Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([N:12]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:13][C@H:14]([OH:23])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][OH:11])=[CH:4][CH:3]=1.[C:31](O)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH2:24]([N:12]([C@H:9]([CH2:10][OH:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:3][CH:4]=1)[CH2:13][C@H:14]([OH:23])[CH2:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccccc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.2 %

Procedure:
To a mixture of (2S)-3-(4-aminophenyl)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-1-propanol (77 mg) and benzoic acid (28 mg) in N,N-dimethylformamide (0.8 ml) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (57 mg), and the mixture was stirred at room temperature for 20 hours. The mixture was partitioned between hexane-ethyl acetate and water. The organic layer was separated, washed successively with water and brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated to give N-[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino)-3-hydroxypropyl]phenyl]-benzamide (95 mg) as a white amorphous powder.
Reaction SMILES: [C:1]([NH:20][C@H:21]([C:25]([O:27][CH2:28][CH:29]([CH2:36][O:37][C:38](=[O:56])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:26])[CH:22]([CH3:24])[CH3:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:57][C@@H:58]1[C@@H:62]([CH2:63]O)[O:61][C@@H:60]([N:65]2[C:75]3[N:74]=[C:72]([NH2:73])[NH:71][C:69](=[O:70])[C:68]=3[N:67]=[CH:66]2)[CH2:59]1.CN(C1C=CC=CN=1)C.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[F:57][C@@H:58]1[C@@H:62]([CH2:63][O:34][C:33](=[O:35])[CH2:32][CH2:31][CH2:30][CH:29]([CH2:28][O:27][C:25](=[O:26])[C@H:21]([CH:22]([CH3:24])[CH3:23])[NH:20][C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:36][O:37][C:38](=[O:56])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[O:61][C@@H:60]([N:65]2[C:75]3[N:74]=[C:72]([NH2:73])[NH:71][C:69](=[O:70])[C:68]=3[N:67]=[CH:66]2)[CH2:59]1
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC(CCCC(=O)O)COC(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(CCCC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1F)COC(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)C
Reaction time: 8 h

Procedure:
To a solution of 5-(N-trityl-L-valyloxymethyl)-6-stearoyloxyhexanoic acid (462 mg, 0.6 mmole) and 2′,3′-dideoxy-3′-fluoroguanosine (340 mg, 1.25 mmol) in DMF (3 ml) were added dimethylaminopyridine (7 mg, 0.06 mmole), and DCC (136 mg, 0.66 mmol). The reaction was kept at room temperature overnight, and then at 40° C. for two hours. The reaction mixture was filtered through Celite and poured into dichloromethane, and washed with aqueous sodium hydrogen carbonate solution. The product 2′,3′-dideoxy-3′-fluoro-5′-O-[5-(N-trityl-L-valyloxymethyl)-6-stearoyloxyhexanoyl]guanosine was isolated by silica gel column chromatography. (93 mg)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1.[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:10][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[CH2:8][OH:9]
Reactant: O=[N+]([O-])c1cc(Br)ccc1CO
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cc(Br)ccc1CO
Temperature: 75 °C
Yield: 95 %

Procedure:
A mixture of (4-bromo-2-nitro-phenyl)-methanol (1.85 g, 7.97 mmol), iron powder (2.23 g, 39.9 mmol), ammonium chloride (213 mg, 3.99 mmol), ethanol (20 mL), and water (10 mL) was heated at 75° C. for 1 h, then after cooling filtered through a pad of diatomaceous earth. The filtrate was evaporated and the residue partitioned between ethyl acetate and water, the organic layer was washed with brine, dried (MgSO4), and evaporated to produce (2-amino-4-bromophenyl)-methanol (1.53 g, 90%). Off-white solid, MS (EI)=201.0 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.[NH2:35][C@H:36]([CH3:48])[C:37]([NH:39][C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[C:42]([CH3:47])[CH:41]=1)=[O:38]>ClCCl>[CH3:46][C:44]1[CH:45]=[C:40]([NH:39][C:37](=[O:38])[C@H:36]([NH:35][C:6]([C:5]2[CH:4]=[C:3]([N+:14]([O-:16])=[O:15])[C:2]([Cl:1])=[C:10]([N+:11]([O-:13])=[O:12])[CH:9]=2)=[O:8])[CH3:48])[CH:41]=[C:42]([CH3:47])[CH:43]=1
Reactant: Cc1cc(C)cc(NC(=O)[C@@H](C)N)c1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClCCl
Product: Cc1cc(C)cc(NC(=O)[C@@H](C)NC(=O)c2cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c2)c1

Procedure:
To the solution of 4-chloro-3,5-dinitrobenzoic acid (1.058 g, 4.29 mmol) and EEDQ (1.062 g, 4.29 mmol) in dichloromethane (25 ml) is added (2R)-2-amino-N-(3,5-dimethylphenyl)propanamide, prepared in Example 5 (0.825 g, 4.29 mmol) in dichloromethane (25 ml). After 16 h of mixing at room temperature the product is recovered on a G-4 filter and washed with dichloromethane (30 ml). The product is dried at 50° C. for 4 h. 1.026 g (56%) of yellowish powder are obtained, mp 202°–204° C.
Reaction SMILES: O[C:2]1[C:11]2C(=C(C(F)(F)F)C=CC=2)N=C(C(O)CC)[C:3]=1C(NC1SC=CN=1)=O.[C:28]([OH:33])(=[O:32])[CH2:29][CH2:30][CH3:31]>>[C:28]([O:33][CH2:3][CH2:2][CH3:11])(=[O:32])[CH2:29][CH2:30][CH3:31]
Reactant: CCC(O)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Reactant: CCCC(=O)O
Product: CCCOC(=O)CCC

Procedure:
Using the procedure of Example 5, 8 g of 4-hydroxy-2-(1-hydroxypropyl)-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline carboxamide and 2 ml of butyric acid were reacted to obtain 7.8 g of 1-[4-hydroxy-3-[(2-thiazolylamino)-carboxyl]-8-trifluoromethyl)-2-quinolinyl]-propyl butanoate melting at 203° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](O)=[O:12].S(Cl)([Cl:19])=O>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([Cl:19])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(Oc2ccccn2)c1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc(Oc2ccccn2)c1

Procedure:
To a suspension of 3-(2-pyridyloxy)benzoic acid (1.80 g) in thionyl chloride (5.4 ml), dimethylformamide (0.2 ml) is added, and the resultant mixture is stirred at room temperature for 2.5 hours. The reaction mixture is evaporated under reduced pressure to remove the excessive thionyl chloride, and the residue is combined with anhydrous pyridine (0.73 g) and anhydrous benzene (40 ml). The precipitated pyridine hydrochloride is filtered off. The filtrate is evaporated to remove the benzene, and the residue is dissolved in anhydrous ether (20 ml). The ether solution is filtered to remove the insoluble substance. The filtrate is evaporated to remove the ether, whereby 3-(2-pyridyloxy)benzoyl chloride is obtained. IR (CCl4): 1774 cm-1.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([OH:25])[CH:21]=[CH:22][C:23]=1[Br:24].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[NH2:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][C:23]=1[Br:24])[O:25][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1
Reactant: Nc1cc(O)ccc1Br
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1Br
Temperature: 110 °C
Reaction time: 24 h
Yield: 47.7 %

Procedure:
A mixture of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (3.28 g, 10 mmol), 3-amino-4-bromophenol (2.82 g, 15 mmol), potassium carbonate (2.76 g, 20 mmol) and N,N-dimethylformamide (20 mL) was stirred at 110° C. for 24 hr, then at 150° C. for 24 hr. The reaction mixture was diluted with water and extracted with a mixed solvent of ethyl acetate/tetrahydrofuran (1:1). The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→40/100) and recrystallized from ethyl acetate to give the title compound (1.85 g, yield 48%) as a pale-yellow solid.
Reaction SMILES: FC(F)(F)S([O:6][C:7]1[C:8]2[S:16][C:15](=[O:17])[N:14]([C@H:18]3[C@H:22](OS(C(F)(F)F)(=O)=O)[CH2:21][C@@H:20]([CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[O:19]3)[C:9]=2[N:10]=[C:11]([NH2:13])[N:12]=1)(=O)=O.[C-:42]#[N:43].[Na+].CCOC(C)=O>CN(C=O)C>[NH2:13][C:11]1[NH:12][C:7](=[O:6])[C:8]2[S:16][C:15](=[O:17])[N:14]([C@H:18]3[C@H:22]([C:42]#[N:43])[CH2:21][C@@H:20]([CH2:31][O:32][Si:33]([C:36]([CH3:38])([CH3:39])[CH3:37])([CH3:34])[CH3:35])[O:19]3)[C:9]=2[N:10]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](OS(=O)(=O)C(F)(F)F)[C@H](n2c(=O)sc3c(OS(=O)(=O)C(F)(F)F)nc(N)nc32)O1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](C#N)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 118 %

Procedure:
To a stirred solution of [5-amino-3-[(2R,3R,5S)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-(trifluoromethylsulfonyloxy)tetrahydrofuran-2-yl]-2-oxo-thiazolo[4,5-d]pyrimidin-7-yl] trifluoromethanesulfonate (compound 38g, crude, 120 mg, 0.2 mmol) in DMF (2 mL) was added sodium cyanide (100 mg, 2.3 mmol). After being stirred at room temperature for 2 hours, the resulting solution was diluted by EtOAc, washed with brine, dried over Na2SO4 and concentrated in vacuo to afford 100 mg crude product of (2R,3S,5S)-2-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]tetrahydrofuran-3-carbonitrile (compound 38h), which was used in next step without further purification. MS obsd. (ESI+) [(M+H)+]: 424.
Reaction SMILES: [C:1]12([OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([OH:11])([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:13](O)(=[O:16])[CH:14]=[CH2:15].COC1C=CC(O)=CC=1.S(=O)(=O)(O)O.O=O.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[C:13]([O:12][C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([OH:11])([CH2:4]3)[CH2:2]1)[CH2:8]2)(=[O:16])[CH:14]=[CH2:15]
Reactant: OC12CC3CC(C1)CC(O)(C3)C2
Reactant: C=CC(=O)O
Agent: COc1ccc(O)cc1
Agent: O=O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: C=CC(=O)OC12CC3CC(CC(O)(C3)C1)C2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a 2 L jacket-equipped separable flask provided with a stirrer, a thermometer, a Dean-Stark water separator, a Dimroth condenser and a prepared gas introduction tube, 84 g of 1,3-adamantanediol, 108 g of acrylic acid, 0.76 g of p-methoxyphenol as a polymerization inhibitor, 1.3 g of concentrated sulfuric acid as an acid catalyst, and 750 ml of toluene as a solvent were put. Prepared gas diluted with nitrogen so as to have an oxygen concentration of about 5% by volume was supplied at a rate of 0.2 L/min. The reaction operation was performed as follows. While the solution was heated and water generated as a secondary product was removed by the Dean-Stark water separator, the reflux state was continued for 6 hours. Thus, 3-hydroxy-1-adamantyl acrylate was synthesized. The obtained reaction solution was cooled down to room temperature, and then a 10% by weight of aqueous solution of sodium hydroxide was added while stirring to neutralize the residual acrylic acid and sulfuric acid. Then, the neutralized water phase was drawn out from the two-phase solution. To the residual organic phase, 0.85 g of p-methoxyphenol was added as a polymerization inhibitor. The resultant solution was washed with 5% by weight of dilute sulfuric acid and with 500 ml of ion exchange water, twice for each. After the washing, precise filtration was performed by use of a Teflon® filter having a pore diameter of 0.1 μm. Then, cooling crystallization was performed at a temperature of an ice water bath to separate the crystal by filtration. The crystal was rinsed with heptane twice, and then dried at a reduced pressure at 25° C. for 24 hours. During the process from the dehydration esterification reaction to the solid-liquid separation and until the termination of rinsing performed by use of ion exchange water, the prepared gas was kept blown into the solution. Table 1 shows the analysis results of the obtained 3-hydroxy-1-adamantyl acrylate. Methylethylketone was used as the solvent for measuring the turbidity.
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[ClH:15].Cl.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]2[C:33]3[C:32]4[C:27]5=[C:28]([C:34](=[O:43])[N:35]([CH2:38][CH2:39][N:40]([CH3:42])[CH3:41])[C:36](=[O:37])[N:26]5[C:25]=3[CH:24]=[CH:23][C:22]=2[CH:44]=1)[CH:29]=[CH:30][CH:31]=4.Cl>ClCCl.C(O)C.CO>[ClH:15].[C:8]([NH:17][C:18]1[CH:19]=[CH:20][C:21]2[C:33]3[C:32]4[C:27]5=[C:28]([C:34](=[O:43])[N:35]([CH2:38][CH2:39][N:40]([CH3:41])[CH3:42])[C:36](=[O:37])[N:26]5[C:25]=3[CH:24]=[CH:23][C:22]=2[CH:44]=1)[CH:29]=[CH:30][CH:31]=4)(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)CCn1c(=O)c2cccc3c4c5ccc(N)cc5ccc4n(c1=O)c23
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc2c(ccc3c2c2cccc4c(=O)n(CCN(C)C)c(=O)n3c42)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4 ml of triethylamine and 2 ml of acetic anhydride were successively added to a suspension of 141 mg (0.379 mmol) of the free base of the compound of Example 49 in dichloromethane (20 ml) under stirring at room temperature and stirring was continued for 16 hours. After concentrating, 30 ml of methanol was added to the residue. Next, the obtained mixture was made basic by adding an aqueous solution of sodium hydrogencarbonate thereto. The precipitate was recovered by filtration and washed with water. The solid matter thus obtained was suspended in ethanol and conc. hydrochloric acid was added thereto under stirring at room temperature. After further adding methanol and dichlromethane thereto, stirring was continued. After concentrating, ethanol was added thereto and the obtained mixture was heated under reflux and then brought back to room temperature. The precipitate was recovered by filtration to thereby give 148 mg of the title compound.
Reaction SMILES: CC([N:5]([C@H:9]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:19]=[C:18]([F:20])[C:17]([C:21]([CH3:24])([CH3:23])[CH3:22])=[C:16]([F:25])[CH:15]=2)[CH2:10]1)C(=O)[O-])(C)C.[ClH:26]>O1CCOCC1>[ClH:26].[CH3:24][C:21]([C:17]1[C:16]([F:25])=[CH:15][C:14]([O:13][C@@H:11]2[CH2:10][C@H:9]([NH2:5])[CH2:12]2)=[CH:19][C:18]=1[F:20])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1c(F)cc(O[C@H]2C[C@@H](N(C(=O)[O-])C(C)(C)C)C2)cc1F
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)c1c(F)cc(O[C@H]2C[C@@H](N)C2)cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1,1-dimethylethyl(cis-3-{[4-(1,1-dimethylethyl)-3,5-difluorophenyl]oxy}cyclobutyl)carbamate (6.85 g, 19.27 mmol) in 1,4-dioxane (50 mL) was added a solution of hydrogen chloride in 1,4-dioxane (50 mL, 4M, 200 mmol) in one charge. The reaction vessel was sealed and the reaction stirred at ambient temperature for 16 hours. The reaction was concentrated to approximately half volume in vacuo and the resultant slurry was diluted with diethyl ether (200 mL) and the mixture stirred rapidly for 10 min. The precipitate was collected by filtration and dried in vacuo to give the title compound as a white solid (3.39 g). The mother liquors were concentrated in vacuo to give a yellow sticky solid. Trituration with diethyl ether (ca 20 mL) gave a white precipitate, the precipitate was collected by filtration and dried in vacuo to give a further batch of the title compound (1.035 g).
Reaction SMILES: [K].[F:2][C:3]1[C:4](=[S:10])[NH:5][C:6](=[O:9])[NH:7][CH:8]=1.[CH2:11](I)[CH3:12]>CO>[CH2:11]([S:10][C:4]1[C:3]([F:2])=[CH:8][NH:7][C:6](=[O:9])[N:5]=1)[CH3:12]
Reactant: CCI
Reactant: O=c1[nH]cc(F)c(=S)[nH]1
Agent: [K]
Solvent: CO
Product: CCSc1nc(=O)[nH]cc1F
Yield: 70 %

Procedure:
The potassium salt of 5-fluoro-4-thiouracil (0.0065 mol) and ethyl iodide (0.014 mol) in methanol (40 ml) were stirred at room temperature for 6 days. The solutions were concentrated at reduced pressure and water (6 ml) added. The slowly precipitated product was recrystallised from water; yield 70%, m.p. 168° C.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>>[O:24]([C:22]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)Oc1ccccc1
Product: CCOC(=NC(=O)Oc1ccccc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and phenyl chloroformate, there is obtained ethyl N-phenoxycarbonyl-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a resin, mass spectrum m/e: 293 (100, M-phenolate radical), 265 (16), 167 (76);
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6](=O)[CH2:5][O:4][CH2:3]1.COCCO[AlH2-]OCCOC.[Na+]>C1(C)C=CC=CC=1>[CH3:1][C@H:2]1[CH2:3][O:4][CH2:5][CH2:6][N:7]1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[C@H]1COCC(=O)N1Cc1ccccc1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@H]1COCCN1Cc1ccccc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 95.4 %

Procedure:
To a 0° C. solution of (5S)-5-methyl-4-(phenylmethyl)-3-morpholinone (12.74 g, 62.07 mmol) in toluene (150 mL) was added Red-Al (65% w/w in PhMe, 38 mL) dropwise via addition funnel. The resulting solution was heated at 60° C. and stirred for 4 h, then cooled to 40° C. and stirred overnight. The solution was then cooled to 0° C. and quenched by dropwise addition of 1 N aq. NaOH (15 mL). The mixture was diluted with Et2O (100 mL) and washed with 1 N aq. NaOH (100 mL) followed by brine (50 mL). The organic phase was dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and azeotroped with MeOH (50 mL) to provide (3S)-3-methyl-4-(phenylmethyl)morpholine (11.33 g, 95%) as a faintly pink oil. LCMS: (M+H)+: 192.2.
Reaction SMILES: [NH2:1][C:2](=[N:8][OH:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[O:10]1[CH:14]=[CH:13][C:12]([C:15](O)=O)=[N:11]1.C(N=C=NC(C)C)(C)C>C(Cl)Cl>[O:10]1[CH:14]=[CH:13][C:12]([C:15]2[O:9][N:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[N:1]=2)=[N:11]1
Reactant: O=C(O)c1ccon1
Reactant: CCOC(=O)C(N)=NO
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: CCOC(=O)c1noc(-c2ccon2)n1
Temperature: 25 °C
Yield: 50.1 %

Procedure:
Ethyl aminohydroxyiminoacetate (3.78 mmol, 0.5 g), 3-isoxazolecarboxylic acid (3.78 mmol, 0.428 g) and 1,3-diisopropylcarbodiimide (4.16 mmol, 0.525 g) were dissolved in DCM (70 ml) under nitrogen atmosphere. The mixture was stirred at RT for a day. The solvent was evaporated to dryness and the residue was dissolved in pyridine and refluxed for 6 h and overnight at RT. Pyridine was evaporated and the residue was diluted with DCM and water. The aqueous phase was extracted four times with DCM. The combined organics were washed with aqueous HCl solution, saturated NaHCO3, water and brine. The organic phase was dried, filtered and evaporated. The crude product was purified by flash chromatography. 0.396 g of the title compound was obtained. Rotamers were obtained in 1H-NMR and analysis was repeated at elevated temperature. 1H-NMR (400 MHz, DMSO-d6, +60° C.): δ 1.38 (t, 3H), 4.49 (q, 2H), 7.21 (d, 1H), 9.05 (d, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#N)=[CH:8][CH:9]=2)[C:4]([C:13]2[N:21]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH:14]=2)=[CH:3]1.[H-].C([Al+]CC(C)C)C(C)C.Cl.[OH-:43].[Na+]>O1CCCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:43])=[CH:8][CH:9]=2)[C:4]([C:13]2[N:21]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH:14]=2)=[CH:3]1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(C#N)cc34)cc3cccnc32)cc1
Reactant: [OH-]
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(C=O)cc34)cc3cccnc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indole-5-carbonitrile [500 mg, Reference Example 13(c)] in tetrahydrofuran (20 mL) at 0° C. was added diisobutylaluminium hydride (12 mL, 1M in tetrahydrofuran) under an atmosphere of nitrogen. The resultant solution was then allowed to warm to ambient temperature and stirred at this temperature for 2 hours. The reaction mixture was then poured into a solution of cold 1N aqueous hydrochloric acid (20 mL). After 1 hour, the mixture was made alkaline with saturated aqueous sodium hydroxide and extracted with ethyl acetate (40 mL). The organic layer was separated and the aqueous further extracted with ethyl acetate (2×20 mL). The organic extracts were combined, dried over magnesium sulfate and concentrated in vacuo to give the title compound (221 mg) as a white solid, m.p. 188-189° C. MS: 430 (MH+).
Reaction SMILES: C([Li])CCC.[I-].[CH2:7]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH3:35][C:36]([CH3:47])([CH2:39][O:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][O:42]1)[CH:37]=O>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C.O1CCCC1.[Cl-].[Na+].O>[CH3:35][C:36]([CH3:47])(/[CH:37]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:39][O:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][O:42]1
Reactant: CCCCC/C=C\CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C=O)COC1CCCCO1
Agent: [Cl-]
Agent: [I-]
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCCCC/C=C\C/C=C\C(C)(C)COC1CCCCO1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
A 2.7 ml portion of n-butyllithium (1.6 M in hexane) was slowly added at -76° C., under argon to a solution of 2.7 g (5.24 mmoles) of (Z)-(3-nonenyl)-triphenylphosphonium iodide in a mixture of 7.5 ml of 2:1 tetrahydrofuran-hexamethylphosphorictriamide by syringe. The solution turned orange-red in color. Without delay, a solution of 0.700 g (3.76 mmoles) of 2,2-dimethyl-3-[(tetrahydro-2H-pyran-2-yl)oxy]-propanal in 1 ml of tetrahydrofuran was added dropwise to the solution. The resulting mixture was stirred at -78° C. for 30 minutes. The temperature was then allowed to rise to 0° C. After 1 hour, the reaction mixture was poured into brine, and the product extracted twice with 1:1 hexane-ether. The organic layer was dried using MgSO4, and the solvents evaporated in vacuo. Purification of the crude product by rapid chromatography on a silica-gel column gave 1.0 g (90.2%) of (Z,Z)-2-[(2,2-dimethyl-3,6-dodecadienyl)oxy]-tetrahydro- 2H-pyran. This material was dissolved in 10 ml of methanol and treated with 0.1 ml of 2 N hydrochloric acid. After stirring for 2 hours at room temperature, the volume of methanol was reduced to about 3 ml by concentration under reduced pressure. The remaining solution was diluted with ether, and the ether solution washed with saturated sodium bicarbonate solution and brine and thereafter dried using MgSO4 and then concentrated under reduced pressure. The residue (0.780 g) was chromatographed on a silica gel column. Hexane-ether (4:1) eluted 0.690 g (79.1%) of pure (Z,Z)-2,2-dimethyl-3,6-dodecadien-1-ol. (98.6% pure by GC-analysis).