Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=O.[CH:11](=[O:15])/[CH:12]=[CH:13]/[CH3:14].C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[OH:10][C:7]1[CH:8]=[CH:9][C:2]2[O:1][CH:13]([CH3:14])[C:12]([CH:11]=[O:15])=[CH:4][C:3]=2[CH:6]=1
Reactant: C/C=C/C=O
Reactant: O=Cc1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC1Oc2ccc(O)cc2C=C1C=O

Procedure:
The starting material is prepared as follows: A mixture of 2,5-dihydroxybenzaldehyde (5.0 g, 36.2 mmol), crotonaldehyde (3.8 g, 54.3 mmol), and potassium carbonate (10.0 g, 72.4 mmol) in 75 ml of 1,4-dioxane is heated at reflux for 6 hours. The mixture is cooled and poured into water. This is extracted (3×) with dichloromethane, and the combined organic layers are dried (MgSO4) and concentrated to dryness to give 6-hydroxy-2-methyl-2H-1-benzopyran-3-carboxaldehyde as a colored solid. Such is converted to 6-benzyloxy-2-methyl-2H-1-benzopyran-3-carboxaldehyde, m.p. 107°-109° C., which is in turn converted to 3-(N-hydroxyaminomethyl)-6-benzyloxy-2-methyl-2H-1-benzopyran as described above.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15](O)=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.C(N1C=CN=C1)([N:23]1C=CN=C1)=O.C([O-])(=O)C.[NH4+]>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([NH2:23])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: NC(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 25 °C
Reaction time: 3.75 h
Yield: 96.7 %

Procedure:
A solution of 7-chloro-3-(carboxy)pyrazolo[3,4c][1]-benzazepine-4,10-(1H,9H)-dione (1 g, 3.44 mmol) (compound of Example 9) and 1,1'-carbonyldiimidazole (0.64 mg, 3.95 mmol) in N,N-dimethylformamide (25 mL) was stirred for 64.5 hours. In one portion, ammonium acetate (0.796 mg, 10.33 mmol) was added, followed by additional N,N-dimethylformamide (15 mL). The solution was stirred for 3.75 hours at room temperature and concentrated in vacuo for 45 minutes. The residue was washed with water (3×20 mL). The insoluble material was filtered and dried to give the title compound (967 mg, 97% yield, m.p. 224-225° C.).
Reaction SMILES: Br[C:2]1[CH2:6][CH:5]([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[C:16]3=[N:17][C:18]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)[N:20]=[C:15]3[CH2:14][CH2:13][CH2:12]2)[O:4][N:3]=1.[CH3:35][O-:36].[Na+]>CO>[C:24]1([CH3:27])[CH:25]=[CH:26][C:21]([C:19]2[N:20]=[C:15]3[CH2:14][CH2:13][CH2:12][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH:5]4[O:4][N:3]=[C:2]([O:36][CH3:35])[CH2:6]4)[C:16]3=[N:17][C:18]=2[C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)=[CH:22][CH:23]=1
Reactant: C[O-]
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCC2CC(Br)=NO2)CCC3)cc1
Agent: [Na+]
Solvent: CO
Product: COC1=NOC(CCCCN2CCCc3nc(-c4ccc(C)cc4)c(-c4ccc(C)cc4)nc32)C1
Temperature: 25 °C

Procedure:
A solution of 3-bromo-5-(4-(2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)butyl)-4,5-dihydroisoxazole (step 1) (5195 mg, 10 mmol) in MeOH (5 ml) was treated with NaOMe (10 ml of 30% solution by weight) and heated at reflux for 2 hours. After cooling to RT, the reaction was quenched with water (100 ml) and the aqueous portion was extracted with EtOAc. The combined organic extracts were washed with brine, dried by passing through a phase separator and were concentrated under reduced pressure. The crude product was purified by chromatography on silica eluting with 0-60% EtOAc in iso-hexane to afford the titled compound as an orange oil;
Reaction SMILES: F[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19]([OH:21])=[O:20])=[CH:14][CH:13]=[CH:12]3)[CH:5]=[CH:4][N:3]=1.[NH4+:22].[OH-]>>[NH2:22][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19]([OH:21])=[O:20])=[CH:14][CH:13]=[CH:12]3)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1cccc2cc(Oc3ccnc(F)n3)ccc12
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1nccc(Oc2ccc3c(C(=O)O)cccc3c2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-(2-Fluoropyrimidin-4-yloxy)-1-naphthoic acid (1.2 g, 4.2 mmol) was dissolved in NH4OH (37% water, 20 mL) and stirred at RT for 3h. Solvent was evaporated. A little bit of MeOH was added to the slurry followed by ether until the compound crashed out. Solid was filtered.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1([CH3:32])[CH2:9][CH2:8][CH2:7][N:6]([C:10]2[C:30]([F:31])=[CH:29][C:13]3[C:14]4[C:15](=[O:28])[C:16]([C:23]([O:25]CC)=[O:24])=[CH:17][N:18]([CH3:22])[C:19]=4[CH:20]=[N:21][C:12]=3[CH:11]=2)[CH2:5]1.Cl>C(O)C.O>[CH3:3][C:4]1([CH3:32])[CH2:9][CH2:8][CH2:7][N:6]([C:10]2[C:30]([F:31])=[CH:29][C:13]3[C:14]4[C:15](=[O:28])[C:16]([C:23]([OH:25])=[O:24])=[CH:17][N:18]([CH3:22])[C:19]=4[CH:20]=[N:21][C:12]=3[CH:11]=2)[CH2:5]1
Reactant: CCOC(=O)c1cn(C)c2cnc3cc(N4CCCC(C)(C)C4)c(F)cc3c2c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1cc(C(=O)O)c(=O)c2c3cc(F)c(N4CCCC(C)(C)C4)cc3ncc21
Temperature: 100 °C
Yield: 81.6 %

Procedure:
1.4 cm3 of 1 N aqueous potassium hydroxide was added, with stirring, to a suspension of 0.5 g of ethyl 8-(3,3-dimethylpiperidin-1-yl)-9-fluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate in 15 cm3 of ethanol and 15 cm3 of water. The mixture was heated at about 100° C. for one hour. The suspension obtained was acidified by addition of 1.4 cm3 of 1 N aqueous hydrochloric acid. After cooling, the precipitate was dewatered, washed three times with 10 cm3 of water, three times with 10 cm3 of ethanol, and three times with 10 cm3 of ether. The solid was dried at about 80° C. at 1 kPa for 4 hours. 0.38 g of 8-(3,3-dimethylpiperidin-1-yl)-9-fluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylic acid was obtained in the form of a yellow solid, which melted with decomposition at about 286-7° C.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.C=O.[C:13]([BH3-])#[N:14].[Na+].[C:17](O)(=O)C>CC#N.CCOCC>[CH3:17][N:14]([CH3:13])[C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1
Reactant: [BH3-]C#N
Reactant: Nc1ccc2sccc2c1
Reactant: CC(=O)O
Agent: C=O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: CN(C)c1ccc2sccc2c1
Reaction time: 1 h
Yield: 88 %

Procedure:
To a stirred solution of 5-aminobenzo[b]thiophene (4.55 g, 0.03 mole) in CH3CN (175 ml) was added 37% aqueous formaldehyde (28 ml, 0.035 mole) followed by sodium cyanoborohydride (6.65 g, 0.105 mole). Glacial acetic acid (3.5 ml) was added in small increments over 15 minutes. After 1 hour, another 3.5 ml of acetic acid was added and after another 1 hour, the mixture was poured into ether (700 ml). The ethereal layer was separated, washed with 1M KOH (3×) then with saturated NaCl solution, dried over anhydrous Na2SO4, and evaporated to dryness in vacuo. The residual dark oily solid was purified by chromatography on 800 ml of silica gel. Elution with 97 hexane: 3 ethyl acetate afforded 4.6 g (88%) of 5-(dimethyl)aminobenzo[b]thiophene as a light yellow solid, m.p. 52°-54° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[N:11]([CH2:19][C:20]3[CH:24]=[C:23]([C:25]4[S:26][C:27]([Cl:30])=[CH:28][CH:29]=4)[O:22][N:21]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3][CH2:2]1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl.CCN(CC)CC>[CH3:31][S:32]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[N:11]([CH2:19][C:20]3[CH:24]=[C:23]([C:25]4[S:26][C:27]([Cl:30])=[CH:28][CH:29]=4)[O:22][N:21]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3][CH2:2]1)(=[O:34])=[O:33]
Reactant: O=C(NC1CCNCC1)c1cc2ccccc2n1Cc1cc(-c2ccc(Cl)s2)on1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(NC(=O)c2cc3ccccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Reaction time: 16 h

Procedure:
To a solution of 50 mg 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid piperidin-4-ylamide in 2 ml DCM, 0.3 ml NEt3 and 20 mg Methanesulfonyl chloride were added at RT and stirred for 16 h. After removal of the solvent under reduced pressure the residue was directly purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). After lyophilization the product was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[CH3:12][S:13]([C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19])(=[O:15])=[O:14].CCN(C(C)C)C(C)C.O>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([S:13]([CH3:12])(=[O:15])=[O:14])[CH:17]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: Clc1nc(Cl)c2ncsc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1cccc(Nc2nc(Cl)nc3scnc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
A mixture of 5,7-dichlorothiazolo[5,4-d]pyrimidine (200 mg, 0.97 mmol), 3-(methylsulfonyl)aniline (182 mg, 1.07 mmol) and DIEA (375 g, 2.91 mmol) in 20 mL of DMSO was stirred at room temperature overnight. The mixture was poured into 150 mL of water and filtered, the solid obtained was washed with petroleum ether dried to give crude product which was purified by silica gel chromatography, silica gel 200-300 mesh, eluting with ethyl acetate to give 5-chloro-N-(3-(methylsulfonyl)phenyl)thiazolo[5,4-d]pyrimidin-7-amine (220 mg, 66%) as a yellow solid. LC-MS: 341 [M+H]+, 3621 [M+Na]+, tR=1.48 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C([N:22]2[CH:26]=NC=C2)=O)C=1.[NH2:27]N.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)Br>C(Cl)Cl>[O:11]1[CH:26]=[N:22][N:27]=[C:10]1[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][CH3:14]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NN
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC[C@@H](NC(=O)OC(C)(C)C)c1nnco1
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.1 %

Procedure:
(2R)-2-(tert-butoxycarbonylamino)butanoic acid (5 g, 24.60 mmol) was dissolved in DCM (500 mL) and cooled to 0° C. CDI (4.188 g, 25.83 mmol) was added and the reaction stirred for 60 minutes. Formic hydrazine (1.477 g, 24.60 mmol) was added and the reaction stirred at 0° C. for 45 minutes then allowed to reach ambient temperature overnight. The reaction was cooled to 0° C. and treated with PS-PPh3 (22.88 g, 49.20 mmol) and CBr4 (16.32 g, 49.20 mmol) The reaction was allowed to warm slowly to ambient temperature over 2 hours, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (25 to 50% EtOAc/Petrol) to give the sub-title compound as a colourless oil (2.30 g, 41%); 1H NMR (400.0 MHz, DMSO) d 0.88 (t, 3H), 1.27-1.39 (2×s, 9H), 1.75-1.87 (m, 2H), 4.71 (dd, 1H), 7.62 (d, 1H), 9.17 (s, 1H) MS ES(+) 228.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[C:14]4[CH2:15][NH:16][CH2:17][CH2:18][C:13]=4[NH:12][C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.Cl[CH2:20][CH2:21][CH2:22][C:23]1[C:27]2[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=2[O:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[C:14]4[CH2:15][NH:16][CH2:17][CH:18]([CH2:20][CH2:21][CH2:22][C:23]5[C:27]6[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=6[O:25][N:24]=5)[C:13]=4[NH:12][C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(CCCCl)noc2c1
Reactant: Clc1ccc2c(c1)ncc1[nH]c3c(c12)CNCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc2c(CCCC3CNCc4c3[nH]c3cnc5cc(Cl)ccc5c43)noc2c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture prepared from 5.15 g of 3-chloro-7,8,9,10-tetrahydro-11H-pyrido[3',4':4,5]pyrrolo[2,3-c]quinoline, 7.0 g of 3-(3-chloropropyl)-6-fluorobenzisoxazole, 4.0 g of potassium carbonate (powdered) and 30 ml of N,N-dimethylformamide was stirred at 100° C. for 2 hours. The mixture was diluted with 150 ml of water and the oily precipitate was purified by high performance liquid chromatography (HPLC) using dichloromethane/methanol mixtures of 95:5 and 10:1 ratios. The clean fractions were combined and concentrated. The residue was stirred in isopropanol and filtered. The yield was 1.2 g, mp=221°-222° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([CH3:26])[C:24]#[N:25])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:27]=[N+:28]=[N-:29].[Na+].Cl.C(N(CC)CC)C>CN(C)C=O>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([C:24]3[NH:29][N:28]=[N:27][N:25]=3)[CH3:26])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C#N)CCCCCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(CCCCCc1nc(-c2ccccc2)c(-c2ccccc2)o1)c1nnn[nH]1
Yield: 68.2 %

Procedure:
3 g of (RS)-7(4,5-diphenyl-2-oxazolyl)-2-methylheptanenitrile in 30 cm3 of dimethylformamide are treated with twice 1.7 g of sodium azide and twice 3.6 g of triethylamine hydrochloride under the (time and temperature) conditions defined in Example 1. After treatment, the product of the reaction is chromatographed on a column 2 cm in diameter containing 78 g of silica gel (50 to 200μ). The column is eluted, collecting 200 cm3 fractions, with 1 liter of diisopropyl ether and then with 1.6 liters of a diisopropyl ether/ethyl acetate (95:5 by volume) mixture. The fractions from the last eluent mixture are concentrated to dryness under reduced pressure (0.2 kPa). 2.3 g (68%) of (RS)-5-[7-(4,5-diphenyl-2-oxazolyl)-2-heptyl]-1H-tetrazole are obtained in the form of a yellowish oil.
Reaction SMILES: [C:1]([C:4]1([OH:25])[CH2:9][CH2:8][N:7]([CH2:10][CH:11]=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1.[H][H]>C(N(CCC)CCC)CC.C(OC(C)C)(C)C>[ClH:26].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:1]([OH:3])([CH3:2])[C:4]3([CH2:5][CH2:6][N:7]([CH2:10][CH:11]=[C:12]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:8][CH2:9]3)[O:25][C:34]2=[O:35])=[CH:29][CH:28]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CC(=O)C1(O)CCN(CC=C(c2ccccc2)c2ccccc2)CC1
Reactant: [H][H]
Agent: CCCN(CCC)CCC
Solvent: CC(C)OC(C)C
Product: CC1(O)N(c2ccc(Cl)cc2)C(=O)OC12CCN(CC=C(c1ccccc1)c1ccccc1)CC2
Product: Cl
Reaction time: 3 h
Yield: 47.3 %

Procedure:
A solution containing 6.4 g of 4-acetyl-1-(3,3-diphenyl-2-propenyl)-4-hydroxypiperidine and 3.4 g of 4-chlorophenyl isocyanate in 30 ml of tripropylamine is gently refluxed under argon while stirring for 3 hours, then the solvent is distilled off under reduced pressure. After adding benzene to the evaporation residue, the insoluble materials are filtered off, the benzene solution is filtered through a silica gel layer and the solution is evaporated under reduced pressure. After recrystallizing the crude product from a mixture of ethanol and hexane under clarifying with activated carbon, the base obtained is converted to its hydrochloride salt by adding a solution of hydrogen in diisopropyl ether. The title hydrochloride is obtained in 47.3% yield, m.p.: 227°-230° C. (with decomposition).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@H:15]2[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[C@H:16]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:30][I:31]>C(OCC)C>[I-:31].[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([CH2:13][O:14][C@H:15]2[CH2:20][CH2:19][CH2:18][N+:17]([CH3:30])([CH3:21])[C@H:16]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:4]=[C:3]([C:2]([F:28])([F:1])[F:29])[CH:8]=1
Reactant: CI
Reactant: CN1CCC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1c1ccccc1
Solvent: CCOCC
Product: C[N+]1(C)CCC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1c1ccccc1
Product: [I-]

Procedure:
The title compound was prepared from the N-methyl amine (0.24 g, Example 10) with methyl iodide (0.178 ml) in diethyl ether (3 ml). After 62 h the white solid which formed was isolated by filtration and washed with ether, m.p.=204°-205° C. Found: C, 46.74; H, 4.29; N, 2.41. Calcd for C22H24NOF6I.0.3H2O; C, 46.79; H, 4.39; N, 2.48%.
Reaction SMILES: CS([O:5][CH2:6][C@@H:7]([O:35]S(C)(=O)=O)[C@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:33])[F:32])[NH:20][C:21]3=[O:24])=[CH:16][CH:15]=2)[CH2:9]1)(=O)=O.[C:40]([O-:43])(=O)[CH3:41].[K+].C(=O)(O)[O-].[Na+].[C:50](OC(=O)C)(=[O:52])[CH3:51]>>[C:50]([O:5][CH2:6][C@H:7]([O:35][C:40](=[O:43])[CH3:41])[C@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:33])[F:32])[NH:20][C:21]3=[O:24])=[CH:16][CH:15]=2)[CH2:9]1)(=[O:52])[CH3:51]
Reactant: CC(=O)[O-]
Reactant: CS(=O)(=O)OC[C@@H](OS(C)(=O)=O)[C@@H]1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Product: CC(=O)OC[C@H](OC(C)=O)[C@@H]1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Temperature: 120 °C
Reaction time: 6 h
Yield: 54 %

Procedure:
The (R)-2-methanesulfonyloxy-2-{(S)-2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-yl}ethyl methanesulfonate (53 mg, 0.0897 mmol) obtained in step A was dissolved in acetic anhydride (1 ml). Thereafter, potassium acetate (44 mg, 0.449 mmol) was added to the solution, and the obtained mixture was then stirred at 120° C. for 6 hours. The reaction solution was cooled to a room temperature. A saturated sodium bicarbonate aqueous solution was added thereto, and the obtained mixture was then extracted with ethyl acetate. The extract was washed with water and a saturated saline solution, and was then dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=50:1), so as to obtain (S)-2-acetoxy-2-{(S)-2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-yl}ethyl acetate (25 mg, 54%).
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]([C:6]([N:8]2C=N[CH:10]=[CH:9]2)=[O:7])[CH:2]=1.C(N(CC)CC)C.Cl.Cl.[N:22]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:27]CC(N)[CH2:24][CH2:23]1>C(Cl)Cl>[N:22]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:27][CH2:10][CH:9]([NH:8][C:6]([N:3]2[CH:2]=[CH:1][N:5]=[CH:4]2)=[O:7])[CH2:24][CH2:23]1
Reactant: NC1CCN(c2ccccn2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCN(c2ccccn2)CC1)n1ccnc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A suspension comprising CDI (2.29 g, 14 mmol) and triethylamine (3.8 ml, 27 mmol) in dry DCM (20 ml) is treated portionwise over 5 minutes with 3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylamine dihydrochloride (prepared using the procedure described in international patent application WO 01/94368) (2.88 g, 13 mmol). The reaction mixture is stirred at room temperature for 4.5 hours to yield the title compound as a 0.43 M solution in DCM.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.[NH2:12][C@H:13]1[CH2:17][CH2:16][C@H:15]([O:18][C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[NH:26][C:27]2[C:28]3[C:35]([CH3:36])=[C:34]([C:37]([NH2:39])=[O:38])[S:33][C:29]=3[N:30]=[CH:31][N:32]=2)[CH2:14]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([NH:12][C@H:13]1[CH2:17][CH2:16][C@H:15]([O:18][C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[NH:26][C:27]2[C:28]3[C:35]([CH3:36])=[C:34]([C:37]([NH2:39])=[O:38])[S:33][C:29]=3[N:30]=[CH:31][N:32]=2)[CH2:14]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CC[C@H](N)C3)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@H]1CC[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(N)=O)c(C)c23)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Acetyl chloride (21 μl) was added at 0° C. to a mixture of 4-[2-((1S,3S)-3-amino-cyclopentyloxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid amide trifluoroacetate (cpd. 229, 206 mg) and DIPEA (348 μl) in DCM (25 ml) and stirred at rt for 4 hours. The reaction mixture was concentrated, diluted with water and extracted with DCM. The organic layer was dried, concentrated and the crude was purified by chromatography to give the desired product.
Reaction SMILES: [F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([C:18]2[N:19]=[CH:20][C:21]([C:24]([O:26]CC)=[O:25])=[N:22][CH:23]=2)[C:8]2[C:15](=[O:16])[N:14]3[C@@H:10]([CH2:11][CH2:12][CH2:13]3)[C:9]=2[N:17]=1.O.CO>C1COCC1>[F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([C:18]2[N:19]=[CH:20][C:21]([C:24]([OH:26])=[O:25])=[N:22][CH:23]=2)[C:8]2[C:15](=[O:16])[N:14]3[C@@H:10]([CH2:11][CH2:12][CH2:13]3)[C:9]=2[N:17]=1
Reactant: CCOC(=O)c1cnc(-c2cc(Cc3ccc(F)cc3F)nc3c2C(=O)N2CCC[C@@H]32)cn1
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cnc(-c2cc(Cc3ccc(F)cc3F)nc3c2C(=O)N2CCC[C@@H]32)cn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 85.2 %

Procedure:
Ethyl 5-[(9aS)-2-(2,4-difluorobenzyl)-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-a]pyrrolizin-4-yl]-2-pyrazinecarboxylate (0.250 g, 0.555 mmol) was dissolved in THF (4 mL), H2O (1 mL) and MeOH (1 mL) and LiOH monohydrate (0.035 g, 0.832 mmol) was added. The reaction mixture was stirred at ambient temperature for 45 min and then acidified to pH 5. The organics were extracted with CH2Cl2 and then dried (Na2SO4), filtered and concentrated to a white solid (0.200 g, 0.473 mmol, 85% yield): 1H NMR (CD3OD, 400 MHz) δ 9.36 (s, 2H), 7.74 (s, 1H), 7.41–7.35 (m, 1H), 6.97–6.91 (m, 2H), 4.86–4.83 (m, 1H), 4.33 (s, 2H), 3.71–3.64 (m, 1H), 3.48–3.41 (m, 1H), 2.46–2.38 (m, 3H), 1.42–1.38 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15]C)=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[N:10][C:11]=2[NH2:17].Cl[S:24]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:29][CH:28]=1)(=[O:26])=[O:25]>C(N(CC)CC)C>[NH2:17][C:11]1[N:10]=[C:9]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])[N:8]=[C:7]2[C:12]=1[NH:13][C:14](=[O:15])[N:6]2[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:24]([C:27]1[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:31][CH:32]=1)(=[O:26])=[O:25]
Reactant: COC(=O)CCc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCN)c2n1
Solvent: CCN(CC)CC
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCNS(=O)(=O)c3ccc(CCC(=O)OC)cc3)c2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
The compound obtained in Example 2-8 step (ii) (308 mg), methyl 3-[4-(chlorosulfonyl)phenyl]propanoate (263 mg) and triethylamine (0.284 ml) were mixed under stirring at 60° C. for 1 hour, and then cooled. After concentration under reduced pressure, the residue was purified by RPHPLC. The resulting white substance was dissolved in methanol, and 4M hydrochloric acid-dioxane was added thereto. The mixture was stirred at room temperature overnight and then concentrated under reduced pressure to give the titled compound as a white solid. Yield: 124 mg (24%); mp 150-152° C., MS APCI+ve 521 (M+H).