Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4]C1C=CC=CC=1)=[O:3].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1N.C([N:20](CC)CC)C>N1C=CC=CC=1>[C:2](=[O:3])([O:4][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=1)[NH2:20]
Reactant: CCN(CC)CC
Reactant: Nc1ccccn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Product: NC(=O)Oc1ccccn1

Procedure:
The reaction of a haloformate, such as phenyl chloroformate, and a pyridinylamine generally is carried out by combining a slight excess of haloformate with the pyridine in an organic solvent, such as triethylamine or pyridine, and stirring the mixture for about 1 to about 24 hours at a temperature of about 0° to about 30° C. The product of the reaction, a pyridinyl carbamate, is generally isolated by acidifying the reaction mixture, for instance by the addition of a mineral acid, such as hydrochloric acid or sulfuric acid, and collecting by filtration the precipitate which forms. The carbamate normally needs no further purification, but if desired it can be crystallized from common solvents, such as benzene, acetone, ethyl acetate, and the like.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[I:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15]#[N:16])[CH:11]=[CH:12][CH:13]=1.Cl.[NH2:18][OH:19].CCO>O>[OH:19][NH:18][C:15](=[NH:16])[CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([I:7])[CH:9]=1
Reactant: N#CCc1cccc(I)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(Cc1cccc(I)c1)NO
Temperature: 50 °C
Yield: 96.7 %

Procedure:
Add sodium carbonate (2.0 g, 18.5 mmol) to a mixture of 3-iodophenylacetonitrile (4.5 g, 18.5 mmol) and hydroxylamine hydrochloride (1.3 g, 18.5 mmol) in 10:1 EtOH:H2O (11 mL). Heat the reaction mixture to 50° C. for 2 days. Cool to RT, then filter to remove the solids. Concentrate the filtrate to afford the title compound (4.94 g). LC-MS (m/e): 277 (M+1).
Reaction SMILES: Br[C:2]1[C:11]([CH2:12][O:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[CH3:21])=[C:10]2[C:5]([NH:6][C:7]([CH3:25])([CH3:24])[C:8](=[O:23])[N:9]2[CH3:22])=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[C:32]([O:34][CH2:35][O:36][CH3:37])[CH:31]=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:20][C:18]1[CH:17]=[CH:16][C:15]([CH3:21])=[C:14]([CH:19]=1)[O:13][CH2:12][C:11]1[C:2]([C:29]2[CH:30]=[CH:31][C:32]([O:34][CH2:35][O:36][CH3:37])=[CH:33][C:28]=2[O:27][CH3:26])=[CH:3][CH:4]=[C:5]2[C:10]=1[N:9]([CH3:22])[C:8](=[O:23])[C:7]([CH3:25])([CH3:24])[NH:6]2
Reactant: COCOc1ccc(B(O)O)c(OC)c1
Reactant: Cc1ccc(F)cc1OCc1c(Br)ccc2c1N(C)C(=O)C(C)(C)N2
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COCOc1ccc(-c2ccc3c(c2COc2cc(F)ccc2C)N(C)C(=O)C(C)(C)N3)c(OC)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 96.8 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 3-1, 2.32 g, 5.70 mmol), 2-methoxy-4-methoxymethoxyphenylboronic acid (Reference Compound No. 7, 2.43 g, 11.5 mmol), cesium carbonate (9.46 g, 29.0 mmol), and bis(triphenylphosphine)palladium (II) dichloride (415 mg, 0.591 mmol) was suspended in anhydrous N,N-dimethylformamide (25 ml) and the mixture was stirred at 80° C. for 5 hours. After cooling down, ethyl acetate (150 mL) and water (150 mL) were added and partitioned. The organic layer was washed with saturated brine (150 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (2.73 g) as a colorless solid. (Yield 97%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C:10](=O)[NH:9]2)=[CH:4][CH:3]=1.F[B-](F)(F)F.C([O+](CC)CC)C.[CH2:31]([NH2:34])[CH2:32][CH3:33]>C(Cl)Cl.C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C:10]([NH:34][CH2:31][CH2:32][CH3:33])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccccc2C(c2ccc(Cl)cc2)N1
Reactant: CCCN
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: CCCNC1=NC(c2ccc(Cl)cc2)c2ccccc2C1
Product: Cl
Reaction time: 3 h
Yield: 77.1 %

Procedure:
1-(4-Chlorophenyl)-1,4-dihydroisoquinol-3-one (6.2 g, 24 mmol) was dissolved in dry methylene chloride (30 ml) and stirred under nitrogen. A solution of triethyloxonium tetrafluoroborate in methylene chloride (1M), (24 ml) was added in one portion at room temperature. After 3 h at room temperature, a solution of n-propylamine (2.0 g, 34 mmol) in ethanol (20 ml) was added and the mixture refluxed for 24 h. The solution was cooled, the solvent removed under reduced pressure and the residue partitioned between ethyl acetate (200 ml) and 10% sodium hydroxide (100 ml). The organic layer was separated, acidified with 5M sulphuric acid (2×50 ml) and washed with water (100 ml). The combined aqueous phases were basified (Care) with 10% sodium hydoxide and the oil so produced extracted with ethyl acetate (2×100 ml). The combined ethyl acetate layers were washed with brine (50 ml) and dried over sodium sulphate. The solution was filtered and reduced to 100 ml under reduced pressure. Ethereal hydrogen chloride was added and the solvent was removed under reduced pressure. Toluene (50 ml) was added to the foam so produced and evaporated off. The foam that remained was dried in the vacuum over (90° C., 1 mm) to give 1-(4-chlorophenyl)-3-n-propylamino-1,4-dihydroisoquinoline hydrochloride (3.1 g, 38%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[N:11]=[N:10]2)=[CH:5][CH:4]=1.[NH2:18][C:19]1[C:20](=[O:32])[N:21]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[N:22]([CH3:25])[C:23]=1[CH3:24].C(N(CC)C(C)C)(C)C>C(Cl)Cl.CO>[CH:26]1([N:21]2[C:20](=[O:32])[C:19]([NH:18][C:15]([C:12]3[N:11]=[N:10][N:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[C:13]=3[CH3:14])=[O:17])=[C:23]([CH3:24])[N:22]2[CH3:25])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: COc1ccc(-n2nnc(C(=O)O)c2C)cc1
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(-n2nnc(C(=O)Nc3c(C)n(C)n(C4CCCCC4)c3=O)c2C)cc1
Reaction time: 4 h

Procedure:
To a vial was added 1-(4-methoxyphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (0.040 g, 0.170 mmol) and a solution of Ghosez reagent (0.047 ml, 0.340 mmol) in DCM (0.95 ml). The mixture was sonicated and heated to aid dissolution. The vial was placed on the IKA shaker for 4 hours. To this mixture was added a solution of 4-amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate A) (10.043 g, 0.204 mmol) and N,N-diisopropylethylamine (0.030 ml, 0.170 mmol) in DCM (0.97 ml) and the vial was shaken for 16 hrs. A few drops of MeOH were added and the solvent was removed using a Genevac HT-4X evaporator. The crude mixture was purified by reverse phase chromatography and the product fraction was concentrated using a Genevac HT-4X evaporator. The crude product was dissolved in MeOH (1 ml) and eluted through a SiCO3 cartridge using MeOH as the eluent. The collected eluent was concentrated to give the title compound.
Reaction SMILES: CN1C(=O)CCC1.Br[CH2:9][CH2:10][C:11]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:12]#[N:13].[Cl:26][C:27]1[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=1)[CH2:30][O:31][CH:32]1[CH2:36][CH2:35][NH:34][CH2:33]1>C(N(CC)CC)C>[Cl:26][C:27]1[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=1)[CH2:30][O:31][CH:32]1[CH2:36][CH2:35][N:34]([CH2:9][CH2:10][C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:12]#[N:13])[CH2:33]1
Reactant: Clc1cccc(COC2CCNC2)c1
Reactant: N#CC(CCBr)(c1ccccc1)c1ccccc1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: N#CC(CCN1CCC(OCc2cccc(Cl)c2)C1)(c1ccccc1)c1ccccc1
Temperature: 140 °C
Reaction time: 20 h
Yield: 49.7 %

Procedure:
To 20 ml of NMP was added 2,54 g of 4-bromo-2,2-diphenylbutyronitrile, 1.79 g of 3-(3-chlorobenzyloxy)pyrrolidine and 1.29 g of triethylamine, and the mixture was stirred for 20 hours at 140° C. The reaction mixture was concentrated under reduced pressure and water was added to the residue, and then extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate. The organic layer was concentrated and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain 1.81 g of the aimed compound as a brown oil.
Reaction SMILES: [N:1]1([C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:10]=2C(O)=O)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1CCCC1.CN1CC[O:31][CH2:30]C1.Cl.C([O:42][C:43](=[O:46])[CH2:44][NH2:45])C1C=CC=CC=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C.CCOC(C)=O>[N:1]1([C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:10]=2[C:30]([NH:45][CH2:44][C:43]([OH:42])=[O:46])=[O:31])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1NC(=O)N1CCCC1
Reactant: NCC(=O)OCc1ccccc1
Reactant: CN1CCOCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: O=C(O)CNC(=O)c1cc(C(F)(F)F)ccc1NC(=O)N1CCCC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2-(Pyrrolidinylcarbonyl)amino-5-trifluoromethylbenzoic acid (made analogously to Example 116 with pyrrolidine in place of iso-butylamine (2.9 g) was dissolved in DMF (40 mL). After cooling to 0° C., 4-methylmorpholine (3.2 mL) and glycine benzyl ester hydrogen chloride (5.6 g) were added. After 5 min, BOP Reagent (5.6 g) was added and the mixture was stirred at rt for 18 h. EtOAc was added along with 1 N HCl solution. The EtOAc layer was washed with 1 N HCl, NaHCO3 solution, and brine. The EtOAc was dried (MgSO4), filtered, and concentrated to a solid (2.6 g). This solid was dissolved in MeOH (14 mL) prior to the addition of 10% Pd/C. A hydrogen balloon was added and the solution was stirred for 1 h. The palladium was filtered and the solution was concentrated to give the title glycine derivative (2.0 g) as a white solid. MS found: (M+H)+=360.2.
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@@H:18]([CH2:55][CH2:56][CH2:57][CH2:58][NH:59][C:60](=[O:98])[CH2:61][N:62]3[CH2:73][CH2:72][N:71]([CH2:74][C:75](=[O:81])[O:76][C:77]([CH3:80])([CH3:79])[CH3:78])[CH2:70][CH2:69][N:68]([CH2:82][C:83](=[O:89])[O:84][C:85]([CH3:88])([CH3:87])[CH3:86])[CH2:67][CH2:66][N:65]([CH2:90][C:91]([O:93][C:94]([CH3:97])([CH3:96])[CH3:95])=[O:92])[CH2:64][CH2:63]3)[C:19](=[O:54])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C@@H:25]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[NH:26][C:27](=[O:46])[NH:28][C@H:29]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[NH2:17][C@H:18]([C:19](=[O:54])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C@@H:25]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[NH:26][C:27](=[O:46])[NH:28][C@H:29]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:55][CH2:56][CH2:57][CH2:58][NH:59][C:60](=[O:98])[CH2:61][N:62]1[CH2:73][CH2:72][N:71]([CH2:74][C:75](=[O:81])[O:76][C:77]([CH3:80])([CH3:79])[CH3:78])[CH2:70][CH2:69][N:68]([CH2:82][C:83](=[O:89])[O:84][C:85]([CH3:88])([CH3:87])[CH3:86])[CH2:67][CH2:66][N:65]([CH2:90][C:91]([O:93][C:94]([CH3:95])([CH3:96])[CH3:97])=[O:92])[CH2:64][CH2:63]1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)[C@H](CCCCNC(=O)CN1CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)[C@@H](N)CCCCNC(=O)CN1CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 66.2 %

Procedure:
To a solution of (5S,12S,16S)-tri-tert-butyl 1-(9H-fluoren-9-yl)-3,6,14-trioxo-5-(4-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)butyl)-2-oxa-4,7,13,15-tetraazaoctadecane-12,16,18-tricarboxylate (115 mg) containing some impurity in DMF (0.30 mL) and piperidine (0.30 mL) was stirred at rt for 1 hr. Solvents were evaporated under reduced pressure to give a residue, which was purified by Biotage eluting with DCM to 10% MeOH in DCM to give (8S,15S,19S)-tri-tert-butyl 8-amino-2,9,17-trioxo-1-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)-3,10,16,18-tetraazahenicosane-15,19,21-tricarboxylate (64 mg, 90%) as a colorless oil. MS (ESI), 1171.6 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[C:11]([CH3:13])[CH3:12])[C:3]=1[C:4]#[N:5].[S:14](Cl)(=[O:17])(=[O:16])[NH2:15]>CN(C)C(=O)C>[S:14]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[C:11]([CH3:13])[CH3:12])[C:3]=1[C:4]#[N:5])(=[O:17])(=[O:16])[NH2:15]
Reactant: CC(C)=Cc1cccc(N)c1C#N
Reactant: NS(=O)(=O)Cl
Solvent: CC(=O)N(C)C
Product: CC(C)=Cc1cccc(NS(N)(=O)=O)c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A solution of 2-amino-6-(2-methylprop-1-enyl)benzonitrile (Example 129b) (1.24 g; 7.23 mmol) in N,N-dimethylacetamide (DMA) (20.0 mL), under a nitrogen atmosphere, was treated with sulfamoyl chloride (1.67 g; 14.45 mmol) at room temperature. The obtained mixture was stirred at room temperature for 2 h and the reaction was quenched with water (40 mL). The mixture was extracted with EtOAc (4×80 mL), the combined extract was washed with water (2×20 mL) and brine, and dried with MgSO4. The filtrate was evaporated and the residue was purified by chromatography on silica gel using gradient (Hexanes/EtOAc 1:0 to 1:1), to give 1.69 g (93%) of the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ9.42 (broad s, 1H), 7.61 (t, J=8.0 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.24 (broad s, 2H), 7.19 (d, J=8.0 Hz, 1H), 6.35 (broad s, 1H), 1.92-1.95 (m, 3H), 1.76-1.79 (m, 3H).
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.[CH3:9][O:10][N:11]=[C:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25]Cl)[C:13]1[O:18][CH2:17][CH2:16][O:15][N:14]=1.O>CN(C)C=O>[O:15]1[CH2:16][CH2:17][O:18][C:13]([C:12](=[N:11][O:10][CH3:9])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH:25]=[O:5])=[N:14]1
Reactant: C[N+]1([O-])CCOCC1
Reactant: CON=C(C1=NOCCO1)c1ccccc1CCl
Solvent: CN(C)C=O
Solvent: O
Product: CON=C(C1=NOCCO1)c1ccccc1C=O
Temperature: 120 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
19.5 g (0.14 mol) of N-methylmorpholine N-oxide are added to a solution of 15 g (0.056 mol) of (2-chloromethyl-phenyl)-(5,6-dihydro-[1,4,2]dioxazin-3-yl)-methanone O-methyl oxime in 150 ml of dimethylformamide and the mixture is stirred at 120° C. for 2 hours. After cooling, the mixture is poured into 1000 ml of water and extracted three times with 200 ml of ethyl acetate each time. The combined organic phases are dried over magnesium sulphate and concentrated under reduced pressure. The residue is stirred with diisopropyl ether and the solid formed is filtered off with suction. 10.5 g (76% of theory) of 2-[(5,6-dihydro-[1,4,2]dioxazin-3-yl)-methoxyimino-methyl]-benzaldehyde are obtained.
Reaction SMILES: [OH:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[N+:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1O)([O-:31])=[O:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[CH3:20][CH:19]([CH3:21])[C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@@H:2]([O:1][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[N+:29]([O-:31])=[O:30])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:12]=1)=[O:22]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](Oc3ccccc3[N+](=O)[O-])c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 34.5 %

Procedure:
A mixture of N-(3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 2-nitrophenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (2.37 mg, 34.5% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.84 (d, 1H), 7.90 (m, 1H), 7.45 (m 1H), 7.30-7.20 (m, 5H), 7.20 (m, 2H), 6.98 (m, 2H), 6.89 (apparent d, 1H, J=7.7 Hz), 5.62 (apparent dd, 1H, J=4.1, 8.9 Hz), 3.10 (m, 2H), 2.60 (m, 2H), 2.53 (m, 2H), 2.30-2.10 (m, 6H), 1.90 (m, 2H), 1.25 (d, 6H, overlapped); ESMS m/e: 502.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([NH:17][NH2:18])=[O:16])=[CH:13][N:12]3[CH:19]=[CH:20][N:21]=[C:11]3[C:10]=2[Cl:22])=[C:4]([F:23])[CH:3]=1.[C:24](=S)=[S:25].[OH-].[K+].Cl>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]3[O:16][C:24]([SH:25])=[N:18][N:17]=3)=[CH:13][N:12]3[CH:19]=[CH:20][N:21]=[C:11]3[C:10]=2[Cl:22])=[C:4]([F:23])[CH:3]=1
Reactant: S=C=S
Reactant: NNC(=O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Fc1cc(Br)ccc1Nc1c(-c2nnc(S)o2)cn2ccnc2c1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
7-(4-Bromo-2-fluoro-phenylamino)-8-chloro-imidazo[1,2-a]pyridine-6-carboxylic acid hydrazide (50 mg, 0.13 mmol) was suspended in ethanol (2.5 mL) and cooled to 0° C. Carbon disulfide (22 mg, 0.29 mmol) was added, followed by powdered potassium hydroxide (7 mg, 0.13 mmol). The reaction mixture was stirred under N2 for 1 hour at 0° C. and then for 30 minutes at room temperature. The reaction mixture was then brought to reflux and stirred under N2 for 5 days. The reaction mixture was diluted with water and acidified to pH 1-2 with aqueous 1 M HCl. This mixture was then extracted with ethyl acetate (2×). The combined organic layers were washed with saturated aqueous NaHCO3, saturated aqueous NaCl, dried over Na2SO4 and concentrated. Purification of the crude product was achieved by flash column chromatography (gradient of dichloromethane to 15:1 dichloromethane/methanol) and then trituration with diethyl ether and dichloromethane to yield the desired product (17 mg, 31%) as a yellow solid. MS ESI (+) m/z 440, 442 (M+, Cl, Br pattern) detected. 1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.16 (s, 1H), 8.08 (br s, 1H), 7.73 (s, 1H), 7.49 (d, 1H), 7.15 (d, 1H), 6.59 (t, 1H). 19F (376 MHz, DMSO-d6)−128.7 (s).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([O:9][C:10]2[C:11]([C:23]#[N:24])=[N:12][CH:13]=[C:14]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:15]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].[OH-:25].[Na+]>S(=O)(=O)(O)O>[CH2:1]([C:3]1[C:8]([O:9][C:10]2[C:11]([C:23]([NH2:24])=[O:25])=[N:12][CH:13]=[C:14]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:15]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1ncccc1Oc1cc(Sc2ccccn2)cnc1C#N
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCc1ncccc1Oc1cc(Sc2ccccn2)cnc1C(N)=O
Temperature: 0 °C

Procedure:
3-(2-Ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (1.4 g, 4.19 mmol) was stirred in concentrated sulfuric acid (10 mL) overnight at ambient temperature. Ice (100 g) was added and the solution was neutralized using 4M NaOH. Ice was added as necessary to maintain the temperature below 20° C. The product was extracted into ethyl acetate, washed with brine, dried over MgSO4, filtered and concentrated to afford 3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinamide (1.5 g, 4.2 mmol).
Reaction SMILES: N.[CH3:2][O:3][C:4]1[N:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.C([O:17]O)(C)(C)C.Cl>C1COCC1.O>[OH:17][C:8]1[C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[N:9]=1
Reactant: COc1ccc([N+](=O)[O-])cn1
Reactant: CC(C)(C)OO
Agent: Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])c(O)n1
Temperature: -78 °C

Procedure:
To a cooled suspension of Na t-OBu (6.24 g, 64.9 mmol) in liquid ammonia was added dropwise a solution of 6-methoxy-3-nitropyridine (2.0 g, 12.98 mmol) and t-butyl hydrogenperoxide (1.53 mL, 14.31 mmol) in THF (20 mL). After the completion of addition, the resulting mixture was stirred at −78° C. under Ar and warmed gradually to room temperature, and then stirred at room temperature overnight, which gave a yellow solid. It was diluted with H2O (30 mL). The resulting mixture was neutralized with the addition of 1N HCl solution. The solid formed was collected and washed with H2O and DCM, and then dried (1.18 g). The filtrate was extracted with DCM (2×20 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to give the second portion (0.59 g, total 1.77 g, 80%). NMR (MeOD-d3, 400 MHz) □ 8.20 (d, J=8.8 Hz, 1H), 5.79 (d, J=8.8 Hz, 1H), 4.87 (s, 3H). MS: m/z=171 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH:6]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([NH:16][NH2:17])=[CH:11][C:10]=2[Cl:18])[C:7]#[N:8])=[CH:4][CH:3]=1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.S([O-])([O-])(=O)=O.[Mg+2]>C(OC(=O)C)C>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH:6]([C:9]2[C:10]([Cl:18])=[CH:11][C:12]([NH:16][N:17]=[CH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:13][C:14]=2[Cl:15])[C:7]#[N:8])=[CH:4][CH:3]=1
Reactant: N#CC(c1ccc(Cl)cc1)c1c(Cl)cc(NN)cc1Cl
Reactant: O=Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Product: N#CC(c1ccc(Cl)cc1)c1c(Cl)cc(NN=Cc2ccccc2)cc1Cl
Reaction time: 1 h

Procedure:
In 30 ml of acetic acid ethyl ester was dissolved 3.26 g of 4-(4-chloro-α-cyanobenzyl)-3,5-dichlorophenyl hydrazine. To the solution was added equimolar benzaldehyde and three times as much mol. of anhydrous magnesium sulfate, then the reaction was allowed to proceed for one hour at room temperature. After completion of the reaction, insolubles were removed, and the solution was concentrated, which was recrystallized from acetonitrile to afford 3.3 g of the titled compound as colorless crystals, m.p. 162-163° C.
Reaction SMILES: O[CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)[C:3]#[N:4].N1C=CC=CC=1.S(Cl)([Cl:22])=O>C(OCC)C>[Cl:22][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)[C:3]#[N:4]
Reactant: O=S(Cl)Cl
Reactant: N#CC(O)c1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: CCOCC
Product: N#CC(Cl)c1cccc([N+](=O)[O-])c1
Yield: 88.7 %

Procedure:
A solution of 2-hydroxy-2-(3-nitrophenyl)acetonitrile (Preparation 113, 1.0 g, 5.62 mmol) in diethyl ether (10 ml) was stirred at room temperature and treated with pyridine (0.1 ml, 1.24 mmol) followed by thionyl chloride (0.82 ml, 11.2 mmol) dropwise over 5 minutes. The mixture was gently heated under reflux and after 30 min the solvent was removed by evaporation to give a pale yellow solid. This was purified by column chromatography on silica gel eluting with hexane:ethyl acetate (3:1 and then 2:1) to give the title compound as a white crystalline solid (980 mg, 89%).