Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[N:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:18]2=[C:25]3[CH2:34][N:33]4[C:28](=[CH:29][C:30]5[C@:39]([CH2:41][CH3:42])([OH:40])[C:38](=[O:43])[O:37][CH2:36][C:31]=5[C:32]4=[O:35])[C:26]3=[N:27][C:16]3[C:17]2=[C:12]([CH:13]=[CH:14][CH:15]=3)[N:11]=1)=O)(C)(C)C.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[NH2:8][CH2:9][C:10]1[N:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:18]2=[C:25]3[CH2:34][N:33]4[C:28](=[CH:29][C:30]5[C@:39]([CH2:41][CH3:42])([OH:40])[C:38](=[O:43])[O:37][CH2:36][C:31]=5[C:32]4=[O:35])[C:26]3=[N:27][C:16]3[C:17]2=[C:12]([CH:13]=[CH:14][CH:15]=3)[N:11]=1
Reactant: CCCCCN1C(CNC(=O)OC(C)(C)C)=Nc2cccc3nc4c(c1c23)Cn1c-4cc2c(c1=O)COC(=O)[C@]2(O)CC
Solvent: O=C(O)C(F)(F)F
Product: CCCCCN1C(CN)=Nc2cccc3nc4c(c1c23)Cn1c-4cc2c(c1=O)COC(=O)[C@]2(O)CC
Reaction time: 1 h
Yield: 80 %

Procedure:
(9S)-2-(t-Butoxycarbonylamino)methyl-9-ethyl-9-hydroxy-1-pentyl-1H,12H-pyrano[3″,4″:6′,7′]indolizino[1′,2′:6,5]pyrido[4,3,2-de]quinazoline-10,13(9H,15H)-dione (33 mg, 0.056 mmol) was dissolved in trifluoroacetic acid (1 ml) and mixture was stirred for 1 hr. at room temperature. The solution was concentrated under reduced pressure and the resulting residue was purified by reverse-phase C-18 column chromatography to obtain pure product (27 mg, 80%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].Cl[S:7]([C:10]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:11]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:9])=[O:8]>C1COCC1>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[S:7]([C:10]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:11]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:8])=[O:9]
Reactant: CNCCO
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)Cl
Solvent: C1CCOC1
Product: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)N(C)CCO
Reaction time: 18 h
Yield: 82.9 %

Procedure:
N-Methylethanolamine (2.96 g, 39.4 mmol) was added to a solution of methyl 2-chlorosulfonyl-6nitrobenzoate (5.5 g, 19.7 mmol) in THF (150 ml) and the mixture stirred at 20°-25° for 18 hours. After removing THF under reduced pressure, the residue was partitioned between EtOAc and H2O. The organic extract was washed with saturated NaCl solution and dried (Na2SO4). Flash chromatography of the residue over silica gel and elution with 1% MeOH-99% CHCl3 afforded pure sulfonamide. Recrystallization from EtOAc-hexane gave analytically pure product (5.2 g, 82.9%), m.p. 98°-101°.
Reaction SMILES: [Na+:1].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:30]=[CH:31][CH:32]=1)[C:9]([NH:11][C:12]1[C:21]2[C:20]([S:22]([O-:25])(=[O:24])=[O:23])=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]([S:26]([O-:29])(=[O:28])=[O:27])=[CH:14][CH:13]=1)=[O:10])([O-])=O.[H][H]>[Pd].O>[Na+:1].[Na+:1].[NH2:3][C:6]1[CH:7]=[C:8]([CH:30]=[CH:31][CH:32]=1)[C:9]([NH:11][C:12]1[C:21]2[C:20]([S:22]([O-:25])(=[O:24])=[O:23])=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]([S:26]([O-:29])(=[O:28])=[O:27])=[CH:14][CH:13]=1)=[O:10]
Reactant: O=C(Nc1ccc(S(=O)(=O)[O-])c2cccc(S(=O)(=O)[O-])c12)c1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Solvent: O
Product: Nc1cccc(C(=O)Nc2ccc(S(=O)(=O)[O-])c3cccc(S(=O)(=O)[O-])c23)c1
Reaction time: 0.33 h

Procedure:
A mixture of 25.0 g of 4-(m-nitrobenzamido)-1,5-naphthalenedisulfonic acid disodium salt (prepared as in Example 5), 200 ml of water and 2.0 g of 10% palladium on charcoal is hydrogenated in a Parr shaker for 4 hours and 20 minutes at room temperature with an initial pressure of 42 pounds of hydrogen. During this time a total of 11.0 pounds of hydrogen is absorbed. The mixture is heated to dissolve some precipitated product and is filtered through diatomaceous earth to remove the catalyst. The filtrate is then evaporated to a small volume in vacuo at 55°-60° C. until crystal formation. The material is then diluted with absolute ethyl alcohol and is triturated. The crystals are then collected by filtration and the product is washed first with two 100 ml portions of absolute ethyl alcohol followed by two 100 ml portions of ether. The product of the example is then oven dried overnight at 120° C.
Reaction SMILES: S(O[C@@H:6]1[C@H:10]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[O:9][C@H:8]([N:20]2[CH:27]=[C:26]([F:28])[C:24]([NH2:25])=[N:23][C:21]2=[O:22])[CH2:7]1)(C)(=O)=O.[N-:29]=[N+:30]=[N-:31].[Li+].CO>CN(C)C=O>[N:29]([C@H:6]1[C@H:10]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[O:9][C@H:8]([N:20]2[CH:27]=[C:26]([F:28])[C:24]([NH2:25])=[N:23][C:21]2=[O:22])[CH2:7]1)=[N+:30]=[N-:31]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1O[C@H](n2cc(F)c(N)nc2=O)C[C@@H]1OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1O[C@H](n2cc(F)c(N)nc2=O)C[C@H]1N=[N+]=[N-]
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 72 %

Procedure:
To a solution of 9 (520 mg, 1.19 mmol) in anhydrous dimethylformamide (12 mL) was added lithium azide moistened with 10% methanol (300 mg, 5.31 mmol). The reaction mixture was stirred at 100° C. during 2.5 h, and then cooled to room temperature, poured onto ice/water (200 mL) and extracted with chloroform (3×100 mL). Combined extracts were washed with saturated aqueous sodium hydrogen carbonate solution (2×100 mL), with water (5×100 mL), and then dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent : methanol (4%) in chloroform] to give pure 10 (327 mg, 72%), which was crystallized from a diethyl ether/methanol mixture: mp 146-147° C.; UV (ethanol): λmax 243 nm (ε 8700), 283 nm (ε8400), λmin 226 nm (ε 7200), 264 nm (ε 6700); 1H NMR (DMSO-d6): δ 7.90 (d, 1H, H-6, J6-F5=7.0 Hz), 7.8-7.5 (br d, 2H, NH2), 6.0 (m, 1H, H-1′), 4.3 (m, 1H, H-3′), 3.9-3.7 (m, 3H, H-4′, H-5′ and H″-5), 2.4-2.2 (m, 2H, H-2′ and H-2″), 0.87 (s, 9H, (CH3)3C—Si), 0.05 (s, 6H, (CH3)2Si); MS (matrix GT): FAB>0 m/z 769 (2M+H)+, 385 (M+H)+, 130 (BH2)+; FAB<0 m/z 383 (M−H)−; [α]D20=−67 (c, 0.96 DMSO).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]([O:9][C:10](=[O:31])[NH:11][CH2:12][C@H:13]([OH:30])[CH2:14][NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([F:25])[CH:24]=1)[N:21]([CH2:26][CH2:27][F:28])[C:20](=[O:29])[CH2:19]2)([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>ClCCl>[C:5]([O:9][C:10](=[O:31])[NH:11][CH2:12][C@@H:13]1[O:30][C:1](=[O:2])[N:15]([C:16]2[CH:17]=[C:18]3[C:22](=[C:23]([F:25])[CH:24]=2)[N:21]([CH2:26][CH2:27][F:28])[C:20](=[O:29])[CH2:19]3)[CH2:14]1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NC[C@H](O)CNc1cc(F)c2c(c1)CC(=O)N2CCF
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@H]1CN(c2cc(F)c3c(c2)CC(=O)N3CCF)C(=O)O1
Reaction time: 0.5 h

Procedure:
Phosgene (20% solution in toluene, 0.414 ml, 4.24 mmol) is added to (R)-{3-[7-fluoro-1-(2-fluoro-ethyl)-2-oxo-2,3-dihydro-1H-indol-5-ylamino]-2-hydroxy-propyl}-carbamic acid tert-butyl ester (0.150 g, 0.424 mmol) and triethylamine (0.295 ml, 2.12 mmol) in dichloromethane (3 ml) at 0° C. and stirred for 30 minutes. The mixture is diluted with dichloromethane, washed with water and brine, dried (Na2SO4) and evaporated to give the title compound as a light brown solid. HPLC r.t. 4.70 min; MS for C19H23F2N3O5 m/z 380.3 (M+H)+.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])/[C:2](=[CH:4]/[CH3:5])/[CH3:3].[C:10]([OH:13])(=[S:12])[CH3:11].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(OCC)C>[C:10]([S:12][CH:4]([CH3:5])[CH:2]([CH3:3])[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:13])[CH3:11]
Reactant: C/C=C(\C)C(=O)OCC
Reactant: CC(O)=S
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C(C)C(C)SC(C)=O
Temperature: 75 °C
Reaction time: 24 h
Yield: 93.4 %

Procedure:
A mixture of 51.27 g (0.40 mol) of ethyl tiglate, 76.12 g (1.00 mol) of thioacetic acid, and 7.60 g (0.04 mol) of para-toluenesulfonic acid was stirred under nitrogen atmosphere at 75° C. for 24 hours. After cooling, diethyl ether and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture. The organic layer was separated and washed twice with brine. The solvent in the organic layer was evaporated off, and vacuum distillation (68 to 71° C./2 torr) was performed to give 76.36 g of the objective compound (GC purity: 98.3%, yield: 91.8%, diastereomer ratio: 80.9/19.1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[C:24]([N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32])(=[O:26])[CH3:25]>>[C:24]([N:27]1[CH2:31][CH2:30][N:29]([C:2]2[CH:7]=[N:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:4][CH:3]=2)[C:28]1=[O:32])(=[O:26])[CH3:25]
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C)cc4C)CC3)nc2)C1=O
Yield: 52 %

Procedure:
Using (5-bromopyridin-2-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (550 mg) described in Preparation Example 134 and 1-acetyl-2-imidazolidinone (188 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (322 mg) was obtained.
Reaction SMILES: [CH2:1]([O:3][P:4]([O:23][CH2:24][CH3:25])([CH:6]1[CH2:10][CH2:9][CH:8]([CH2:11]OS(C2C=CC(C)=CC=2)(=O)=O)[O:7]1)=[O:5])[CH3:2].[Br-:26].[Li+]>CN(C=O)C>[Br:26][CH2:11][C@@H:8]1[O:7][C@@H:6]([P:4]([O:23][CH2:24][CH3:25])([O:3][CH2:1][CH3:2])=[O:5])[CH2:10][CH2:9]1
Reactant: [Br-]
Reactant: CCOP(=O)(OCC)C1CCC(COS(=O)(=O)c2ccc(C)cc2)O1
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)[C@H]1CC[C@H](CBr)O1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a stirring solution of (±)-2-diethoxyphosphinoyl-5-(p-toluenesulfonyloxymethyl)-tetrahydrofuran (example 60) (12.0 g, 30.61 mmol) in dry DMF (60 mL) was added anhydrous lithium bromide (13.3 g, 153.05 mmol). The solution was then stirred at 80° C. for 4 h. The mixture was cooled and concentrated to dryness under reduced pressure. The residue was then dissolved in methylene chloride and the solution was washed with water (2×50 mL), brine (50 mL), dried (MgSO4) and concentrated. The cis-trans mixture was separated by flash chromatography eluting with 10→20% acetone in hexanes.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[N:8]O)=[CH:5][CH:4]=1.N.[H][H]>[Pd].CC(O)C>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:11]=[CH:10][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1
Reactant: ON=Cc1ccc(C(F)(F)F)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: N
Solvent: CC(C)O
Product: NCc1ccc(C(F)(F)F)cc1
Yield: 92.6 %

Procedure:
The second step of the process of the present invention was conducted as follows. At first, a 1-liter autoclave equipped with a mechanical stirrer was charged with 300 g (1.59 mol) of 4-trifluoromethylbenzaldehyde oxime, 460 g of 2-propanol, and 15 g of a catalyst (i.e., a carbon powder (50% wet) carrying thereon 5% palladium), followed by introduction of 40 g of liquid ammonia and then introduction of hydrogen to have a pressure of 1 MPa. Then, the reaction mixture was stirred, while the reaction temperature was maintained at 20° C. and while hydrogen was gradually introduced into the autoclave in a manner to maintain the total pressure at 1 MPa. After conducting the reaction for 4 hr, the reaction was stopped, followed by removing the catalyst by filtration. As a result of analyzing the obtained reaction liquid by gas chromatography, 4-trifluoromethylbenzylamine was formed at a yield of 92.6%.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH:10]2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]3[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:31]=3[CH:41]=2)=[CH:5][CH:4]=1.[NH:42]1[CH:46]=[CH:45][N:44]=[CH:43]1>>[N:42]1([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:16])[CH2:11][CH:10]3[O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]4[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:31]=4[CH:41]=3)=[CH:5][CH:4]=2)[CH:46]=[CH:45][N:44]=[CH:43]1
Reactant: c1c[nH]cn1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CCl)cc3)cc21
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(Cn4ccnc4)cc3)cc21

Procedure:
Analogously to Example 269a, 0.103 g of benzyl 4-(4-chloromethylphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 270b) and 0.013 g of imidazole are reacted. The title compound is obtained as a yellowish oil. Rf=0.47 (200:10:1 dichloromethane-methanol-25% conc. ammonia). Rt=4.34.
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:36])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([CH:15]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:16])[CH:6]=[CH:5][C:4]1=2.[CH:37]([C:40]1[CH:47]=[CH:46][C:43]([CH:44]=O)=[CH:42][CH:41]=1)([CH3:39])[CH3:38]>>[CH:37]([C:40]1[CH:47]=[CH:46][C:43](/[CH:44]=[C:15](/[C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[C:3]([CH3:36])([CH3:2])[CH2:12][CH2:11][C:10]3([CH3:13])[CH3:14])\[CH3:16])=[CH:42][CH:41]=1)([CH3:39])[CH3:38]
Reactant: CC(c1ccc2c(c1)C(C)(C)CCC2(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)c1ccc(C=O)cc1
Agent: [Br-]
Product: C/C(=C\c1ccc(C(C)C)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
In a manner analogous to that described in Example 1, from [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethyl]-triphenylphosphonium bromide and 4-isopropyl-benzaldehyde there can be obtained 6-[(E)-p-isopropyl-α-methylstyryl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene of melting point 86°-87° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=O>CO.C(O)=O>[O:13]([C:3]1[C:4]([C:9]([CH3:10])([CH3:12])[CH3:11])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1/[N:1]=[CH:20]/[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(N)c(O)c(C(C)(C)C)c1
Reactant: O=Cc1ccccn1
Solvent: O=CO
Solvent: CO
Product: Cc1cc(/N=C/c2ccccn2)c(Oc2ccccc2)c(C(C)(C)C)c1
Reaction time: 2 h
Yield: 107.2 %

Procedure:
To a slurry of 2-amino-4-methyl-6-tertbutylphenol (0.70 g, 3.90 mmol) in 5 mL methanol, a methanol solution of pyridine-2-carbaldehyde (0.418 g, 3.90 mmol) was slowly added, forming a dark orange solution. Two drops formic acid were added, quickly forming a yellow precipitate. This was stirred for 2 hr, then collected on a frit, washed with cold methanol and dried under vacuum to yield 0.72 g of 12 (69%).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]([CH3:12])[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:4].[F:13][C:14]1[CH:15]=[C:16]([N:33]2[CH2:37][C@H:36]([CH2:38][N:39]3[CH:43]=[CH:42][N:41]=[N:40]3)[O:35][C:34]2=[O:44])[CH:17]=[CH:18][C:19]=1[C:20]1[CH:21]=[N:22][C:23]([C:26]2[CH2:30][C@@H:29]([CH2:31]O)[O:28][N:27]=2)=[CH:24][CH:25]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([N:5]([CH3:12])[CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:31][C@H:29]1[O:28][N:27]=[C:26]([C:23]2[CH:24]=[CH:25][C:20]([C:19]3[CH:18]=[CH:17][C:16]([N:33]4[CH2:37][C@H:36]([CH2:38][N:39]5[CH:43]=[CH:42][N:41]=[N:40]5)[O:35][C:34]4=[O:44])=[CH:15][C:14]=3[F:13])=[CH:21][N:22]=2)[CH2:30]1)=[O:10])=[O:4]
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Reactant: COC(=O)N(C)CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)N(C)CCCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The carbamate prepared as above (0.32 g, 1.83 mmol), (5R)-3-(3-fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1: 0.2 g, 0.46 mmol), 4-dimethylaminopyridine (0.01 g, 0.08 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.19 g, 0.99 mmol) were combined in DMF (2 ml). The suspension was allowed to stir for 2 hours at room temperature. The mixture was then diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. The residue obtained upon filtration and evaporation was purified via chromatography (silica gel, 0.5 to 10% methanol in dichloromethane). Evaporation of the product containing fractions and trituration of the resulting solid with diethyl ether yielded the title compound as an off-white solid (0.23 g), melting point: 135° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]([OH:8])[C:6](=[NH:9])[N:5]=[C:4](Cl)[CH:3]=1.[NH:11]1[CH2:16][CH2:15][S:14][CH2:13][CH2:12]1>CN(C)C=O>[NH2:1][C:2]1[N:7]([OH:8])[C:6](=[NH:9])[N:5]=[C:4]([N:11]2[CH2:16][CH2:15][S:14][CH2:13][CH2:12]2)[CH:3]=1
Reactant: C1CSCCN1
Reactant: N=c1nc(Cl)cc(N)n1O
Solvent: CN(C)C=O
Product: N=c1nc(N2CCSCC2)cc(N)n1O
Temperature: 110 °C

Procedure:
A mixture of 16.1 g of 6-amino-4-chloro-1,2-dihydro-2-imino-1-pyrimidinol, 32.1 g of thiomorphline, and 75 ml of dimethyl formamide is heated at 110° C in a nitrogen atmosphere for 17 hours. The solvent is removed under high vacuum. The residue is dissolved in 2 normal hydrochloric acid, and the resulting solution made basic with 5% ammonium hydroxide. There is deposited 13.0 g (57%) of a crystalline solid mp 242° (dec). Recrystallization from methanol-ethanol gives an off-white crystalline solid, mp 246° C(dec).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.[CH:14]([NH2:17])([CH3:16])[CH3:15]>>[Cl:13][C:4]1[CH:3]=[C:2]([NH:17][CH:14]([CH3:16])[CH3:15])[C:7]([CH:8]=[O:10])=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Reactant: CC(C)N
Product: CC(C)Nc1cc(Cl)ncc1C=O
Yield: 88.5 %

Procedure:
Using the three-step procedure of Example C5, ethyl 4,6-dichloronicotinate (20 g, 91 mmol) and isopropylamine (60% in water, 18 g, 182 mmol) were converted to 6-chloro-4-(isopropylamino)nicotinaldehyde (16 g, 81% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.82 (s, 1 H), 8.43-8.39 (m, 2 H), 6.83 (s, 1 H), 3.84 (m, 1 H), 1.17 (d, J=6.4 Hz, 6 H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[C@@H:12]([C:13]#[C:14][CH3:15])[CH2:11][CH2:10][C@H:6]1[C:7](O)=[O:8])=[O:4].C[N:17]1CCOCC1.ClC(OCC(C)C)=O.N.O1CCOCC1>C(Cl)Cl.Cl>[Cl:1][CH2:2][C:3]([N:5]1[C@@H:12]([C:13]#[C:14][CH3:15])[CH2:11][CH2:10][C@H:6]1[C:7]([NH2:17])=[O:8])=[O:4]
Reactant: CN1CCOCC1
Reactant: CC#C[C@H]1CC[C@@H](C(=O)O)N1C(=O)CCl
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC#C[C@H]1CC[C@@H](C(N)=O)N1C(=O)CCl
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (5R)-1-(chloroacetyl)-5-propynyl-L-proline (1.10 g, 4.8 mmol) in CH2Cl2 (24 mL) at −15° C. under nitrogen was added 4-methylmorpholine (0.64 mL, 5.76 mmol), and then isobutyl chloroformate (0.81 mL, 6.24 mmol) over 10 minutes. A white precipitate formed. The reaction mixture was stirred at −15° C. under nitrogen for 30 minutes, and a solution of NH3 in dioxane (0.5 M, 29 mL, 14.4 mmol) was added. The reaction mixture was stirred at −15° C. for 30 minutes, warmed to room temperature, and stirred at that temperature for 16 hours. The reaction mixture was diluted with 1M HCl to ˜pH 4 and extracted with ethyl acetate (3×). The extracts were combined, washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by flash column chromatography (60-75% ethyl acetate/hexane) provided the titled compound. MS (DCI) m/z 229 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][O:8][CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])([O-:3])=[O:2]>C(O)=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][O:8][CH2:9][C:10]([OH:12])=[O:11])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)COCc1cccc([N+](=O)[O-])c1
Solvent: O=CO
Product: O=C(O)COCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.7 %

Procedure:
t-Butyl 3-nitrobenzyloxyacetate (5 g, 18.7 mM) was dissolved in formic acid (50 ml) and stirred at ambient temperature for 48 hours. Solvents were removed to give 3-nitrobenzyloxyacetic acid (3.9 g, 98%). NMR (DMSO-d6): δ4.15 (s, 2H); 4.69 (s, 2H); 7.66 (t, 1H); 7.81 (d, 1H); 8.13-8.22 (m, 2H); 12.73 (br, 1H).
Reaction SMILES: C([O:5]C(NCC(O)=O)=O)(C)(C)C.[CH:13]1([N:19]=[C:20]=[N:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(#N)C>[C:20]([NH:19][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)([NH:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:5]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 3 h

Procedure:
To a solution of 9.45 g of N-(t-butoxycarbonyl)-glycine in 60 ml of acetonitrile was added 6.13 g of dicyclohexylcarbodiimide with stirring under ice-cooling. After three hours, dicyclohexylurea produced was filtered off, and the filtrate was concentrated. The oily residue was dissolved in 15 ml of anhydrous pyridine, and to the solution was added 5.00 g of 3'-O-(4-chlorobenzyl)-2'-deoxy-5-fluorouridine. The mixture was left to stand for three hours at room temperature and for 30 minutes at a temperature of 40° C. To the mixture was added 5 ml of water at room temperature and the mixture was left to stand for 30 minutes and then concentrated. The residue was dissolved in 50 ml of ethyl acetate, and the solution was washed three times with saturated aqueous solution of sodium hydrogen carbonate and twice with saturated aqueous solution of sodium chloride. Further the solution was dried over anhydrous magnesium sulfate and concentrated. The residue was placed on silica gel column and eluted with 1% methanol-chloroform, giving 5.33 g (75%) of 5'-O-[N-(t-butoxycarbonyl)glycyl]-3'-O-(4-chlorobenzyl)-2'-deoxy-5-fluorouridine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH3:14])[CH2:9][CH2:10][C:11]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(CCC(=O)O)C(=O)OC(C)(C)C
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CN(CCC(=O)N1CCOCC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a mixture of N-t-butoxycarbonyl-N-methyl-β-alanine (1.02 g) and morpholine (0.48 g) in dry methylene chloride was added N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.05 g), and the mixture was stirred at ambient temperature overnight. After evaporation of the solvent, the residue was dissolved in ethyl acetate. The solution was washed with 1% citric acid aqueous solution, saturated sodium bicarbonate solution, and saturated sodium chloride solution. Then the solution was dried over magnesium sulfate and concentrated under reduced pressure to give 4-(N-t-butoxycarbonyl-N-methyl-β-alanyl)morpholine (1.36 g).