Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.[OH:3][N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]2[N:22]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]3[CH2:33][C:32]([CH3:35])([CH3:34])[N:31]([OH:36])[C:30]([CH3:38])([CH3:37])[CH2:29]3)[N:20]=[C:19]([Cl:39])[N:18]=2)[CH2:6][C:5]1([CH3:41])[CH3:40].S([O-])([O-])=O.[Na+].[Na+].[C:48]([OH:52])([CH3:51])([CH3:50])[CH3:49]>O.C(OCC)(=O)C>[OH:52][C:48]([CH3:51])([CH3:50])[CH2:49][O:36][N:31]1[C:32]([CH3:35])([CH3:34])[CH2:33][CH:28]([CH2:27][CH2:26][CH2:25][CH2:24][NH:23][C:21]2[N:22]=[C:17]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:7]3[CH2:6][C:5]([CH3:41])([CH3:40])[N:4]([O:3][CH2:49][C:48]([CH3:51])([OH:52])[CH3:50])[C:9]([CH3:11])([CH3:10])[CH2:8]3)[N:18]=[C:19]([Cl:39])[N:20]=2)[CH2:29][C:30]1([CH3:38])[CH3:37]
Reactant: CC1(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(O)C(C)(C)C3)n2)CC(C)(C)N1O
Reactant: CC(C)(C)O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(O)CON1C(C)(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OCC(C)(C)O)C(C)(C)C3)n2)CC1(C)C
Temperature: 42.5 °C
Yield: 99.9 %

Procedure:
A total of 40 g (0.59 mol) of 50% aqueous hydrogen peroxide is added in two portions over five hours to a mixture of 43.2 g (0.076 mol) of 2,4-bis[N-(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-6-chloro-s-triazine and 7.0 g (0.035 mol) of ferrous chloride tetrahydrate in 150 g of tert-butyl alcohol and 15 g of water. Another portion of 50% aqueous hydrogen peroxide (3 g, 0.044 mol) is added to the reaction mixture while the temperature is maintained at 40-45° C. for 2.25 hours. The reaction mixture is diluted with 100 g of ethyl acetate. A solution of 100 g of 20% aqueous sodium sulfite is added and the reaction mixture is heated at 60° C. for one hour to decompose residual peroxide. The aqueous layer is extracted with ethyl acetate, and the combined organic layers are concentrated. The crude product is purified by flash chromatography on silica gel with 1:1 (v/v) hexane/ethyl acetate to afford 54.1 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[F:10].C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1C=CC=CC=1.Cl>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:12]/[C:13]([OH:15])=[O:14])=[CH:4][C:3]=1[F:10]
Reactant: O=Cc1ccc(Cl)c(F)c1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)/C=C/c1ccc(Cl)c(F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
4-Chloro-3-fluorobenzaldehyde (15.0 g, 94.6 mmol) was combined with malonic acid (10.8 g, 104 mmol) and pyridine (11.5 mL, 142 mmol). The mixture was heated to 50° C. and agitated 1 hour. Then it was heated to 100° C. and agitated 16 hours. Ice (100 g) and 6M HCl (25 mL) were added, and the mixture was agitated one hour. Precipitation was filtered, washed with water and dried in vacuo to give (E)-3-(4-chloro-3-fluorophenyl)acrylic acid (17.6 g, 87.7 mmol, 92.7% yield) as a solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH:9]1([NH2:13])[CH2:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[Cl:8][C:4]1[N:3]=[C:2]([NH:13][CH:9]2[CH2:12][CH2:11][CH2:10]2)[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: NC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Clc1cncc(NC2CCC2)n1
Yield: 80 %

Procedure:
A solution of 2,6-dichloropyrazine (4.47 g), cyclobutanamine (3.8 mL) and potassium carbonate (6.20 g) in DMA (30 mL) was stirred at 80° C. for 14 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 5→15% ethyl acetate/hexane) to give the title compound (4.42 g, 80%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([OH:13])([CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:5][CH3:6].[CH2:14](Br)[CH:15]=[CH2:16]>CN(C)C=O>[CH2:16]([O:13][C:4]([CH3:3])([CH2:5][CH3:6])[CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: CCC(C)(O)CCC=C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC(C)(CC)CCC=C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 786.7 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 6.8 g, 170 mmol) and dimethylformamide (100 mL) were added to a three necked 500 mL flask fitted with thermocouple, condenser and addition funnel. To the stirred reaction mixture was added dropwise 3,7-dimethyloct-6-en-3-ol (22 g, 139 mmol) at room temperature. The mixture was stirred for 1 hr, cooled to ice bath temperature then allyl bromide (97% pure by GC RPA, 19 g, 15 mmol) was added dropwise whilst maintaining cooling. After a further 3 hr stirring ice/water was added to the reaction mixture and then extracted with methyltert-butyl ether (3×30 mL). The combined organic phase was washed with dilute hydrochloric acid (100 mL), saturated brine (100 mL) and dried with magnesium sulphate. The solvent was removed in vacuo and the residue fractionally distilled to give 6-(allyloxy)-2,6-dimethyloct-2-ene (25.4 g, 92% pure by GC RPA, 118 mmol, chemical yield 70%).
Reaction SMILES: [OH-:1].[K+].Cl[C:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:11][CH:12]=2)[N+:7]([O-:18])=[CH:6][CH:5]=1>>[OH:1][C:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:11][CH:12]=2)[N+:7]([O-:18])=[CH:6][CH:5]=1
Reactant: [O-][n+]1ccc(Cl)c2ccc(C(F)(F)F)cc21
Reactant: [OH-]
Agent: [K+]
Product: [O-][n+]1ccc(O)c2ccc(C(F)(F)F)cc21

Procedure:
A mixture of potassium hydroxide (50.4 g), 4-chloro-7-trifluoromethylquinoline-1-oxide (21.8 g) and industrial methylated spirit (800 ml) was heated under reflux for 150 minutes. The solvent was evaporated, the residue was triturated with water (600 ml) and filtered. The filtrate was neutralised with glacial acetic acid (150 ml) with cooling and the resultant precipitate collected by filtration, washed with water (50 ml) and dried. The crude product was crystallised from methanol to give the novel compound 4-hydroxy-7-trifluoromethylquinoline-1-oxide, m.p. 208°-210°.
Reaction SMILES: [CH2:1]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C:14]4[CH2:15][CH:16]=[C:17]([O:22]C)[CH2:18][C:19]=4[CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[OH:24])[CH2:2][CH2:3][CH3:4].Cl>O.CO>[CH2:1]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C@@H:14]4[C:19]([CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[OH:24])=[CH:18][C:17](=[O:22])[CH2:16][CH2:15]4)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CC[C@@H]2O)CC(OC)=CC4
Agent: Cl
Solvent: CO
Solvent: O
Product: CCCC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reaction time: 2 h
Yield: 68.2 %

Procedure:
Shake 13β-n-butyl-3-methoxy-gona-2,5(10)-dien-17β-ol (0.49 g.) with concentrated hydrochloric acid (1.2 cc.) in water (0.8 cc.) and methanol (18 cc.) until solution is complete. Allow to stand 2 hours at room temperature, pour the mixture into water and extract the product with ether. Evaporate the washed and dried ether extracts and recrystallize the solid from a mixture of ethyl acetate and ether to obtain the title compound (0.32 g.), m.p. 169°-70°; ultraviolet absorption peak at 240 mμ (ε17,000); infrared absorption peaks at 2.92, 6.01 μ.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6]2[C:10]3([CH2:12][CH2:11]3)[CH2:9][O:8][C:7]=12.CN(C=O)C.Cl[C:20]1[N:25]=[CH:24][C:23]([N:26]2[C:30](=[O:31])[C@:29]([CH2:33][CH3:34])([CH3:32])[NH:28][C:27]2=[O:35])=[CH:22][N:21]=1>>[CH2:33]([C@@:29]1([CH3:32])[NH:28][C:27](=[O:35])[N:26]([C:23]2[CH:24]=[N:25][C:20]([O:13][C:5]3[C:6]4[C:10]5([CH2:9][O:8][C:7]=4[C:2]([CH3:1])=[CH:3][CH:4]=3)[CH2:12][CH2:11]5)=[N:21][CH:22]=2)[C:30]1=[O:31])[CH3:34]
Reactant: Cc1ccc(O)c2c1OCC21CC1
Reactant: CC[C@@]1(C)NC(=O)N(c2cnc(Cl)nc2)C1=O
Solvent: CN(C)C=O
Product: CC[C@@]1(C)NC(=O)N(c2cnc(Oc3ccc(C)c4c3C3(CC3)CO4)nc2)C1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
To a solution of 7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-ol (Intermediate 13, 18 mg, 0.1 mmol) in dry DMF (1 ml) potassium carbonate (27.6 mg, 0.2 mmol) and then (5R)-3-(2-chloropyrimidin-5-yl)-5-ethyl-5-methyl-imidazolidine-2,4-dione (Intermediate 22, 20 mg, 0.08 mmol) were added and the reaction mixture was stirred for 2 hours at 80° C. After cooling the reaction mixture was quenched with water (1 ml), diluted with brine (5 ml) and extracted with ethyl acetate (2×10 ml). The organic layer was dried over sodium sulfate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 7:3 to cyclohexane/ethyl acetate 3:7 as eluents affording the title compound (21 mg) as a white solid.
Reaction SMILES: C[N:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]1=O.[CH3:15][N:16]1[CH2:21]CC[C:18](=O)[CH2:17]1.N>CO>[CH3:15][N:16]1[CH2:17][CH2:18][C:6]2[C:7](=[N:2][CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=2)[CH2:21]1
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Reactant: CN1CCCC(=O)C1
Agent: N
Solvent: CO
Product: CN1CCc2cc([N+](=O)[O-])cnc2C1
Temperature: 60 °C

Procedure:
A mixture of 400 mg (2.0 mmol) 1-methyl-3,5-dinitro-pyridone, 300 mg 1-methyl-piperidin-3-one and 15 ml 2M ammonia in methanol are heated to 60° C. for 20 h. It is concentrated and purified by chromatography (silica gel, CH2Cl2/MeOH 98/2).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:15][CH:16]=[C:17]([CH2:19][OH:20])[N:18]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH:27]1([O:33][C:34]([O:36][CH:37](I)[CH3:38])=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH:37]([O:36][C:34]([O:33][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:35])[CH3:38])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:15][CH:16]=[C:17]([CH2:19][OH:20])[N:18]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CC(I)OC(=O)OC1CCCCC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3nc(CO)cs3)[C@H](C)[C@H]12
Agent: [Na+]
Product: CC(OC(=O)OC1CCCCC1)OC(=O)C1=C(S/C=C\c2nc(CO)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 89.9 %

Procedure:
In the same manner as in Example 81, 52.7 mg of the title compound was prepared from 42.9 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-2-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 48 mg of 1-(cyclohexyloxycarbonyloxy)ethyl iodide.
Reaction SMILES: [CH:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([OH:12])=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC.Cl.[N:29]1([C:35]2[N:44]=[C:43]([NH2:45])[C:42]3[C:37](=[CH:38][C:39]([O:48][CH3:49])=[C:40]([O:46][CH3:47])[CH:41]=3)[N:36]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>CC(C)=O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][C:10]([N:32]2[CH2:33][CH2:34][N:29]([C:35]3[N:44]=[C:43]([NH2:45])[C:42]4[C:37](=[CH:38][C:39]([O:48][CH3:49])=[C:40]([O:46][CH3:47])[CH:41]=4)[N:36]=3)[CH2:30][CH2:31]2)=[O:12])=[CH:13][CH:14]=1)([CH3:2])[CH3:3]
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: CC(C)c1ccc(C=CC(=O)O)cc1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc2nc(N3CCN(C(=O)C=Cc4ccc(C(C)C)cc4)CC3)nc(N)c2cc1OC
Reaction time: 8 h

Procedure:
To a mixture of 342 mg. of 4-isopropylcinnamic acid and 727 mg. of triethylamine in 20 ml. of acetone were added dropwise under ice-cooling 195 mg. of ethyl chlorocarbonate and the resulting mixture was stirred for 3.5 hours. Then, 543 mg. of 2-(piperazin-1-yl)-4-amino-6,7-dimethoxyquinazoline.hydrochloride were added thereto and stirring was continued at room temperature overnight. Then, the acetone was distilled off, the residue was dissolved in 20 ml. of 10% K2CO3 and extracted with ethyl acetate. After drying over magnesium sulfate, the extract was concentrated and recrystallization from methanol gave 361 mg. of the desired product.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][CH:9]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[CH2:8]2)([O:3]C)=[O:2].[OH-].[Na+]>CO.O>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][CH:9]([N:16]([CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH3:22])[CH2:8]2)([OH:3])=[O:2]
Reactant: CCCN(CCC)C1Cc2cc(OC)c(C(=O)OC)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCN(CCC)C1Cc2cc(OC)c(C(=O)O)cc2C1

Procedure:
A solution of 5-carbomethoxy-6-methoxy-2-(di-n-propylamino)indan (Example 57) in methanol/water is hydrolyzed with sodium hydroxide. After work-up and purification, the title compound is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[F:9].[Li]CCCC.B(F)(F)F.CCOCC.[CH2:24]([N:31]1[CH2:38][CH2:37][C:34]2([O:36][CH2:35]2)[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[CH2:24]([N:31]1[CH2:38][CH2:37][C:34]([CH2:35][C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=2[F:9])([OH:36])[CH2:33][CH2:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: c1ccc(CN2CCC3(CC2)CO3)cc1
Reactant: Cc1ccc(F)c(Br)c1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(F)c(CC2(O)CCN(Cc3ccccc3)CC2)c1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-1-fluoro-4-methylbenzene (0.76 g, 4 mmol) in THF (15 ml) at −70° C. under Ar a solution of n-BuLi (1.6 M in hexane, 2.5 ml, 4 mmol) was added dropwise. The reaction mixture was stirrred at −70° C. for 1 h, then BF3.Et2O (0.5 ml, 4 mmol) was added. After stirring for 20 min at −70° C., a solution of 6-benzyl-1-oxa-6-azaspiro[2.5]octane (0.41 g, 2 mmol) in dry THF (5 ml) was added dropwise. The stirring was continued for 2 h at −70° C., then the reaction mixture was quenched with sat. aq. NH4Cl (20 ml). The layers were separated, the aqueous layer extracted with THF. The combined organic layers were dried over Na2SO4. The solvent was removed in vacuo. Diethyl ether (50 ml) was added to the residue, folowed by a 2 M HCl in Et2O (5 ml). The precipitate was collected, washed with Et2O, and dissolved in minimal volume of methanol (ca. 5 ml). Water (50 ml) was added, and pH adjusted to 10 by addition of 2 M aq. NaOH. The mixture was extracted with ethyl acetate (2×25 ml), and the combined organic extracts were dried with Na2SO4. Evaporation of solvent afforded brownish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH2:20]([C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[N:28]1[C:33](=[O:43])[C@H:34]([CH2:38][S:39](Cl)(=[O:41])=[O:40])[CH:35]([CH3:37])[CH3:36])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[N:28]1[C:33](=[O:43])[C@H:34]([CH2:38][S:39]([N:17]1[CH2:18][CH2:19][CH:14]([C:11]2[N:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:9][N:10]=2)[CH2:15][CH2:16]1)(=[O:41])=[O:40])[CH:35]([CH3:37])[CH3:36])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: Clc1ccc(-c2cnc(C3CCNCC3)nc2)cc1
Product: CC(C)[C@@H](CS(=O)(=O)N1CCC(c2ncc(-c3ccc(Cl)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 100.1 %

Procedure:
Prepared according to the method for the preparation of 4-(R)-benzyl-3-(2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-ulfonylmethyl}-3-methyl-butyryl)oxazolidin-2-one, from 5-(4-chlorophenyl)-2-piperidin-4-ylpyrimidine (0.123 g) and 4-(R)-benzyl-3-(2-(R)-chlorosulfonylmethyl-3-methylbutyryl)-oxazolidin-2-one (0.269 g), to yield the title compound as a cream foam (0.275 g, 100%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH3:17])[CH2:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[CH2:18]([N:20]1[C:32]2[CH:31]=[CH:30][C:29]([C:33](O)=[O:34])=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[C:15]([C:12]1[CH:11]=[CH:10][C:9]([S:6]([NH:5][CH2:4][CH:3]([CH3:17])[CH2:2][NH:1][C:33]([C:29]2[CH:30]=[CH:31][C:32]3[N:20]([CH2:18][CH3:19])[C:21]4[C:26]([C:27]=3[CH:28]=2)=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:34])(=[O:8])=[O:7])=[CH:14][CH:13]=1)#[N:16]
Reactant: CC(CN)CNS(=O)(=O)c1ccc(C#N)cc1
Reactant: CCn1c2ccccc2c2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c2ccccc2c2cc(C(=O)NCC(C)CNS(=O)(=O)c3ccc(C#N)cc3)ccc21
Yield: 65.4 %

Procedure:
A solution of the compound obtained in Step 2 (65.7 mg, 0.26 mmol), 9-ethyl-9H-carbazole-3-carboxylic acid (62.1 mg, 0.26 mmol), HATU (128 mg, 0.34 mmol) and TEA (0.108 mL, 0.78 mmol) in DMF (1.25 mL) was stirred at room temperature for 16 hr. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 50% ethyl acetate/hexane) to give the title compound (81 mg, 0.170 mmol, 65.7%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@@:8]2([CH:15]([F:17])[F:16])[NH:13][C:12](=S)[CH2:11][O:10][CH2:9]2)[C:5]([F:18])=[CH:4][CH:3]=1.[NH3:19]>CO.C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[C:6]([C@:8]2([CH:15]([F:17])[F:16])[CH2:9][O:10][CH2:11][C:12]([NH2:19])=[N:13]2)[C:5]([F:18])=[CH:4][CH:3]=1
Reactant: Fc1ccc(Br)nc1[C@]1(C(F)F)COCC(=S)N1
Reactant: N
Solvent: CO
Solvent: CCOC(C)=O
Product: NC1=N[C@@](c2nc(Br)ccc2F)(C(F)F)COC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 31 %

Procedure:
To a solution of (R)-5-(6-bromo-3-fluoro-pyridin-2-yl)-5-difluoromethyl-morpholin-3-thione (611 mg, 1.79 mmol) in methanol (15 ml) was added ammonia (5.12 ml, 35.8 mmol, 7M in methanol), the vial was sealed and the reaction mixture was stirred at rt for 20 h. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with aq. sodium thiosulfate solution (10%), water and brine, dried over sodium sulfate, filtered and evaporated. The crude product (640 mg) was chromatographed over silica gel (14 g, dichloromethane/methanol 95/5+0.5% NH3) to give the title compound. 180 mg (31% yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:15]2[S:24][C:23]3[C:22]4[CH:25]=[CH:26][C:27]([C:29]([OH:31])=O)=[CH:28][C:21]=4[O:20][CH2:19][CH2:18][C:17]=3[CH:16]=2)[N:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[F:14])[N:6]=1.[CH2:32]([CH2:34][NH2:35])[OH:33]>>[NH2:1][C:2]1[N:3]=[C:4]([C:15]2[S:24][C:23]3[C:22]4[CH:25]=[CH:26][C:27]([C:29]([NH:35][CH2:34][CH2:32][OH:33])=[O:31])=[CH:28][C:21]=4[O:20][CH2:19][CH2:18][C:17]=3[CH:16]=2)[N:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[F:14])[N:6]=1
Reactant: Nc1nc(-c2cc3c(s2)-c2ccc(C(=O)O)cc2OCC3)n(-c2ccc(F)cc2F)n1
Reactant: NCCO
Product: Nc1nc(-c2cc3c(s2)-c2ccc(C(=O)NCCO)cc2OCC3)n(-c2ccc(F)cc2F)n1

Procedure:
Similarly to as described in General Procedure D, 2-[5-Amino-2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-8-carboxylic acid was reacted with ethanolamine to give 151 as a colorless solid after reverse phase HPLC (85 mg). LCMS: 484.1
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:29])[C@H:17]([NH:24][C:25]([O:27][CH3:28])=[O:26])[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:10])C1C=CC=CC=1>CO.[Pd]>[CH3:28][O:27][C:25]([NH:24][C@H:17]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:9]([OH:10])=[O:8])=[O:29])=[O:26]
Reactant: COC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)C1CCCCC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)O)C1CCCCC1
Yield: 88.1 %

Procedure:
1.17 g 1-[(R)-methoxycarbonylamino-cyclohexyl-acetyl]-pyrrolidine-2-(S)-carboxylic acid benzyl ester were dissolved in 90 mL of methanol and hydrogenated for 3 h at room temperature using 0.8 g palladium on charcoal (10%) as catalyst. Filtration followed by concentration in vacuo affords 0.80 g (89%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([CH:3]([NH:13][C:14](=O)[CH:15]([CH3:17])[CH3:16])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:39]>C(#N)C>[Cl:39][C:1]1[N:2]=[C:14]([CH:15]([CH3:17])[CH3:16])[NH:13][C:3]=1[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)C(=O)NC(C#N)COCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)c1nc(Cl)c(COCc2ccccc2)[nH]1
Reaction time: 0.17 h
Yield: 41.3 %

Procedure:
A solution of N-{1-cyano-2-[(phenylmethyl)oxy]ethyl}-2-methylpropanamide (1.60 g, 6.5 mmol), triphenylphosphine (4.2 g, 16.0 mmol), and carbon tetrachloride (1.6 mL, 16.6 mmol) in acetonitrile (65 mL) was heated at 45° C. for 4.5 h. The reaction was concentrated and the residue was stirred in CH2Cl2 (70 mL) and 0.5 N NaOH (60 mL) for 10 min. The organic layer was isolated, dried (Na2SO4), filtered, concentrated and the residue was purified by silica gel flash column chromatography (5-50% EtOAc:hexanes) to give the title compound (0.710 g, 41%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 10.69 (br. s., 1H), 7.28-7.36 (m, 5H), 4.51 (s, 2H), 4.48 (s, 2 H), 2.92 (sept, 1H), 1.24 (d, 6H).
Reaction SMILES: [C:1]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:5])[C@H:2]([CH3:4])[OH:3].N1C=CC=CC=1.Cl[C:21]([O:23][CH2:24][Cl:25])=[O:22]>C(OCC)C>[C:21](=[O:22])([O:23][CH2:24][Cl:25])[O:3][C@H:2]([C:1]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])[CH3:4]
Reactant: O=C(Cl)OCCl
Reactant: C[C@H](O)C(=O)OCc1ccccc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: C[C@H](OC(=O)OCCl)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.2 %

Procedure:
To a mixture of benzyl (S)-lactate (30.6 g), pyridine (13.4 g) and diethyl ether (300 ml), a solution of chloromethyl chloroformate (21.9 g) in diethyl ether (100 ml) was added dropwise under ice cooling over the period of 30 minutes. After stirring at room temperature for 5 hours, the resulting solid was removed off by filtration. The filtrate was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (200 ml). The solution was washed with water (100 ml×2) and a saturated sodium chloride aqueous solution (100 ml). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain [(1S)-1-(benzyloxycarbonyl)ethyl] chloromethyl carbonate (45.0 g) as a colorless liquid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([C:13]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[C:16]([OH:22])=[C:15]([O:23]C)[CH:14]=2)=[O:12])=[CH:3][CH:2]=1.[BrH:25]>O>[BrH:25].[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([C:13]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[C:16]([OH:22])=[C:15]([OH:23])[CH:14]=2)=[O:12])=[CH:3][CH:2]=1
Reactant: COc1cc(C(=O)c2ccnc3ccccc23)cc([N+](=O)[O-])c1O
Agent: Br
Solvent: O
Product: O=C(c1cc(O)c(O)c([N+](=O)[O-])c1)c1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1 g of 4-hydroxy-3-methoxy-5-nitrophenyl 4-quinolyl ketone dissolved in 30 ml of 48 percent aqueous hydrobromic acid is stirred at 100° for 18 hours. After cooling to room temperature, the reaction mixture is diluted with 30 ml of water and the precipitate is filtered under suction. There is obtained 3,4-dihydroxy-5-nitrophenyl 4-quinolyl ketone hydrobromide of m.p. 273°-275° (from acetonitrile).