Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[N+:9]([CH2:12][CH3:13])([O-:11])=[O:10].[OH-].[Na+]>CCO.O>[N+:9]([CH:12]([CH3:13])[CH:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[OH:8])([O-:11])=[O:10]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C(O)c1ccncc1)[N+](=O)[O-]

Procedure:
A solution of 1.0 eq. of 4-pyridinecarboxaldehyde (63, Aldrich, cat. no. P6,240-2) and 1.5 eq of nitroethane (Aldrich, cat. no. 22,787-0) in absolute EtOH was stirred at 0° C. as a solution of 2.0 eq. of NaOH in water was added. After a time sufficient for reaction completion, the reaction mixture was concentrated by rotary evaporation and neutralized (pH 7-8) with conc. HCl. A white precipitate formed. The mixture was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and the solvent removed by rotary evaporation. The material was purified by flash chromatography on silica gel using a mixture of MeOH—CH2Cl2 as eluant to afford 64 as a mixture of diastereomers.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(O)C.[C:16]([O:21][CH2:22][CH3:23])(=[O:20])[C:17]([CH3:19])=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>Cl.CO>[CH2:22]([O:21][C:16](=[O:20])/[C:17](=[N:12]/[C:9]1[CH:10]=[CH:11][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:7][CH:8]=1)/[CH3:19])[CH3:23]
Reactant: Nc1ccc(-n2ccnc2)cc1
Reactant: CCOC(=O)C(C)=O
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCO
Product: CCOC(=O)/C(C)=N/c1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-imidazol-1-yl-phenyl amine (637 mg) was dissolved in 2 M hydrochloric acid/MeOH (3 ml), and this was concentrated under reduced pressure. The residue was suspended in concentrated hydrochloric acid (1 ml), and an aqueous solution of sodium nitrite (304 mg, 2.5 ml) was added dropwise thereto over 30 minutes at 0° C. on ice. The reaction mixture was slowly added dropwise to an aqueous solution prepared in advance from aqueous solutions of sodium hydrosulfite (2.3 g, 13 ml) and 5 M sodium hydroxide (400 μl), while keeping the temperature of the reaction mixture at 5° C. or lower. Then, the mixture was stirred at 25° C. for one hour. An ethanol solution (5 ml) of ethyl pyruvate (465 μl) was added dropwise to the reaction mixture. After stirring at 50° C. for 30 minutes, the mixture was further stirred at 25° C. for 10 hours. The pH of the mixture was adjusted to 11 using an aqueous solution (about 10 ml) of 20% potassium phosphate. The resulting precipitate was collected by filtration, and dried. Thus, 2-[(E)-4-imidazol-1-yl-phenylimino]-propionic acid ethyl ester was obtained as a pale yellow powder (1.1 g, 99%).
Reaction SMILES: [I-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][S:11]/[C:10]/2=[N:14]\[C:15]([N:17]2[CH:21]=[CH:20][N+](C)=[CH:18]2)=[O:16])=[CH:5][CH:4]=1.[CH3:23]NCC#C.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:13][CH2:12][S:11]/[C:10]/2=[N:14]\[C:15](=[O:16])[N:17]([CH3:18])[CH2:21][C:20]#[CH:23])=[CH:7][CH:8]=1
Reactant: C[n+]1ccn(C(=O)/N=C2\SCCN2c2ccc(Cl)cc2)c1
Reactant: C#CCNC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C#CCN(C)C(=O)/N=C1\SCCN1c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
1-({[(2Z)-3-(4-Chlorophenyl)-1,3-thiazolidin-2-ylidene]amino}carbonyl)-3-methyl-1H-imidazol-3-ium iodide (97 mg, 0.216 mmol, Example 25B), N-methylprop-2-yn-1-amine (0.020 mL, 0.238 mmol) and diisopropylethylamine (0.041 mL, 0.238 mmol) were heated in acetonitrile at 65° C. After 1 hour, the mixture was concentrated and the residue was purified by chromatography over silica using dichloromethane:methanol 95:5 as eluant to provide the title compound.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCN2C(=NCCC2)CC1.[CH3:24][CH:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26]>C(Cl)Cl>[C:1]1([C@@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH:12][S:27]([CH:25]([CH3:26])[CH3:24])(=[O:29])=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H]1CCC[C@H]1c1ccccc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
(+,−) Trans-2-phenyl-cyclopentylamine (5.95 g, 37.0 mmol, preparation 3) was dissolved in dry methylene chloride and cooled to 0° C. under a nitrogen atmosphere. 6.1 mL (40.7 mmol) of DBU was added followed by dropwise addition of 2-propanesulfonyl chloride (4.6 mL, 40.7 mmol). The reaction was allowed to warm to room temperature and stirred overnight. The reaction was judged incomplete by TLC and an additional 20% of DBU and 2-propanesulfonyl chloride were added. Stirring at room temperature was continued for 3 days. The reaction was diluted with methylene chloride and washed (1×100 mL) with 1N HCl. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to 9.3 g. The product was purified on silica by Chromatotron® eluting with 99:1 methylene chloride:ethyl acetate to yield 5.7 g (31%) of the title compound as a white solid. The NMR was consistent with the assigned structure.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[CH:25]=[C:24]([S:26]([CH2:29][CH:30]([CH3:32])[CH3:31])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=1[CH3:33]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:22]2[CH:23]=[C:24]([S:26]([CH2:29][CH:30]([CH3:31])[CH3:32])(=[O:27])=[O:28])[CH:25]=[CH:20][C:21]=2[CH3:33])[CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)CC(C)C)cc1Br
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: Cc1ccc(S(=O)(=O)CC(C)C)cc1C#Cc1cc(Cl)ccc1OCC(=O)O

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl(4-chloro-2-ethynyl phenoxy)acetate (Intermediate 3) and 2-bromo-4-(isobutylsulfonyl)-1-methylbenzene (Intermediate 66), the title compound was obtained as a yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:6][CH:7]=1.Cl.Cl.[CH3:16][O:17][C:18]1[C:19]([N:24]2[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:20][CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:16][O:17][C:18]1[C:19]([N:24]2[CH2:30][CH2:29][CH2:28][N:27]([CH2:2][C:3]3[N:4]=[C:5]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[S:6][CH:7]=3)[CH2:26][CH2:25]2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: COc1cccnc1N1CCCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccnc1N1CCCN(Cc2csc(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(Chloromethyl)-2-phenyl-1,3-thiazole (52 mg, 0.25 mmol), 1-(3-methoxy-pyridin-2-yl)-[1,4]diazepane dihydrochloride (70 mg, 0.25 mmol), and Cesium carbonate (325 mg, 1.0 mmol) were suspended in anhydrous DMF (1.25 mL). The mixture was stirred at room temperature for 18 hours. The reaction was diluted with EtOAc and washed with H2O (3×25 mL), then brine (25 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified on silica (CH2Cl2:MeOH+1% NH4OH) to afford the product. 1H NMR (400 MHz, CDCl3) δ 7.94 (m, 2H), 7.79 (dd, 1H, J=1.6, 4.8 Hz), 7.40 (m, 3H), 7.15 (s, 1H), 6.96 (dd, 1H, J=1.4, 8.2 Hz), 6.66 (dd, 1H, J=4.8, 7.6 Hz), 3.93 (s, 2H), 3.80 (s, 3H), 3.71 (m, 4H), 2.98 (t, 2H, J=5.0 Hz), 2.85 (t, 2H, J=5.6 Hz), 2.04 (quin., 2H, J=5.9 Hz). MS (ES) m/z 381.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Cl[CH2:31][C:32]1[O:36][C:35]([C:37]([O:39][CH3:40])=[O:38])=[CH:34][CH:33]=1>>[CH3:40][O:39][C:37]([C:35]1[O:36][C:32]([CH2:31][N:19]2[C:18](=[O:23])/[C:17](=[CH:16]/[C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=3[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]4)/[S:21][C:20]2=[O:22])=[CH:33][CH:34]=1)=[O:38]
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: COC(=O)c1ccc(CCl)o1
Product: COC(=O)c1ccc(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)o1

Procedure:
5-{[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}furan-2-carboxylic acid methyl ester was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and methyl 5-chloromethylfuroate following General Procedure S (reaction time of 16 h).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:13][CH2:14][CH3:15])[C:11]=1I)[CH:7]=[O:8])[CH3:2].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[O:8])[CH:9]=[C:10]([O:13][CH2:14][CH3:15])[C:11]=1[C:21]1[CH:22]=[CH:23][C:18]([C:17]([F:28])([F:27])[F:16])=[CH:19][CH:20]=1)[CH3:2]
Reactant: CCOc1cc(C=O)cc(OCC)c1I
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CCOc1cc(C=O)cc(OCC)c1-c1ccc(C(F)(F)F)cc1

Procedure:
The necessary intermediate 2,6-Diethoxy-4′-trifluoromethyl-biphenyl-4-carbaldehyde was prepared as described in example 94, but coupling in the Suzuki reaction 3,5-diethoxy-4-iodo-benzaldehyde instead of 3-benzyloxy-5-ethoxy-4-iodo-benzaldehyde with 4-trifluoromethyl-phenyl boronic acid instead of 4-fluorophenyl boronic acid, as white crystals.
Reaction SMILES: [CH2:1]([C@H:8]([CH:12]=[CH2:13])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([Si:17]([CH3:20])([CH3:19])[CH3:18])C=C>C(Cl)Cl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[CH2:1]([C@H:8]([CH:12]=[CH:13][CH2:14][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C[C@@H](Cc1ccccc1)C(=O)O
Reactant: C=CC[Si](C)(C)C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: ClCCl
Product: C[Si](C)(C)CC=C[C@@H](Cc1ccccc1)C(=O)O

Procedure:
To a solution of (2R)-2-benzylbut-3-enoic acid (1.4 mmol, 250 mg) and allyltrimethylsilane (4.2 mmol, 0.67 mL) in DCM (3 mL) at reflux was added Hoveyda-Grubbs second generation catalyst (5 mol %, 44 mg). The reaction was allowed to stir at reflux for 50 hrs. The solvent was removed in vacuo. The crude product was purified by column chromatography (184 mg, 50%). 1H NMR (400 MHz, CDCl3): δ=7.15-7.30 (m, 5H), 5.48-5.56 (m, 1H), 5.26 (dd, J=8.8, 15.2, 1H), 3.30 (m, 1H), 3.10 (dd, J=7.1, 13.9, 1H), 2.80 (dd, J=7.8, 13.6, 1H), 1.43 (d, J=8.3, 2H), −0.08 (s, 9H); 13C NMR (125 MHz, CDCl3): δ=179.5, 138.7, 131.4, 130.1, 129.1, 129.0, 128.3, 126.4, 126.3, 124.3, 123.7, 50.8, 38.5, 22.9, 18.9, −2.08; IR (CHCl3): v 2955, 1797; HMRS required for C15H21O2Si ([M−H]−) 261.1311 found 261.1318; [α]D21=−39.4 (c, 0.5, CHCl3).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:20])(C)(C)C.[Cl:22][C:23]1[CH:24]=[C:25]([C:29]2OC(C)(C)O[C:31](=[O:37])[CH:30]=2)[CH:26]=[CH:27][CH:28]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:22][C:23]1[CH:24]=[C:25]([C:29]2[CH2:30][C:31](=[O:37])[NH:20][C:9]3[CH:10]=[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: CC1(C)OC(=O)C=C(c2cccc(Cl)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(Cl)c2)=Nc2ccc(-c3ccccc3)cc2N1
Yield: 54.2 %

Procedure:
Prepared from (3-amino-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G9) (284 mg, 1.0 mmol) and 6-(3-Chloro-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J6) (358 mg, 1.2 mmol) according to the general procedure K. The obtained material (339 mg) was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (188 mg).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1.C1C(=O)N([I:23])C(=O)C1.[Al]>CC#N>[CH3:15][O:14][CH:3]([O:2][CH3:1])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][C:5]=1[I:23]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(OC)c1ccc2c(n1)NCCC2
Agent: [Al]
Solvent: CC#N
Product: COC(OC)c1nc2c(cc1I)CCCN2
Reaction time: 4 h

Procedure:
A solution of 7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 4, 1 g, 4.8 mmol) in MeCN (15 ml) was treated with NIS (1.13 g, 5.04 mmol), stirred for 4 h in a flask covered with aluminum foil. Them, the reaction mixture was concentrated. The residue was treated with Et2O and DCM, washed with water (2×) and brine, dried over Na2SO4, filtered and concentrated.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K].O>CS(C)=O>[CH2:2]([N:15]1[C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]2[C:11]1=[O:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=CCCCCCCCBr
Agent: [K]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCCCCN1C(=O)c2ccccc2C1=O
Reaction time: 8 h
Yield: 70 %

Procedure:
This example illustrates a synthesis of N-(9,8-Oxidononyl)phthalimide (inventive compound no. 1105). 1-bromo-8-nonene (8.2 g, 40 mmol) was added to a suspension of potassium phthalimide (7.4 g, 40 mmol) in 50 mL of dimethyl sulfoxide and stirred overnight. After 12 hours of stirring at room temperature, the reaction product was poured into a separatory funnel containing 300 mL of water and extracted with dichloromethane (5×200 mL). Organic extracts were combined, washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel (using an eluant of 10% acetone/hexane) to yield 7.6 g (70.4% yield) of N-(8-Nonenyl)phthalimide (inventive compound no. 1101).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:14][C:15]([NH:17][C:18]2[CH:28]=[CH:27][C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][CH:19]=2)=[O:16])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH:13]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:14][C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:27][CH:28]=2)=[O:16])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NC(=O)CC(CNS(=O)(=O)c2ccc(C)cc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NCC(CC(=O)Nc2ccc(C(=O)O)cc2)c2ccccc2)cc1
Yield: 85.5 %

Procedure:
A solution of the ester 55 (0.106 g, 0.220 mmol) in methanol (3 ml) and THF (3 ml) was stirred in presence of NaOH (aq, 1M, 1 ml) at room temperature overnight. The solvent was removed under reduced pressure. HCl (aq, 1M, 1.5 ml) was added and the white precipitate was filtered, washed with water (5 ml) and dried under vacuum. Pure 59 was obtained as a white solid (0.085 g, 0.188 mmol, 85%) without further purification, mp 225-227° C. 1H NMR (400 MHz, CD3OD) δ2.39 (3H, s), 2.62 (1H, dd, J 8.4, 14.8 Hz), 2.35 (1H, dd, J 6.6, 14.6 Hz), 3.05 (1H, dd, J 8.0, 13.0 Hz), 3.12 (1H, dd, J 7.2, 12.8 Hz), 7.16-7.19 (3H, m), 7.24-7.27 (2H, m), 7.30 (2H, d, J 7.6 Hz), 7.53 (2H, d, J 8.4 Hz), 7.65 (2H, d, J 8.4 Hz), 7.91 (2H, d, J 9.2 Hz). 13C NMR (100 MHz, DMSO-d3) δ 21.61, 40.65, 42.32, 48.33, 118.95, 125.61, 127.18), 127.26, 128.38, 128.96, 130.02, 130.98, 138.09, 142.47, 143.22, 143.72, 167.55, 170.64. νmax (solid)/(cm−1) 3316, 3277), 1668, 1595, 1531, 1408, 1317, 1254, 1152. MS (API-ES): m/z 451[M−H]− (100%), HRMS (API-ES) m/z found 451.1334 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][O:17][C:16]([CH3:21])([CH3:20])[CH2:15]3)C(=O)[NH:10][C:5]2=[N:4][CH:3]=1.BrC1C(N)=NC=C(Br)N=1.Cl.CC1(C)CC(CCN)CCO1.C(N(C(C)C)CC)(C)C>CS(C)=O>[Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][O:17][C:16]([CH3:20])([CH3:21])[CH2:15]2)[C:5]([NH2:10])=[N:4][CH:3]=1
Reactant: CC1(C)CC(CCn2c(=O)[nH]c3ncc(Br)nc32)CCO1
Agent: CC1(C)CC(CCN)CCO1
Agent: Cl
Agent: Nc1ncc(Br)nc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC1(C)CC(CCNc2nc(Br)cnc2N)CCO1
Yield: 42 %

Procedure:
6-Bromo-1-(2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one. 3,5-Dibromopyrazin-2-amine (161 mg, 0.6 mmol), 2-(2,2-dimethyl-tetrahydro-pyran-4-yl)-ethylamine hydrochloride (100 mg, 0.5 mmol), diisopropylethylamine (0.5 mL), and dimethylsulfoxide (2 mL) were heated in a Biotage Emrys Optimizer microwave reactor to 150° C. for 2 h to give crude 6-bromo-N2-(2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)ethyl)pyrazine-2,3-diamine. MS (ESI) m/z 329.5, 331.5 [M+1]+. 1,1′-Carbonyldiimidazole (194 mg, 1.2 mmol) was added to the reaction mixture and then heated again in a Biotage Emrys Optimizer microwave reactor to 150° C. for 10 min. The product was purified by reverse-phase semi-preparatory HPLC (10-70% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Product containing fractions were concentrated and then triturated with ether to give a white solid (90 mg, 42% yield over two steps). MS (ESI) m/z 355.4 [M]+, 357.4 [M+2]+.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:12][CH2:13][CH3:14])=[C:7]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:6]=1)C.[OH-].[Li+]>C1COCC1.O>[CH2:15]([N:11]([CH2:12][CH2:13][CH3:14])[C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:24])=[O:3])=[CH:6][C:7]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:16]([CH3:18])[CH3:17]
Reactant: CCCN(CC(C)C)c1ccc(C(=O)OCC)cc1NS(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCN(CC(C)C)c1ccc(C(=O)O)cc1NS(C)(=O)=O
Temperature: 70 °C

Procedure:
To a solution of ethyl-4-[isobutyl(propyl)amino]-3-[(methylsulfonyl)amino]benzoate (7 g, 0.0196 mol) in THF (70 mL) was added lithium hydroxide (4.12 g, 0.098 mol) and water (70 mL). The reaction mixture was heated at 70° C. for 5 h. The reaction mixture was diluted with water (30 mL), washed with diethyl ether (50 mL). The aqueous layer was acidified with 1M HCl until pH=2, extracted with EtOAc (2×75 mL), washed with brine, dried over sodium sulphate and evaporated to afford the title compound as an off white solid (5.6 g, 86%). 1H NMR: (DMSO-d6, 400 MHz), δ 12.78 (s, 1H), 8.39 (s, 1H), 7.87 (s, 1H), 7.65 (m, 1H), 7.28 (m, 1H), 3.09 (s, 3H), 2.97 (m, 2H) 2.84 (m, 2H), 1.67 (m, 1H), 1.41 (m, 2H), 0.84 (m, 9H). LC/MS (Method A): 329.0 (M+H)+. HPLC (Method B) Rt 4.53 min (purity: 99.12%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[N:5]([NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])[CH2:4]1)(=[O:27])=[O:26]
Reactant: CC(C)(C)OC(=O)NN1C[C@H](CO)OC1=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NN1C[C@@H](COS(C)(=O)=O)OC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
To a turbid solution of (R)-tert-butyl 5-(hydroxymethyl)-2-oxooxazolidin-3-ylcarbamate (840 mg, 3.62 mmol) in DCM (10 mL), triethylamine (458 mg, 4.52 mmol) and methanesulfonyl chloride (518 mg, 4.52 mmol) were added and the reaction was stirred, at r.t., under nitrogen, for 2 h 30 min. The solution was washed with: cold water (resulting pH=7-8), cold citric acid (resulting pH=4-5) and cold brine. The organic layer was dried over Na2SO4 and evaporated and the residue (beige foam) was triturated with diisopropyl ether, affording (S)-(3-(tert-butoxycarbonylamino)-2-oxooxazolidin-5-yl)methyl methanesulfonate (1.055 g, 3.40 mmol) as a white solid, that was dissolved in 7 mL of DMF. Sodium methanethiolate (317 mg, 4.52 mmol) was added to the solution and the mixture was stirred at 60° C. for 3 h. AcOEt was added and the solution was washed with cold water, cold citric acid (until pH=6) and cold brine. The organic layer was dried over Na2SO4 and evaporated to leave a yellow oil. The title compound was precipitated by crystallization from diisopropyl ether as a white solid, recovered by filtration on Buchner (429 mg, 1.635 mmol). Yield=45%.
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][NH:10][C:11](=[O:24])[CH:12]([OH:23])[C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][N:17]=[CH:18]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:27](OC(=O)C)(=[O:29])[CH3:28]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:27]([O:23][CH:12]([C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][N:17]=[CH:18]2)[C:11]([NH:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:26][CH:25]=1)=[O:24])(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)c1ccc(CNC(=O)C(O)c2cccc3cnccc23)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC(C(=O)NCc1ccc(C(C)(C)C)cc1)c1cccc2cnccc12
Reaction time: 0.5 h

Procedure:
The product from Example 277B (100 mg, 0.287 mmol) and DMAP (59 mg, 0.480 mmol) in CH2Cl2 (1 mL) was treated with acetic anhydride (38 μL). After stirring for 30 minutes, the mixture was treated with CH2Cl2 (5 mL) and the phases separated. The organic layer was washed with water (10 mL×3), dried (Na2SO4), filtered, and the filtrate was concentrated to provide the title compound. MS (ESI+) m/z 391 (M+H)+; MS (ESI−) m/z 389 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.25 (s, 9H), 4.27 (dq, J1 14.9, J2 6.1, 2H), 6.56 (s, 1H), 7.09 (d, J 8.5, 2H), 7.28 (d, J 8.5, 2H), 7.72 (t, J 7.1, 1H), 7.90 (d, J 6.1, 1H), 8.07 (d, J 6.1, 1H), 8.17 (d, J 8.1, 1H), 8.53 (d, J 6.1, 1H), 8.86 (t, J 6.1, 1H), 9.35 (s, 1H);Anal. Calcd for C24H26N2O3+0.8H2O: C, 71.19; H, 6.87; N, 6.92. Found: C, 70.87; H, 6.47; N, 6.92.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:27]=[CH:26][C:9]3[C:10]4[N:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:13]=[C:12]([C:18]2[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.Cl[CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31].CO>C(Cl)Cl>[CH:23]([N:19]1[C:18]([C:12]2[N:11]=[C:10]3[C:9]4[CH:26]=[CH:27][C:6]([CH:4]5[CH2:3][N:2]([CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[CH2:5]5)=[CH:7][C:8]=4[O:17][CH2:16][CH2:15][N:14]3[CH:13]=2)=[N:22][CH:21]=[N:20]1)([CH3:24])[CH3:25]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CNC3)cc1OCC2
Reactant: CN(C)C(=O)CCl
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CN(CC(=O)N(C)C)C3)cc1OCC2

Procedure:
Following the procedure for 143, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (Example 65) was reacted with 2-chloro-N,N-dimethylacetamide, the crude product subjected to flash chromatography (SiO2, gradient 0 to 6% MeOH in DCM) to give 198 as a white solid. 1H NMR δ (ppm) (CDCl3): 8.44 (1H, d, J=8.28 Hz), 7.84 (1H, d, J=0.71 Hz), 7.60 (1H, s), 7.10 (1H, dd, J=8.33, 1.81 Hz), 6.97 (1H, d, J=1.72 Hz), 6.01-5.91 (1H, m), 4.48-4.39 (4H, m), 3.99-3.90 (2H, m), 3.86-3.77 (1H, m), 3.46-3.38 (4H, m), 3.00 (3H, s), 2.93 (3H, s), 1.56 (6H, d, J=6.63 Hz). LCMS: RT=5.87 min, M+H+=436.