Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[F:16])[NH:12][CH:11]=[CH:10]2.CC([O-])(C)C.[K+].[C:23](=[O:25])=[O:24]>CCCCCC.C1COCC1.O>[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[C:14]([C:23]([OH:25])=[O:24])[C:15]=1[F:16])[NH:12][CH:11]=[CH:10]2
Reactant: O=C=O
Reactant: Fc1cc2[nH]ccc2cc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Temperature: 10 °C
Reaction time: 2 h

Procedure:
35 ml of THF were cooled to −75° C. and 19.05 ml (30.5 mmol) of a 1.6M solution of n-butyllithium in hexane were added under argon. Then a solution of 2.35 g (13.7 mmol) of 5-chloro-6-fluoro-1H-indole in THF (9 ml) was added dropwise (temperature kept between −70 and −75° C.) over 15 min. After 5 additional min of stirring at this temperature a solution of 3.7 g of potassium tert-butylate in THF (15 ml) was added over period of 10 min (temperature kept between −70 and −75° C.). The resulting brown solution was then stirred for 2 hours at the same temperature and treated with a large excess of solid CO2. The temperature was then raised to 10° C. over a period of 75 min and water (30 ml) was added to the reaction mixture. After separation of the organic layer, the aqueous layer was extracted with ether and treated with concentrated HCl to adjust the pH to 1. The resulting suspension was then filtered and the solid was washed with water and dried in high vacuo. The remaining residue was suspended in 10 ml of hexane/ether 9:1 and stirred for 15 min, filtered off, washed with 5 ml of the same solvent mixture and was dried in high vacuo, leading to 2.2 g of 5-chloro-6-fluoro-1H-indole-7-carboxylic acid as a light brown solid (75%). MS: 212.2 (M−H)−
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]O)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:42]I>C1(C)C=CC=CC=1>[I:42][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: II
Reactant: COc1ccc(CCCCCCCCO)cc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CCCCCCCCI)cc1
Temperature: 65 °C

Procedure:
To a stirred solution of 8-(4-methoxyphenyl)octan-1-ol (12.3 g, 52 mmol) in dry toluene (200 mL) under an argon atmosphere was added triphenylphosphine (17.8 g, 67.6 mmol) and imidazole (10.6 g, 156 mmol). After the imidazole had dissolved, I2 (17.1 g, 67.6 mmol) was added. The reaction was then heated at 65° C. for 30 minutes. Upon cooling to room temperature the reaction was concentrated to 1/4 volume. The remaining solution was diluted with Et2O and washed with H2O and brine and dried (MgSO4). The solvent was removed and the resulting residue was dissolved in CH2Cl2 and applied to a flash chromatography column (silica). Elution with 2% EtOAc in hexane provided the product as a colorless oil (slight contamination with triphenylphosphine): 1H NMR (250 MHz, CDCl3) δ7.08 (d, J=8.6 Hz, 2H, aryl), 6.82 (d, J=8.6 Hz, 2H, aryl), 3.78 (s, 3H, OCH3), 3.17 (t, J=7.4 Hz, 2H, I-CH2), 2.54 (t, J=7.6 Hz, 2H, benzylic), 1.85 (m, 2H, CH2), 1.60 (m, 2H, CH2), 1.31 (m, 8H, aliphatic); MS (CI): 364.2 (M+NH4).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C>[CH2:12]([O:19][C:20]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCNc2ccccc21
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1CCN(C(=O)OCc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 93 %

Procedure:
In 20 mL of tetrahydrofuran was dissolved 5.04 g of 2,3-dihydro-4-quinolone at 25° C., then, to the solution were added 5.6 mL of benzyloxycarbonyl chloride, 15 mL of water and 4.73 g of potassium carbonate under ice-cooling, and said mixture was stirred at 25° C. for 24 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was separated, dried over anhydrous magnesium sulfate, and then, filtered. The filtrate was concentrated, and the residue was dissolved in 35 mL of isopropyl alcohol under heating. Said solution was gradually cooled, and the precipitated crystals were collected by filtration under ice-cooling. The resulting crystals were washed with 25 mL of cold isopropyl alcohol, and dried at 50° C. for 16 hours to obtain 8.98 g (Yield: 93%) of 1-benzyloxycarbonyl-2,3-dihydro-4-quinolone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[C:9](O)=[O:10])=[CH:4][CH:3]=1.[C:13]1([NH2:20])[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1.[OH2:21]>ClC1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[C:9]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([NH:20][C:9](=[O:10])[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[OH:12])=[CH:14][CH:15]=2)=[O:21])=[CH:4][CH:3]=1
Reactant: O=C(O)C(O)c1ccc(Br)cc1
Reactant: O
Reactant: Nc1ccc(N)cc1
Solvent: Clc1ccccc1
Product: O=C(Nc1ccc(NC(=O)C(O)c2ccc(Br)cc2)cc1)C(O)c1ccc(Br)cc1
Reaction time: 21 h
Yield: 95 %

Procedure:
In a 250 cm3 flask fitted with a consender and a reverse Dean-Stark apparatus, the (4-bromo-phenyl)-hydroxy-acetic acid (25.00 g, 108.2 mmol) and 1,4-phenylenediamine (3.900 g, 36.07 mmol) are dissolved in chlorobenzene (100 cm3). The reaction mixture is heated to 132° C. while the generated water is distilled off the using the reverse Dean-Stark apparatus. After 21 hours, the reaction mixture is cooled down, the precipitate is filtered off and washed with methanol to yield the product (18.21 g, Yield: 95%). NMR (1H, 300 MHz, CDCl3): δ 9.90 (br, 2H); 7.59 (s, 4H); 7.56 (d, J=8.5 Hz, 4H); 7.45 (d, J=8.5 Hz, 4H); 6.53 (d, J=4.7 Hz, 2H), 5.08 (d, J=4.7 Hz, 2H).
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[NH:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[O:14].C(CN)O.Cl>O>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:8]=1[OH:9])[CH:2]=[C:18]1[NH:12][C:13](=[O:14])[NH:15][C:16]1=[O:17]
Reactant: COc1cc(C=O)ccc1O
Reactant: O=C1CNC(=O)N1
Agent: Cl
Solvent: O
Solvent: NCCO
Product: COc1cc(C=C2NC(=O)NC2=O)ccc1O
Reaction time: 0.5 h

Procedure:
Vanillin (3.04 g.) and hydantoin (2.0 g.) in water (20 ml were heated on the steam-bath for a few minutes until dissolution occurred. Ethanolamine (0174 g.) was then added and the solution heated at 85°-90° (bath temperature) for 4.5 hours. The solution deposited crystals and solidified within 0.5 hours. Concentrated HCl (5 ml) was added, the mixture was refrigerated overnight (18 hours), filtered, water washed and dried. The title compound was obtained as a yellow solid (4.18 g; 93%), m.p. 266°-271° decomp.
Reaction SMILES: COC1C=CC(CN(CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:30][C:31]4[CH:32]=[CH:33][C:34]5[S:38][CH:37]=[N:36][C:35]=5[CH:39]=4)=[N:18][CH:19]=[C:20]([CH:22]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH3:23])[CH:21]=3)[N:10]=2)=CC=1.C([N:53](CC)CC)C.[CH3:58][N:59]([CH3:63])[C:60](Cl)=[O:61]>ClCCl>[NH2:53][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[CH:21]=[C:20]([CH:22]([N:24]3[CH2:25][CH2:26][N:27]([C:60]([N:59]([CH3:63])[CH3:58])=[O:61])[CH2:28][CH2:29]3)[CH3:23])[CH:19]=[N:18][C:17]=2[NH:30][C:31]2[CH:32]=[CH:33][C:34]3[S:38][CH:37]=[N:36][C:35]=3[CH:39]=2)[N:10]=1
Reactant: CCN(CC)CC
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)N4CCNCC4)cnc3Nc3ccc4scnc4c3)n2)cc1
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Product: Cc1nc(N)nc(-c2cc(C(C)N3CCN(C(=O)N(C)C)CC3)cnc2Nc2ccc3scnc3c2)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of N-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-(1-(piperazin-1-yl)ethyl)pyridin-2-yl)benzo[d]thiazol-5-amine (0.300 g, 0.436 mmol) in dichloromethane (10 mL) was chilled to 0° C. in an ice bath, then triethylamine (0.304 mL, 2.181 mmol) was added to the mixture. After 10 min, dimethylcarbamic chloride (Aldrich; 0.141 g, 1.308 mmol) was added into the mixture dropwise via syringe. After the addition, the ice bath was removed and the mixture was allowed to stir under inert atmosphere overnight. The mixture was diluted with chloroform (20 mL) and water (10 mL). The organic layer was extracted with chloroform (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a SiliCycle SiliaSep pre-packed silica-gel column (40 g), eluting with 20% MeOH in CH2Cl2 to give the urea as a tan oil. This material was diluted with trifluoroacetic acid (1.803 mL, 23.40 mmol) and stirred 5 min. Then trifluoromethanesulfonic acid (0.214 mL, 2.406 mmol) was added to the mixture. The reaction mixture was placed into a pre-heated (70° C.) bath and allowed to stir under inert atmosphere for 10 min. The heating bath was removed and the mixture was allowed to cool to ambient temperature. The mixture was concentrated in vacuo. The residue was diluted with dichloromethane (10 mL), then sodium carbonate (2.0 g) was added into the mixture with stirring. After 5 min, methanol (5 mL) was added into the mixture and allowed to stir 20 min. The mixture was filtered and concentrated in vacuo. The mixture was recrystallized from ethyl acetate/ethyl ether. This gave 4-(1-(5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(benzo[d]thiazol-5-ylamino)pyridin-3-yl)ethyl)-N,N-dimethylpiperazine-1-carboxamide (0.070 g, 0.135 mmol, 61.7% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 12.24 (s, 1H) 9.36 (s, 1H) 8.92 (s, 1H) 8.92 (s, 1H) 8.37 (s, 1H) 7.91 (s, 1H) 8.05 (s, 1H) 7.83 (s, 2H) 3.53 (m, 1H) 3.10 (s, 4H) 2.70 (s, 6H) 2.43-2.55 (m, 3H) 2.36 (d, J=4.50 Hz, 4H) 1.38 (d, J=6.06 Hz, 3H). m/z (ESI, +ve ion) 519.1 (M+H)+.
Reaction SMILES: Br[CH:2]([C:27]1[O:31][C:30]([C:32]2[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=2)=[N:29][N:28]=1)[CH:3](Br)[C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:7]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][N:17]=2)=[N:6][N:5]=1.C(O[K])(C)(C)C.C(O)(=O)C.C(OCC)(=O)C>C1C=CC=CC=1>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N:8]1[C:7]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][N:17]=2)=[N:6][N:5]=[C:4]1[C:3]#[C:2][C:27]1[O:31][C:30]([C:32]2[CH:33]=[CH:34][C:35]([C:36]#[N:37])=[CH:38][CH:39]=2)=[N:29][N:28]=1
Reactant: CS(=O)(=O)c1ccc(-c2nnc(C(Br)C(Br)c3nnc(-c4ccc(C#N)cc4)o3)n2-c2ccccc2Cl)nc1
Agent: CC(C)(C)O[K]
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2nnc(C#Cc3nnc(-c4ccc(C#N)cc4)o3)n2-c2ccccc2Cl)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(5-{1,2-Dibromo-2-[4-(2-chloro-phenyl)-5-(5-methanesulfonyl-pyridin-2-yl)-4H-[1,2,4]triazol-3-yl]-ethyl}-[1,3,4]oxadiazol-2-yl)-benzonitrile 2 (0.1 g, 0.19 mmol) in benzene (10 mL) was added tBuOK (0.05 g, 0.28 mmol) portionwise at 0° C. The mixture was stirred at 0° C. for 1 h, treated with diluted acetic acid and ethyl acetate, washed with H2O, dried over Na2SO4 and concentrated. The residue was subjected to FCC (50-100% ethyl acetate/hexanes) to afford 4-{5-[4-(2-Chloro-phenyl)-5-(5-methanesulfonyl-pyridin-2-yl)-4H-[1,2,4]triazol-3-ylethynyl]-[1,3,4]oxadiazol-2-yl}-benzonitrile. Yield: 0.03 g, 39%.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.O[CH2:13][C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:22]([O:21][C:19]([N:15]1[CH2:16][CH2:17][CH2:18][C@H:14]1[CH2:13][N:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=2[C:10]([I:11])=[CH:9]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: Clc1ncnc2[nH]cc(I)c12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1Cn1cc(I)c2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.9 %

Procedure:
To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (4.0 g, 14.34 mmol, 1.0 eq), (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (4.04 g, 20.08 mmol, 1.4 eq), and PPh3 (7.5 g, 28.68 mmol, 2.0 eq) in dry THF (30 mL), DIAD (5.80 g, 28.68 mmol, 2.0 eq) was added dropwise at 0° C. The mixture was stirred at RT for 5 h. The reaction mixture was concentrated and purified by silica gel chromatography (eluted with PE:EtOAc=1:1) to afford (S)-2-(4-chloro-5-iodo-pyrrolo[2,3-d]pyrimidin-7-ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (5.1 g, 77% in yield).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:23])[C:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=3[CH3:22])=[C:6]2[N:5]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:3]=1.[NH3:30]>CO>[CH3:23][C:9]1[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=2[CH3:22])=[C:6]2[N:5]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:3]=[C:2]([NH2:30])[N:7]2[N:8]=1
Reactant: N
Reactant: Cc1nn2c(Cl)cc(N3CCOCC3)nc2c1Cc1cccc(C(F)(F)F)c1C
Solvent: CO
Product: Cc1nn2c(N)cc(N3CCOCC3)nc2c1Cc1cccc(C(F)(F)F)c1C
Temperature: 0 °C

Procedure:
To a suspension of 7-chloro-2-methyl-3-{{2-methyl-3-(trifluoromethyl)phenyl}methyl}-5-(4-morpholinyl)pyrazolo[1,5-a]pyrimidine (70 mg, 0.16 mmol) in methanol (2 mL) stirred under nitrogen at 0° C. was added a 2 M ammonia solution of in CH3OH (0.82 mL, 1.64 mmol) dropwise. The reaction mixture was stirred at 135° C. for 3 hours. Reaction mixture was concentrated to dryness. Crude product was purified by reverse-phase HPLC to provide titled compound. (16 mg, 24%); LC/MS: MS (ES+) m/e 406 (MH+); 1H NMR (400 MHz, MeOD) δ ppm 2.20 (s, 3H) 2.52 (s, 3H) 3.15 (dt, J=3.28, 1.64 Hz, 1H) 3.50 (dt, J=3.28, 1.64 Hz, 1H) 3.57 (d, J=5.31 Hz, 3H) 3.55 (s, 1H) 3.82 (s, 1H) 3.81 (d, J=5.05 Hz, 3H) 4.10 (s, 2H) 5.59 (s, 1H) 7.12 (s, 1H) 7.26 (s, 1H) 7.55 (s, 1H).
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O-:10])=[O:9].[H-].[Na+].[CH3:20][C:21](=[C:23]([CH3:25])[CH3:24])[CH3:22]>ClCCl.C1COCC1>[CH3:20][C:21]1([CH3:22])[C:23]([CH3:25])([CH3:24])[O:7][C:6]([O:17][C:14]2[CH:15]=[CH:16][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=2)=[N:5][S:2]1(=[O:4])=[O:3]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)=C(C)C
Reactant: O=C=NS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC1(C)OC(Oc2ccc([N+](=O)[O-])cc2)=NS(=O)(=O)C1(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 16.2 %

Procedure:
7.40 g of chlorosulfonyl isocyanate and 7.27 g of 4-nitrophenol were dissolved in 75 ml of dichloromethane and stirred at room temperature for 90 minutes. The reaction solution was freed of the solvent under reduced pressure, and the residue was dissolved in 50 ml of THF and, under inert gas and at −78° C., admixed with 2.18 g of sodium hydride. After stirring for 5 minutes, 4.38 g of 2,3-dimethyl-2-butene were added and the reaction mixture was heated, gradually because of commencement of evolution of gas, to 35° C. After stirring for 30 minutes, the suspension was added to ice and the resulting THF/water mixture was extracted twice with 100 ml of ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated by rotary evaporation. The residue was purified in a purification laboratory by means of preparative HPLC. After lyophilization of the product-containing fractions, the product (2.76 g) was thus obtained with a molecular weight of 328.4 g/mol (C13H16N2O6S).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCOCC1
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Reaction time: 64 h
Yield: 88.9 %

Procedure:
To a solution of methyl 3-amino-5-bromo-2-methylbenzoate (3.0 g, 12 mmol) in 1,2-Dichloroethane (48 ml) under nitrogen, was added oxan-4-one (2.3 ml, 25 mmol) followed by acetic acid (4.2 ml, 74 mmol). The reaction mixture was stirred for 5 minutes before the addition of sodium triacetoxyborohydride (7.8 g, 37 mmol). After stirring for 64 hours, deionized water (100 ml) was added and the mixture was neutralized with solid NaHCO3. The phases were separated and the aqueous layer was extracted with EtOAc (4×50 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in-vacuo. The residue was purified by flash column chromatography (50 g silica, Isolute cartridge, 10-30% EtOAc:Heptanes) to give the title compound (3.5 g 85%) as a white solid. LC-MS 99.8%, 2.18 min (3.5 minute LC-MS method), m/z=327.9, 328.9, 329.9, 330.9; 1H NMR (500 MHz, Chloroform-d) δ ppm 7.24 (d, J=1.73 Hz, 1H) 6.85 (d, J=1.58 Hz, 1H) 4.03 (dt, J=11.82, 3.31 Hz, 2H) 3.88 (s, 3H) 3.66 (br.s., 1H) 3.56 (td, J=11.55, 1.97 Hz, 2H) 3.47-3.55 (m, 1H) 2.24 (s, 3H) 2.06 (d, J=13.56 Hz, 2H) 1.47-1.60 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:3]([C:22]([NH2:24])=[O:23])=[N:4][C:5]([C:18](O)([CH3:20])[CH3:19])=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:7]=1.[CH3:25][N:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH:36]=[C:35]([NH2:37])[CH:34]=[N:33]2)[CH2:28][CH2:27]1.C(N(C(C)C)CC)(C)C.CN1CCCC1=O>[Cl-].[Na+].O.O>[CH3:25][N:26]1[CH2:27][CH2:28][CH:29]([N:32]2[CH:36]=[C:35]([NH:37][C:2]3[C:3]([C:22]([NH2:24])=[O:23])=[N:4][C:5]([C:18]([CH3:20])=[CH2:19])=[C:6]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=4)[N:7]=3)[CH:34]=[N:33]2)[CH2:30][CH2:31]1
Reactant: CC(C)(O)c1nc(C(N)=O)c(Cl)nc1Oc1cccc([N+](=O)[O-])c1
Reactant: CN1CCC(n2cc(N)cn2)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: C=C(C)c1nc(C(N)=O)c(Nc2cnn(C3CCN(C)CC3)c2)nc1Oc1cccc([N+](=O)[O-])c1
Yield: 52.1 %

Procedure:
A mixture of 3-chloro-6-(2-hydroxypropan-2-yl)-5-(3-nitrophenoxy)pyrazine-2-carboxamide (300 mg), 1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-amine (184 mg), diisopropylethylamine (291 μL), and N-methylpyrrolidone (3 mL) was reacted in a microwave reaction device at 180° C. for 2 hours. To the reaction mixture were added water and saturated brine, followed by extraction with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=1:0-9:1). The obtained solid was purified by silica gel column chromatography (NH2 type, eluent; chloroform:methanol=100:0-98:2) to obtain 3-{[1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl]amino}-5-(3-nitrophenoxy)-6-(prop-1-en-2-yl)pyrazine-2-carboxamide (212 mg) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:12]([O-])=O)[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: O=[N+]([O-])c1cc(F)cc2c1OCCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cc(F)cc2c1OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
7-Fluoro-5-nitro-2,3-dihydro-1,4-benzodioxin (6.96 g, 35 mmol) and 5% Pd/C (4 g) in MeOH (500 ml) was stirred overnight in the presence of hydrogen at atmospheric pressure at rt. The catalyst was filtered off and solvent removed; the residue was dissolved in MeOH (100 ml), more 5% Pd/C (paste, 3 g) was added and mixture stirred overnight in presence of hydrogen (45 psi) at rt. The catalyst was filtered off and solvent removed; the residue treated with DCM (20 ml), the solid filtered off and compound in DCM loaded on silica (pre-wet with petroleum ether) and purified using a 10%-50% EtOAc: 40-60 petroleum ether gradient to provide the desired compound (3 g, 51%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:30])[NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH:25]=C)[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=2)[C:12]=1[F:29])=[O:8].I([O-])(=O)(=O)=[O:32].[Na+]>C1COCC1.O.CCOC(C)=O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[N:3]=[C:4]([CH3:30])[NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH:25]=[O:32])[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=2)[C:12]=1[F:29])=[O:8]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(C)nc3Cl)c2F)c1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(C#N)cc(C=O)c3)c2F)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
To a solution of 4-chloro-N-({4-chloro-3-[(3-cyano-5-ethenylphenyl)oxy]-2-fluorophenyl}methyl)-2-methyl-1H-imidazole-5-carboxamide (0.260 g, 0.584 mmol) and sodium periodate (0.375 g, 1.752 mmol) in THF (4 ml) and water (2 ml) was added osmium tetroxide (2.5 weight % in t-butanol) (0.147 ml, 0.012 mmol) and the reaction mixture was stirred at rt for 3 hours. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-({4-chloro-3-[(3-cyano-5-formylphenyl)oxy]-2-fluorophenyl}methyl)-2-methyl-1H-imidazole-5-carboxamide (0.245 g, 0.548 mmol, 94% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.95 (s, 1H), 8.12 (s, 1H), 8.07 (s, 1H), 7.92 (s, 1H), 7.45-7.56 (m, 1H), 7.27-7.44 (m, 1H), 6.91 (d, 1H), 4.52 (d, 2H), 2.23 (s, 3H).
Reaction SMILES: S(O[CH:12]([CH2:21][CH3:22])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])(C1C=CC(C)=CC=1)(=O)=O.[N-:23]=[N+:24]=[N-:25].[Na+]>CS(C)=O>[N:23]([CH:12]([CH2:21][CH3:22])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[N+:24]=[N-:25]
Reactant: CCC(CC(=O)OC(C)(C)C)OS(=O)(=O)c1ccc(C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCC(CC(=O)OC(C)(C)C)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 66 h
Yield: 88.9 %

Procedure:
t-Butyl 3-tosyloxypentanoate (7.75 g, 23.6 mmol) was added to a suspension of sodium azide (3.07 g, 47.2 mmol) in dry DMSO (135 ml) and stirred at room temperature for 66 h. The reaction mixture was poured into ice-water (200 ml) and extracted with CH2Cl2 (2×150 ml). The organic extracts were combined, washed with water (4×150 ml) and dried over anhydrous MgSO4. Evaporation of CH2Cl2 under reduced pressure gave an oil (4.18 g, 89.4%). ir (neat) νmax : 2096 (N3) and 1720 cm-1 (C=O of ester); 1Hmr (CDCl3) δ: 1.0 (3H, t), 1.27-1.85 (2H, m) 1.48 (9H, s) 2.40 (2H, d) and 3.68 ppm (H, m).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[N:12]=[C:11]([C:13]3[O:21][C:20]4[CH:19]=[CH:18][N:17]=[CH:16][C:15]=4[CH:14]=3)[O:10][N:9]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[CH2:28]([O:31][C:32](Cl)=[O:33])[CH2:29][CH3:30]>C(Cl)Cl.CCOCC>[CH2:28]([O:31][C:32]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[N:12]=[C:11]([C:13]3[O:21][C:20]4[CH:19]=[CH:18][N:17]=[CH:16][C:15]=4[CH:14]=3)[O:10][N:9]=2)[CH2:3][CH2:2]1)=[O:33])[CH2:29][CH3:30]
Reactant: c1cc2oc(-c3nc(CC4CCNCC4)no3)cc2cn1
Reactant: CCCOC(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCOC(=O)N1CCC(Cc2noc(-c3cc4cnccc4o3)n2)CC1
Reaction time: 16 h

Procedure:
A solution of 2-(3-piperidin-4-ylmethyl-[1,2,4]oxadiazol-5-yl)furo[3,2-c]pyridine (Preparation 12, 0.65 g, 2.3 mmol) and pyridine (0.37 mL, 4.6 mmol) in anhydrous CH2Cl2 (25 mL) was added via cannula to a stirred solution of n-PrOCOCl (0.51 mL, 4.6 mmol) in anhydrous CH2Cl2 (35 mL). After 16 h, the reaction mixture was diluted with Et2O (200 mL), before being washed with H2O (100 mL), saturated aqueous Na2CO3 (100 mL), and H2O (100 mL). The organic phase was dried, filtered and concentrated. Flash chromatographic purification (EtOAc) of the residue furnished the title compound: RT=3.11 min; m/z (ES+)=371.1 [M+H]+.