Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(O)C2C(C)=C(CC3C=CC(Cl)=CC=3)C(C)=NC=2C=1.ClC1C=C(O)C=C2C=1C(C)=C(CC1C=CC(Cl)=CC=1)C(C)=N2.C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[Cl:72][C:73]1[CH:82]=[C:81]([O:83][S:84]([C:87]([F:90])([F:89])[F:88])(=[O:86])=[O:85])[CH:80]=[C:79]2[C:74]=1[C:75]([CH3:100])=[C:76]([CH2:92][C:93]1[CH:98]=[CH:97][C:96]([Cl:99])=[CH:95][CH:94]=1)[C:77]([CH3:91])=[N:78]2>O1CCCC1>[Cl:72][C:73]1[CH:74]=[C:79]2[C:80]([C:75]([CH3:100])=[C:76]([CH2:92][C:93]3[CH:98]=[CH:97][C:96]([Cl:99])=[CH:95][CH:94]=3)[C:77]([CH3:91])=[N:78]2)=[C:81]([O:83][S:84]([C:87]([F:89])([F:90])[F:88])(=[O:85])=[O:86])[CH:82]=1
Reactant: Cc1nc2cc(OS(=O)(=O)C(F)(F)F)cc(Cl)c2c(C)c1Cc1ccc(Cl)cc1
Agent: Cc1nc2cc(Cl)cc(O)c2c(C)c1Cc1ccc(Cl)cc1
Agent: Cc1nc2cc(O)cc(Cl)c2c(C)c1Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Cc1nc2cc(Cl)cc(OS(=O)(=O)C(F)(F)F)c2c(C)c1Cc1ccc(Cl)cc1
Temperature: 130 °C

Procedure:
A mixture of 7-chloro-3-(4-chlorobenzyl)-2,4-dimethylquinolin-5-ol and 5-chloro-3-(4-chlorobenzyl)-2,4-dimethylquinolin-7-ol (0.66 g), N-phenyltrifluoromethanesulfonimide (0.86 g), potassium carbonate (0.82 g) and tetrahydrofuran (10 mL) was heated by microwave irradiation at 130° C. for 20 minutes. The mixture was filtered and the filtrate concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with 1,2-dichloroethane gave a 50:50 mixture of title compound and trifluoromethanesulfonic acid 5-chloro-3-(4-chlorobenzyl)-2,4-dimethylquinolin-7-yl ester as a honey coloured gum, 0.86 g.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([C:7]1[S:8][C:9]([Br:20])=[CH:10][C:11]=1[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:6].Cl>C1COCC1.O>[Br:20][C:9]1[S:8][C:7]([C:5]([OH:6])=[O:4])=[C:11]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:10]=1
Reactant: COC(=O)c1sc(Br)cc1NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(Br)sc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An aqueous 2 M lithium hydroxide solution (1 mL) was added to a solution of 5-bromo-3-tert-butoxycarbonylaminothiophene-2-carboxylic acid methyl ester (330.0 mg) in THF/water (1.6 mL/1.6 mL). The solution was stirred at room temperature overnight and was then neutralized with diluted HCl solution, and the solvent was removed in vacuo. The product with the molecular weight of 322.18 (C10H12BrNO4S) was obtained in this way; MS (ESI): 221, 223 (M-Boc+H+).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].C1(C)C=CC=CC=1.[F:13][C:14]1[CH:34]=[CH:33][C:17]([CH2:18][N:19]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=2)[N:20]2[CH:24]=[N:23][N:22]=[CH:21]2)=[CH:16][C:15]=1[OH:35]>O.C(OCC)(=O)C.CN(C)C(=O)C>[C:31]([C:28]1[CH:29]=[CH:30][C:25]([N:19]([CH2:18][C:17]2[CH:33]=[CH:34][C:14]([F:13])=[C:15]([O:35][S:1](=[O:4])(=[O:3])[NH2:2])[CH:16]=2)[N:20]2[CH:21]=[N:22][N:23]=[CH:24]2)=[CH:26][CH:27]=1)#[N:32]
Reactant: NS(=O)(=O)Cl
Reactant: N#Cc1ccc(N(Cc2ccc(F)c(O)c2)n2cnnc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(N(Cc2ccc(F)c(OS(N)(=O)=O)c2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sulphamoyl chloride solution in toluene (3 ml, 0.7 M, 2.1 mmol) was concentrated under reduced pressure (30° C. water bath temperature) to ca. 0.5 ml volume. The residue was cooled to 0° C. (ice bath) and N,N-dimethyl acetamide (5 ml) was added. 4-[(4-Fluoro-3-hydroxybenzyl)-[1,2,4]triazol-4-yl-amino]-benzonitrile (STX488, 155 mg, 0.50 mmol) was added to the colourless solution and the mixture was stirred for 4 hours at room temperature. Ethyl acetate (50 ml) and water (30 mL) were added to the solution, the organic layer was separated, washed with water (2×30 ml) and brine (1×20 ml), dried over sodium sulphate and concentrated under reduced pressure. The residue was dissolved in acetone (5 ml) and precipitated by addition of diethyl ether. The precipitate (STX1122) was filtered off and dried under high vacuum. Yield: 157 mg (83%) white powder. 1H-NMR (400 MHz, DMSO-d6) δ5.07 (s, 2H), 6.74 (d, J=8.9 Hz, 2H), 7.20-7.26 (m, 1H), 7.33 (dd, J=10.1, 8.6 Hz, 1H), 7.38 (dd, J=7.4, 2.3 Hz, 1H), 7.75 (d, J=8.9 Hz, 2H), 8.25 (s, 2H, —NH2), 8.77 (s, 2H); MS (FAB+): m/z 389.0 (100%, [C16H13FN6O3S2+H]+); HRMS (FAB+) for C16H14FN6O3S: 389.08321; found, 389.08300; HPLC tR=1.763 min (100%); Anal. (C16H13FN6O3S) C, H, N;
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=O)=[C:24]([CH:28]=[CH2:29])[N:23]=[C:22]3[O:30][CH2:31][CH2:32][CH3:33])=[C:16]([F:34])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:36][OH:37].O>N1C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:36][OH:37])=[C:24]([CH:28]=[CH2:29])[N:23]=[C:22]3[O:30][CH2:31][CH2:32][CH3:33])=[C:16]([F:34])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C=Cc1nc(OCCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=O
Reactant: NO
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: C=Cc1nc(OCCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=NO
Temperature: 40 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
Intermediate (18b) (7.2 g, 15.5 mmol) was dissolved in pyridine (30 mL). Hydroxylamine hydrochloride (4.0 g, 57.9 mmol) was added followed by water (20 mL) and the mixture was stirred at 40° C. for 2 hours. The reaction was quenched with water, extracted with 200 mL EtOAc, washed with 3×100 mL 1M phosphoric acid, 1×100 mL saturated sodium bicarbonate solution, and 2×100 mL saturated aqueous NaCl, then dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-80% EtOAc:hexanes) to yield intermediate (18c) as a white solid (7.4 g). Anal. HPLC retention time=4.9 minutes. Gradient conditions: 25% solvent B/75% solvent A to 95% solvent B/5% solvent A over 6 minutes. MS m/z: [M+H+] calcd for C27H30FN2O4, 480.23; found 480.4. 1H-NMR (DMSO-d6) 10.99 (1H, s), 8.21 (1H, s), 7.67 (1H, d), 7.54 (1H, m), 7.44 (1H, s), 7.34 (1H, m), 7.11 (2H, m), 6.81 (2H, m), 5.73 (1H, d), 5.36 (2H, s), 5.10 (1H, d), 1.66 (2H, m), 1.13 (9H, s), 0.85 (4H, m).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C1(=O)O[CH2:15][CH2:14][O:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)(Cl)Cl>[CH:7]1[C:8]2[C:3](=[C:2]([O:1][CH2:15][CH2:14][OH:13])[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: O=C1OCCO1
Reactant: Oc1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: OCCOc1cccc2cnccc12
Temperature: 155 °C
Yield: 67.5 %

Procedure:
A mixture of 5-hydroxyisoquinoline (2.05 g, 14.1 mmol), ethylene carbonate (1.43 g, 16.2 mmol), K2CO3 (0.97 g, 7.1 mmol) in DMF (6 mL) was heated at 155° C. for 1.5 h under stirring in a sealed tube. After cooling, the mixture was diluted with CHCl3 and filtered through a pad of Celite. The brownish filtrate was concentrated in vacuo, and the residue was purified by chromatography on silica gel using EtOAc as eluent to give 1.8 g (67%) of the title product as a beige oil which solidified on standing: mp 64-67° C.; HRMS m/z calcd for C11H11NO2 (M)+189.0790, found 189.0789. Anal. (C11H11NO2) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH2:14][C:15]2[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=2)[CH2:9][C:10]([O:12]C)=O)[C:5]([N+:25]([O-])=O)=[C:4]([S:28][CH3:29])[N:3]=1.CO>C(O)(=O)C.C(Cl)Cl.[Fe]>[NH2:1][C:2]1[N:3]=[C:4]([S:28][CH3:29])[C:5]2[NH:25][C:10](=[O:12])[CH2:9][N:8]([CH2:14][C:15]3[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=3)[C:6]=2[N:7]=1
Reactant: COC(=O)CN(Cc1ncc(C)c(OC)c1C)c1nc(N)nc(SC)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1c(C)cnc(CN2CC(=O)Nc3c(SC)nc(N)nc32)c1C
Temperature: 70 °C
Yield: 28.7 %

Procedure:
To a solution of methyl 2-[(2-amino-6-methylsulfanyl-5-nitro-pyrimidin-4-yl)-[(4-methoxy-3,5-dimethyl-pyridin-2-yl)methyl]amino]acetate (Intermediate 26)(212 mg) in glacial acetic acid (5 mL) stirred at 70° C. was added iron powder (120 mg). The reaction mixture was heated at 70° C. for 30 minutes then allowed to cool to room temperature. The reaction mixture was filtered, the filtrate evaporated to dryness and azeotroped with toluene to give a brown gum. This material was stirred with 5% methanol in DCM (10 mL) and then filtered to remove iron residues. The filtrate was purified by flash chromatography on silica eluting with an increasingly polar gradient of methanol/DCM (0/100 to 5/95) to give the title compound (52 mg) as a beige solid. 1H NMR spectrum (400 MHz, DMSO-d6) 2.11 (6H, s), 2.37 (3H, s), 3.66 (3H, s), 3.88 (2H, s), 4.68 (2H, s), 5.80 (2H, s), 8.07 (1H, s), 9.34 (1H, s); Mass spectrum: (M+H)+ 361.44.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[C:5]#[N:6].[CH2:12]([Sn](CC)(CC)CC)[CH3:13].[Cl-].[Li+]>CN(C=O)C>[CH2:12]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[C:5]#[N:6])[CH3:13]
Reactant: CC[Sn](CC)(CC)CC
Reactant: COc1ccc(C#N)cc1Br
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCc1cc(C#N)ccc1OC
Temperature: 135 °C

Procedure:
To a solution of 3-bromo-4-methoxybenzonitrile (8-1, 0.3 g, 1.42 mmol) in DMF (14 mL) was added tetraethyl tin (0.56 mL, 2.83 mmol), bis-tri-t-butylphosphine palladium (0.072 g, 0.141 mmol), and lithium chloride (0.18 g, 4.24 mmol) and the system was heated to 135° C. for 30 minutes in a microwave reactor. The mixture was partitioned between saturated NaHCO3 and EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by gradient elution on silica gel (0 to 10% EtOAc in hexanes) to yield the desired product (8-2) as a clear oil. ESI+ MS [M+H]+ C10H11NO: 162.1 found, 162.2 required.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[Br:10]Br.[OH-].[Na+]>C(O)(=O)C>[NH2:8][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([CH3:1])[C:7]=1[Br:10]
Reactant: BrBr
Reactant: Cc1cc(N)cc(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1cc(N)c(Br)c(C)n1
Temperature: 25 °C
Yield: 39.7 %

Procedure:
A solution of 2,6-dimethylpyridin-4-ylamine (2.00 g, 16.4 mmol) in 5 mL of acetic acid was treated dropwise with a solution of bromine (0.84 mL, 16.3 mmol) in 2 mL of acetic acid at room temperature in a water bath over a period of 10 minutes. After I hour, the resulting slurry was treated with 40 mL of 20% sodium hydroxide solution and extracted with three 100 mL portions of dichloromethane (CH2Cl2). The combined extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid (starting material-desired product-dibromo byproduct (1:3:1)) was dissolved in 100 mL of hot hexanes and hot filtered to remove the insoluble starting material. The filtrate was allowed to cool to room temperature, which gave the title product as fine white needles (1.30 g, 40% yield).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[CH:12]=[CH:13][C:14]([CH:16]([OH:18])[CH3:17])=[CH:15][C:4]=2[N:3]=1>C(Cl)Cl.O=[Mn]=O>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[CH:12]=[CH:13][C:14]([C:16](=[O:18])[CH3:17])=[CH:15][C:4]=2[N:3]=1
Reactant: CC(O)c1ccc2c(c1)nc(N)c1ncccc12
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)nc(N)c1ncccc12

Procedure:
A solution 1-(5-aminobenzo[f][1,7]naphthyridin-8-yl)ethanol (from Example 88) (1.0 eq.) and activated MnO2 (20 eq.) in DCM (0.1 M) was stirred at ambient temperature over night. The reaction mixture was diluted with DCM. The MnO2 was filtered off, and the filtrate was concentrated en vaccuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% MeOH/DCM to give 1-(5-aminobenzo[f][1,7]naphthyridin-8-yl)ethanone as a yellow solid: 1H NMR (acetone-d6): δ 9.11 (dd, 1H), 8.99 (dd, 1H), 8.56 (d, 1H), 8.20 (d, 1H), 7.94-7.88 (m, 2H), 6.90 (br s, 2H), 2.70 (s, 3H). LRMS [M+H]=238.1.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.[C:10]([O:17][CH3:18])(=[O:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13].[H-].[Na+].[NH4+].[OH-]>O1CCOCC1.[Cu]Br.C(Cl)Cl>[CH3:15][O:14][C:12](=[O:13])[CH:11]([C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Br:9])[CH:3]=1)[C:10]([O:17][CH3:18])=[O:16]
Reactant: Clc1cc(Br)cc(Br)c1
Reactant: COC(=O)CC(=O)OC
Agent: [Cu]Br
Agent: [H-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)C(C(=O)OC)c1cc(Cl)cc(Br)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1,3-Dibromo-5-chlorobenzene (25 g, 93 mmol), dimethyl malonate (23.4 mL, 204 mmol), and copper(I) bromide (29.2 g, 204 mmol) were combined in 1,4-dioxane (300 mL) and cooled to 0° C. Sodium hydride (60% in mineral oil; 8.2 g, 204 mmol) was added slowly, and the reaction was stirred at room temperature for 20 minutes, and then stirred at 105° C. for 4 hours. After cooling to room temperature, the mixture was worked-up with CH2Cl2 and aqueous NH4OH. The organic layer was concentrated, and the residue was purified by silica gel chromatography (0-20% EtOAc in hexanes) to give the title compound.
Reaction SMILES: BrN1C(=O)CCC1=O.[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[C:12](/[CH:27]=[CH:28]/OCC)[N:11]=1.O1CCOCC1.[NH2:38][C:39]1[C:44]([CH3:45])=[CH:43][CH:42]=[CH:41][N:40]=1>C(OCC)(=O)C.O>[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:25])[CH3:26])=[C:12]([C:27]2[N:40]3[CH:41]=[CH:42][CH:43]=[C:44]([CH3:45])[C:39]3=[N:38][CH:28]=2)[N:11]=1
Reactant: Cc1cccnc1N
Reactant: CCO/C=C/c1nc(Cl)nc2c1ncn2COCC[Si](C)(C)C
Agent: O=C1CCC(=O)N1Br
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cccn2c(-c3nc(Cl)nc4c3ncn4COCC[Si](C)(C)C)cnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
200 mg of N-bromosuccinimide was added to the mixture of 400 mg of 2-chloro-6-[(E)-2-ethoxyvinyl]-9-{[2-(trimethylsilyl)ethoxy]methyl}-9H-purine [56-2], 10 mL of 1,4-dioxane, and 2 mL of water under an ice-cold condition, and stirred at the same temperature for 30 minutes. Thereto, 122 mg of 2-amino-3-picoline was added, stirred at 50° C. for 1 hour, and the reaction mixture was cooled back to room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine in the subsequent order, and the thus obtained organic layer was dried over anhydrous magnesium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to obtain 360 mg of 2-chloro-6-(8-methylimidazo[1,2-a]pyridin-3-yl)-9-{[2-(trimethylsilyl)ethoxy]methyl}-9H-purine [56-3] as a light brown solid.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH3:24][O:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:28][CH2:27]1>CN(C=O)C>[CH3:24][O:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([NH:37]/[C:4](=[C:11]3\[C:12](=[O:23])[NH:13][C:14]4[C:15]\3=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=4)/[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:38][CH:39]=2)[CH2:28][CH2:27]1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: COC1CCN(Cc2ccc(N)cc2)CC1
Solvent: CN(C)C=O
Product: COC1CCN(Cc2ccc(N/C(=C3\C(=O)Nc4ccc([N+](=O)[O-])cc43)c3ccccc3)cc2)CC1

Procedure:
Prepared analogously to Example 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(4-methoxypiperidinomethyl)-aniline in DMF.
Reaction SMILES: [C:1]([NH2:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:12][CH2:13][C:14]([CH2:16]Cl)=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:12][CH2:13][C:14]1[N:11]=[C:1](/[CH:2]=[CH:3]/[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:10][CH:16]=1
Reactant: NC(=O)C=Cc1ccccc1
Reactant: O=C(CCl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: ClCc1coc(/C=C/c2ccccc2)n1
Temperature: 130 °C
Yield: 46.7 %

Procedure:
A mixture of cinnamamide (25.3 g) and 1,3-dichloroacetone (20.9 g) was heated for one hour at 130° C. The reaction mixture was poured into water, which was neutralized with potassium carbonate, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The concentrate was purified by column chromatography on silica gel. From the fraction eluted with ether-hexane (1:5, v/v), was obtained 4-chloromethyl-2-[(E)-styryl] oxazole (16.9 g, 47%), which was recrystallized from ether-hexane to yield colorless needless, m.p.72-73° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][CH:35]1[CH2:40][CH2:39][O:38][C:37]([CH3:42])([CH3:41])[CH2:36]1>CN(C=O)C>[CH3:41][C:37]1([CH3:42])[CH2:36][CH:35]([CH2:34][CH2:33][N:20]2[C:19]([O:23][CH3:24])=[N:18][C:17]3[C:21]2=[N:22][C:14]([O:13][C@H:9]([CH3:8])[CH2:10][CH2:11][CH3:12])=[N:15][C:16]=3[NH2:25])[CH2:40][CH2:39][O:38]1
Reactant: CCC[C@@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: CC1(C)CC(CCBr)CCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCOC(C)(C)C3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.8 %

Procedure:
2-{[(1R)-1-Methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate (100 mg, 0.274 mmol) was heated with potassium carbonate (37.8 mg, 0.274 mmol) in dry DMF (2 ml) at 60° C. under nitrogen for 1 hour and then cooled to room temperature. 4-(2-Bromoethyl)-2,2-dimethyltetrahydro-2H-pyran (72.6 mg, 0.328 mmol) was added and the reaction mixture heated at 50° C., for 16 hours. LCMS indicated the reaction to be incomplete and more 4-(2-bromoethyl)-2,2-dimethyltetrahydro-2H-pyran (35 mg) was added, and the reaction stirred at 50° C. for a further 5 hours and then partitioned between water (2 ml) and DCM (5 ml). The aqueous layer was further extracted with DCM (2×5 ml). The combined organic layers were combined and dried by passing through a hydrophobic frit and then evaporated to dryness using a nitrogen blowdown unit. The residue was dissolved in methanol (0.6 ml) and purified by mass directed autopreparation. Evaporation of the product containing fractions under a stream of nitrogen in a blowdown apparatus gave the title compound as a white solid (92 mg).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:13]=[C:12]([O:14][CH2:15][C:16](=[O:18])[NH2:17])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.[OH-].[Na+]>CO>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:12]([O:14][CH2:15][C:16](=[O:18])[NH2:17])[CH:13]=[C:4]([C:3]([OH:19])=[O:2])[CH:5]=1
Reactant: COC(=O)c1cc(OCC(N)=O)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1cc(OCC(N)=O)cc(C(=O)O)c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Next, to a solution of 5-carbamoylmethoxyisophthalic acid dimethyl ester (371 mg, 1.39 mmol) in MeOH (10 mL) is added aqueous 1M NaOH (1.39 mL, 1.39 mmol) and the mixture is stirred at 50° C. for 18 hours. The solvent is removed under reduced pressure and water is added to the residue. The aqueous solution is acidified with aqueous 1M HCl and the resulting precipitate is filtered, washed with water and dried under reduced pressure to give 5-carbamoylmethoxyisophthalic acid monomethyl ester. MS 254.3 (M+1); 1H-NMR (400 MHz, DMSO-d6); δ ppm 3.89 (s, 3H), 4.59 (s, 2H), 7.43 (s, 1H), 7.70 (m 3H), 8.10 (s, 1), 13.38 (s, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].Br[C:9]1[O:13][C:12]2[C:14]([O:20]C(=O)C)=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=2[C:10]=1[C:24](=[O:37])[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=1>O1CCCC1.C1(C)C=CC=CC=1>[N:1]1([C:9]2[O:13][C:12]3[C:14]([OH:20])=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:24](=[O:37])[C:25]2[CH:26]=[C:27]([O:35][CH3:36])[C:28]([O:33][CH3:34])=[C:29]([O:31][CH3:32])[CH:30]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2c(-n3cncn3)oc3c(O)c(OC)ccc23)cc(OC)c1OC

Procedure:
To a solution of 1,2,4-triazole (22 mg, 0.32 mmol) in dry tetrahydrofuran (2 mL) was added sodium hydride (60%, 24 mg, 0.60 mmol) and resulting suspension was treated with a solution of 2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzo[b]furan (50 mg, 0.10 mmol) in dry toluene (2 mL). The mixture was stirred at reflux for 6 hours (tlc), quenched with saturated ammonium chloride solution, extracted with dichloromethane (10 mL), dried over magnesium sulphate and the solvent distilled under vacuum. The crude residue was purified by PTLC (eluent=ethyl acetate: 1% triethylamine) to give the title compound as a yellow solid; (22 mg, 50%); 1H NMR (300 MHz, CDCl3) δ 8.64 (bs, 1H), 8.06 (bs, 1H), 7.10 (d, 1H, J=8.60 Hz), 7.05 (s, 2H, benzoyl Hs), 6.98 (d, 1H, J=8.65 Hz), 3.98 (s, 3H, OMe), 3.89 (s, 3H, OMe), 3.77 (s, 6H, 2×OMe).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[N:18][C:19]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5OC)=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Br-].C([Zn+])C1C=CC=CC=1.O1C2C=CC(C3(C(NC4C=NC(Br)=CC=4)=O)CC3)=CC=2OC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[N:18][C:19]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[CH:20][CH:21]=4)=[O:14])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccccc1Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cn1
Agent: O=C(Nc1ccc(Br)nc1)C1(c2ccc3c(c2)OCO3)CC1
Agent: [Br-]
Agent: [Zn+]Cc1ccccc1
Product: O=C(Nc1ccc(Cc2ccccc2)nc1)C1(c2ccc3c(c2)OCO3)CC1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-benzylpyridin-3-yl)cyclopropanecarboxamide was synthesized using the procedure of 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-(2-methoxybenzyl)pyridin-3-yl)cyclopropanecarboxamide using benzylzinc(II) bromide and 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-bromopyridin-3-yl)cyclopropanecarboxamide.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][C:10]2[N:9]=[C:8](SC)[C:7]([C:14]#[N:15])=[CH:6][C:5]=2[C:4](=[O:16])[CH2:3]1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C>[CH3:1][C:2]1([CH3:17])[CH2:11][C:10]2[N:9]=[C:8]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:7]([C:14]#[N:15])=[CH:6][C:5]=2[C:4](=[O:16])[CH2:3]1
Reactant: C1CCNCC1
Reactant: CSc1nc2c(cc1C#N)C(=O)CC(C)(C)C2
Solvent: CCO
Product: CC1(C)CC(=O)c2cc(C#N)c(N3CCCCC3)nc2C1
Yield: 28.2 %

Procedure:
A solution of 7,7-dimethyl-2-methylsulfanyl-5-oxo-5,6,7,8-tetrahydro-quinoline-3-carbonitrile (0.25 g, 1 mmol) and piperidine (0.32 ml, 4 mmol) in dry ethanol (3 ml) was stirred at reflux for 36 h. The reaction mixture was then evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (chloroform-methanol, 50:1) to give the title compound (0.08 g, 28%) as a colorless solid.