N HCl (2×), and brine. The organics were dried over MgSO4, filtered, and concentrated to give 6-cyclopropylmethyl-bicyclo[3.1.0]hexan-2-ol as clear oil; 1H NMR (400 MHz, CDCl3): δ 4.19 (d, 1H, J=5.5 Hz), 2.15–2.06 (m, 1H), 1.75 (dd, 1H, J1=11.0 Hz, J2=9.7 Hz), 1.69–1.52(m, 4H), 1.42 (dd, 1H, J1=8.1 Hz, J2=6.2 Hz), 0.98–0.87 (m, 2H), 0.75–0.68 (m, 1H), 0.46–0.41 (m, 2H), 0.03 (dd, 2H, J1=9.1 Hz, J2=4.7 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[C:6]([C:8]2[C:9]3[CH:18]=[CH:17][NH:16][C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.[F:26][C:27]([F:34])([F:33])[CH2:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>ClCCl>[F:26][C:27]([F:34])([F:33])[CH2:28][S:29]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[C:6]([C:8]2[C:9]3[CH:18]=[CH:17][NH:16][C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1)(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: Cn1cc(-c2cc(N)ccc2OC2CCOCC2)c2cc[nH]c2c1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(-c2cc(NS(=O)(=O)CC(F)(F)F)ccc2OC2CCOCC2)c2cc[nH]c2c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.7 %

Procedure:
To a solution of Example 99b (43.2 mg, 0.127 mmol) in dichloromethane (2 mL) was added 2,2,2-trifluoroethanesulfonyl chloride (0.015 mL, 0.140 mmol) and triethylamine (0.053 mL, 0.382 mmol). The mixture was stirred for 18 hours at ambient temperature. The reaction mixture was concentrated and the residue was purified by flash column chromatography (silica gel, 0.5-5% methanol in dichloromethane) to provide the title compound (20.8 mg, 33.7% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 12.00 (s, 1H), 10.16 (s, 1H), 7.25-7.32 (m, 3H), 7.14-7.20 (m, 2H), 6.18-6.24 (m, 1H), 4.36-4.55 (m, 3H), 3.52-3.68 (m, 5H), 3.33-3.45 (m, 2H), 1.79-1.94 (m, 2H), 1.39-1.57 (m, 2H). MS (ESI+) m/z 486.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.Br.Br[CH2:13][C:14]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:14]([C:13]2[O:10][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=3[CH:7]=2)=[O:15])[CH:17]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: O=C(CBr)c1cccnc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(c1cccnc1)c1cc2cc(Br)ccc2o1
Reaction time: 5 h
Yield: 72.2 %

Procedure:
A mixture of 5-bromosalicylaldehyde (17.7 g), 3-bromoacetylpyridine hydrobromide (25.3 g) and anhydrous potassium carbonate (60.8 g), in 2-butanone (200 ml) was heated under reflux with stirring for 5 hours. The mixture was filtered and the solid was washed with 2-butanone. The combined filtrate and washings were evaporated and the residue was crystallised from methanol to give 5-bromobenzofuran-2-yl pyrid-3-yl ketone (19.2 g), m.p. 144°-145°.
Reaction SMILES: C(O[C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]=O)(C)(C)C.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([CH2:27][NH2:28])[CH2:25][NH2:26])=[C:20]([CH3:29])[CH:19]=1.C(O)(C)(C)C>CN(C)C=O>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:27][N:28]3[C:6](=[O:16])[NH:7][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=4[C:14]3=[N:26][CH2:25]2)=[C:20]([CH3:29])[CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1C=O
Reactant: Cc1cc(N)ccc1C(CN)CN
Solvent: CN(C)C=O
Solvent: CC(C)(C)O
Product: Cc1cc(N)ccc1C1CN=C2c3ccccc3NC(=O)N2C1
Temperature: 75 °C
Yield: 13.1 %

Procedure:
A flask was charged with (2-Formyl-phenyl)-carbamic acid tert-butyl ester (8.8 g, 0.040 mol), 2-(4-Amino-2-methyl-phenyl)-propane-1,3-diamine (10.0 g, 0.056 mol), t-butanol (177 mL), and N,N-dimethylformamide (53 mL) and purged well with nitrogen. The mixture was stirred at 75° C. for at least 3 h. To the cooled mixture were added anhydrous potassium carbonate (16.6 g) and iodine (12.2 g). The batch was stirred at 80° C. for 10 h. The cooled mixture was filtered through a celite pad (4.4 g) and the filter cake was rinsed with methanol (177 mL). The filtrate and wash were diluted with toluene (88 mL) and concentrated to dryness under reduced pressure. The residue was stirred with aqueous 15 wt % sodium thiosulfate pentahydrate (88 mL) and saturated aqueous sodium chloride (44 mL) for 1 h at ambient temperature. The resulting mixture was extracted with CH2Cl2 (2×177 mL). The separated organic layer was dried over anhydrous magnesium sulfate (4.4 g), filtered, and concentrate to dryness in vacuo. The concentrate (20 g) was dissolved with methanol (20 mL) and loaded onto a KP-Sil samplet (34 g). The sample was allowed to dry before loading it into a Biotage KP-Sil SNAP cartridge (340 g). A Biotage unit was used to elute the cartridge with a ethyl acetate-hexane gradient (0% to 90%). Clean fractions were collected, combined, and concentrated to dryness under reduced pressure to provide the title compound as a yellow solid (1.6 g, 13% yield).
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH:16]([N:19](C(C)C)C#N)(C)C>C1C=CC=CC=1.CCCCCC>[C:16]([CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)#[N:19]
Reactant: c1cnc2c(c1)CCCC2
Reactant: CC(C)N(C#N)C(C)C
Agent: [Li]CCCC
Solvent: c1ccccc1
Solvent: CCCCCC
Product: N#CC1CCCc2cccnc21
Yield: 71 %

Procedure:
A solution of 5,6,7,8-tetrahydroquinoline (6.5 ml, 50 mM) in benzene (35 ml) maintained below 10° was treated with 1.6M butyl lithium in hexane (31.25 ml, 50 mM). The resulting anion solution was heated to reflux then treated with a solution of diisopropylcyanamide (6.3 g, 50 mM) in benzene (15 ml). After 15 min. the mixture was cooled and quenched with water (20 ml). The organic phase was separated, dried and evaporated. Distillation of the residue gave the title compound (5.6 g, 71%) Bp. 135°-140°/2 mm, identical with authentic material. Hydrochloride mp 185° C.--see Example 37 UK Pat. No. 1,432,378.
Reaction SMILES: [S:1]1[C:5]2[NH:6][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:8][C:4]=2[CH:3]=[CH:2]1.Br[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>>[CH3:12][O:11][C:9]([C:7]1[N:6]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:5]2[S:1][CH:2]=[CH:3][C:4]=2[CH:8]=1)=[O:10]
Reactant: COC(=O)c1cc2ccsc2[nH]1
Reactant: BrCc1cccc2ccccc12
Product: COC(=O)c1cc2ccsc2n1Cc1cccc2ccccc12

Procedure:
Using general procedure B, methyl 6H-thieno[2,3-b]pyrrole-5-carboxylate was coupled with 1-bromomethyl-naphthalene to give 6-naphthalen-1-ylmethyl-6H-thieno[2,3-b]pyrrole-5-carboxylic acid methyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a white solid. MS: 306.3 ([M−H]−).
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]3[O:20][C:19]([C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)=[C:18]([C:27]4[CH:28]=[C:29]5[C:33](=[CH:34][CH:35]=4)[C:32](=NO)[CH2:31][CH2:30]5)[CH:17]=3)[CH2:11]2)=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N1CC[O:41]CC1.C(N(CC)CC)C>ClCCl>[N:1]1([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]3[O:20][C:19]([C:21]4[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=4)=[C:18]([C:27]4[CH:28]=[C:29]5[C:33](=[CH:34][CH:35]=4)[C:32](=[O:41])[CH2:31][CH2:30]5)[CH:17]=3)[CH2:11]2)=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(CN1CCOCC1)N1CCCC(c2cc(-c3ccc4c(c3)CCC4=NO)c(-c3ccncc3)o2)C1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCc2cc(-c3cc(C4CCCN(C(=O)CN5CCOCC5)C4)oc3-c3ccncc3)ccc21
Yield: 54.7 %

Procedure:
A solution of the product of Step 1 (140 mg, 0.32 mmol) in dry dichloromethane (10 ml) was treated with morpholine (0.031 ml, 0.35 mmol) and triethylamine (0.049 ml, 0.35 mmol) and heated at reflux for 3 hours. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried, concentrated in vacuo and then purified by silica gel chromatography eluting with chloroform/ethanol/0.880 ammonia solution (98:1.8:0.2) to yield the title compound (85 mg, 55%); MS(ES+) m/e 486 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([C:24]2[N:25]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:26]3[C:31]([CH:32]=2)=[CH:30][C:29]([CH:33]=O)=[CH:28][CH:27]=3)=[C:18]2[C:14]=1[CH2:15][NH:16][C:17]2=[O:42])(=[O:11])=[O:10])#[N:2].[NH:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([C:24]2[N:25]([C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])[C:26]3[C:31]([CH:32]=2)=[CH:30][C:29]([CH2:33][N:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)=[CH:28][CH:27]=3)=[C:18]2[C:14]=1[CH2:15][NH:16][C:17]2=[O:42])(=[O:11])=[O:10])#[N:2]
Reactant: C1CCNC1
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(=O)(=O)c1ccccc1C#N)CNC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1cc(-c2cc3cc(CN4CCCC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(=O)(=O)c1ccccc1C#N)CNC2=O

Procedure:
In a similar manner to Step 2 of Example 6, 4-(2-cyanobenzenesulfonyloxy)-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (0.140 g, 0.238 mmol) was dissolved in acetonitrile (6.0 mL), and the solution was treated with pyrrolidine (0.398 mL, 4.77 mmol), acetic acid (0.273 mL, 4.77 mmol) and sodium triacetoxyborohydride (0.151 g, 0.715 mmol), followed by purification of the residue by flash column chromatography (chloroform/methanol=85/15, 80/20) to obtain 4-(2-cyanobenzenesulfonyloxy)-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(pyrrolidin-1-ylmethyl)indol-2-yl]isoindolinone (0.0773 g, ESI-MS m/z: 643 [M+H]+; 1H-NMR (CD3OD)8(ppm): 1.18 (s, 9H), 1.83-1.92 (m, 4H), 2.88-2.96 (m, 4H), 3.25 (s, 3H), 4.04 (s, 2H), 4.49 (s, 2H), 6.55 (s, 1H), 7.00 (s, 1H), 7.28 (dd, J=1.6, 8.7 Hz, 1H), 7.52 (d, J=1.6 Hz, 1H), 7.77-7.93 (m, 3H), 8.08 (dd, J=1.6, 7.3 Hz, 1H), 8.17 (d, J=8.7 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([C@@H:12]1[C@H:17]([CH3:18])[CH2:16][CH2:15][NH:14][CH2:13]1)[C:3]1[C:4]2[CH:11]=[CH:10][NH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[C:19](Cl)(=[O:21])[CH3:20]>ClCCl.N1C=CC=CC=1>[CH3:18][C@@H:17]1[CH2:16][CH2:15][N:14]([C:19](=[O:21])[CH3:20])[CH2:13][C@@H:12]1[N:2]([CH3:1])[C:3]1[C:4]2[CH:11]=[CH:10][NH:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: C[C@@H]1CCNC[C@@H]1N(C)c1ncnc2[nH]ccc12
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CC[C@@H](C)[C@@H](N(C)c2ncnc3[nH]ccc23)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.3 %

Procedure:
To a stirred solution of the product from Method B (0.03 grams, 0.114 mmol) dissolved in 5 mL of 10:1 dichloromethane/pyridine was added (0.018 grams, 0.228 mmol) of acetylchloride and the resulting mixture stirred at room temperature for 18 hours. The reaction mixture was then partitioned between dichloromethane and saturated sodium bicarbonate (NaHCO3). The organic layer was washed again with saturated NaHCO3, dried over sodium sulfate and concentrated to dryness in vacuo. The residue was purified by preparative thin layer chromatography (PTLC) (silica; 4% methanol in dichloromethane) affording 0.005 g (15%) of the title compound as a colorless oil.
Reaction SMILES: [OH:1][CH:2]([CH2:25][OH:26])[CH2:3][NH:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[C:10]([O:22][CH3:23])[N:11]2[CH2:14][C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)=[C:7]([NH2:24])[N:6]=1.C(N(CC)CC)C.[C:34](OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:35]>CN(C)C=O>[CH3:23][O:22][C:10]1[N:11]([CH2:14][C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:12]2[C:8]([N:9]=1)=[C:7]([NH2:24])[N:6]=[C:5]([NH:4][CH2:3][CH:2]1[CH2:25][O:26][C:34](=[O:35])[O:1]1)[N:13]=2
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COc1nc2c(N)nc(NCC(O)CO)nc2n1Cc1ccc(C)nc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1nc2c(N)nc(NCC3COC(=O)O3)nc2n1Cc1ccc(C)nc1
Reaction time: 14 h
Yield: 26.6 %

Procedure:
2-(2,3-Dihydroxypropylamino)-8-methoxy-9-{(6-methyl-3-pyridyl)methyl}adenine (230 mg, 0.64 mmol) obtained by Reference example 18, 4-dimethylaminopyridine (5 mg, 0.04 mmol) and triethylamine (0.02 ml, 0.14 mmol) were dissolved in dimethylformamide (2 ml). Thereto was added di-t-butyl dicarbonate (410 mg, 1.9 mmol) in the oil bath kept at 50° C. and the mixture was stirred for 14 hours. The reaction mixture was concentrated and the residue was purified by preparative thin layer chromatography to give the captioned compound (64 mg, 0.17 mmol, yield 26%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH2:9].[I:10]I>CO.OO>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([I:10])[C:3]=1[NH2:9]
Reactant: Cc1ccc(N)c(F)c1
Reactant: II
Agent: OO
Solvent: CO
Product: Cc1cc(F)c(N)c(I)c1
Reaction time: 18 h
Yield: 87.6 %

Procedure:
A solution of 2-fluoro-4-methylphenylamine (1.25 g, 10 mmol) in 5 mL of methanol was treated with a solution of iodine (1.27 g, 5 mmol) in a mixture of 25 mL of methanol and 3 mL of hydrogen peroxide over a period of 15 minutes at room temperature. After 18 hours, the reaction mixture was quenched with 30 mL of saturated aqueous sodium thiosulfate and extracted with three 50 mL portions of dichloromethane. The combined organic layers were washed with two 30 mL portions of saturated sodium bisulfite solution, three 50 mL portions of water, dried over sodium sulfate, and concentrated in vacuo. Chromatography on SiO2 (10% ethyl acetate in hexanes) gave 1.1 g of the title product as a light brownish oil (44% yield).
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:9]([O:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:28]=[C:27]([CH2:29][NH:30][CH3:31])[S:26][CH:25]=2)=[CH:20][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])[CH3:10].C(N(CC)CC)C>O1CCCC1>[CH2:9]([O:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:28]=[C:27]([CH2:29][N:30]([C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH3:31])[S:26][CH:25]=2)=[CH:20][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])[CH3:10]
Reactant: CCCCCC(=O)Cl
Reactant: CCO[C@@H](Cc1ccc(-c2csc(CNC)c2)cc1)C(=O)OC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCC(=O)N(C)Cc1cc(-c2ccc(C[C@H](OCC)C(=O)OC)cc2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
0.18 ml (1.3 mmol) of hexanoyl chloride is added to a solution, cooled beforehand to 0° C., of 0.4 g (1.2 mmol) of methyl 2(S)-ethoxy-3-[4-(5-methylaminomethylthiophen-3-yl)phenyl]propanoate and 0.18 ml (1.3 mmol) of triethylamine in 20 ml of tetrahydrofuran. The reaction medium is stirred at room temperature for 2 hours, washed with water and extracted with ethyl acetate. The ethyl acetate phase is dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by thin-layer chromatography on silica eluted with a 70/30 heptane/ethyl acetate mixture. 0.4 g (83%) of methyl 2(S)-ethoxy-3-(4-{5-[(hexanoylmethylamino)methyl]thiophen-3-yl}phenyl)propanoate is obtained.
Reaction SMILES: [C:1](=[O:21])([O:17][CH:18](Cl)[CH3:19])[O:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]([O:13][N+:14]([O-:16])=[O:15])[CH2:8][O:9][N+:10]([O-:12])=[O:11].[CH2:22]([C:26]1[N:27]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[C:48]3[N:52](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:51]=[N:50][N:49]=3)=[CH:38][CH:37]=2)[C:28]([C:32]([OH:34])=[O:33])=[C:29]([Cl:31])[N:30]=1)[CH2:23][CH2:24][CH3:25].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH2:22]([C:26]1[N:27]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[C:48]3[NH:52][N:51]=[N:50][N:49]=3)=[CH:38][CH:37]=2)[C:28]([C:32]([O:34][CH:18]([O:17][C:1]([O:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]([O:13][N+:14]([O-:16])=[O:15])[CH2:8][O:9][N+:10]([O-:12])=[O:11])=[O:21])[CH3:19])=[O:33])=[C:29]([Cl:31])[N:30]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CC(Cl)OC(=O)OCCCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-]
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc(Cl)c(C(=O)OC(C)OC(=O)OCCCC[C@H](CO[N+](=O)[O-])O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
(5R)-5,6-bis(nitrooxy)hexyl 1-chloroethyl carbonate (7.67 g, 23.2 mmol) was added to a stirred solution of 2-butyl-4-chloro-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylic acid (6.30 g, 9.3 mmol) and Cs2CO3 (3.02 g, 9.3 mmol) in DMF (186 mL). The solution was stirred at 70° C. for 2 h. Water (50 mL) was added and the solution was extracted with EtOAc (3×100 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The residue was redissolved in MeOH (186 mL). After stirring at 70° C. for 2 h, the solution was concentrated in vacuo. The residue was purified by HPLC chromatography (50×100 mm C-18) eluting with 40-100% MeCN/water+0.05% TFA. The diastereomers were then separated by HPLC chromatography on silica gel (ChiralPak AD-H) eluting with 20% MeOH in supercritical CO2 to give the title compound as a white solid. 1H NMR (500 MHz, CD3OD) δ 8.06 (d, J=7.5 Hz, 1H), 7.62 (td, J=7.5, 1.0 Hz, 1H), 7.56 (td, J=6.5, 1.0 Hz, 1H), 7.44 (d, J=6.5 Hz, 1H), 7.17 (d, J=8.0 Hz, 2H), 6.99 (d, J=8.0 Hz, 2H), 6.87 (q, J=5.5 Hz, 1H), 5.54 (d, J=6.0 Hz, 2H), 5.24 (ddd, J=13.0, 6.2, 3.0 Hz, 1H), 4.73 (dq, J=12.5, 1.5 Hz, 1H), 4.46 (dd, J=13.0, 6.5 Hz, 1H), 4.14-4.04 (m, 1H), 2.76 (t, J=7.7 Hz, 2H), 1.76-1.59 (m, 6H), 1.61 (d, J=5.5 Hz, 3H) 1.55-1.40 (m, 2H), 1.38 (hex, J=7.5 Hz, 2H), 0.90 (t, J=7.5 Hz, 3H); LCMS (M+H) found 731.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([F:18])=[C:12]([F:17])[CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].CI.[C:21](=O)([O-])[O-].[K+].[K+]>O>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([F:18])=[C:12]([F:17])[CH:13]=2)[N:8]([CH3:21])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2cc(F)c(F)cc2c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: CCOC(=O)c1cn(C)c2cc(F)c(F)cc2c1=O
Yield: 63 %

Procedure:
6,7-Difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester (10.0 g, 39.5 mmol), methyl iodide (56 g, 395 mmol) and potassium carbonate (10.9 g, 79 mmol) were combined in dimethylsformamide and heated to 90° for 20 hours. The reaction mixture was cooled and poured into cold water (1.5 l). The precipitate was filtered, washed with cold water and recrystallized from ethyl acetate to yield the title product as white needles, m.p. 210°-212° (6.60 g, 24.7 mmol, 63% yield).