Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([OH:37])[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CCO[C:47]([CH3:49])=O.[CH3:50][N:51](C=O)[CH3:52]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:37][CH2:49][CH2:47][N:51]([CH3:52])[CH3:50])[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CCOC(C)=O
Reactant: CC(C)c1cc(C(=O)N2Cc3ccc(O)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)c1cc(C(=O)N2Cc3ccc(OCCN(C)C)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 90 °C

Procedure:
A mixture of (2,4-bis-benzyloxy-5-isopropyl-phenyl)-(5-hydroxy-1,3-dihydro-isoindol-2-yl)-methanone (100 mg, 0.2 mmol), 2-dimethylaminoethylchloride. HCl (72 mg, 0.5 mol) and K2CO3 (173 mg, 1.25 mmol) in DMF (5 ml) was heated at 90° C. for 16 hours. Dilute reaction mixture with EtOAc and filtered. The reaction mixture was diluted with EtOAc and filtered. The filtrate was reduced in vacuo and purified by flash column chromatography, eluting 100% DCM then 90% DMAW 90 to give the title compound as an off white gel (79 mg). MS: [M+H]+ 565
Reaction SMILES: [C:1]1([C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([OH:23])=[CH:15][CH:14]=2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>CC(C)=O>[C:1]1([C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:15][CH:14]=2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1cccc2ccccc12)c1ccc(O)c2ccccc12
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCOc1ccc(C(=O)c2cccc3ccccc23)c2ccccc12
Reaction time: 0.03 h

Procedure:
11.0 g of naphthalen-1-yl-(4-hydroxy-naphthalen-1-yl)-methanone and 6.1 g of potassium carbonate in 130 ml of acetone are stirred for 15 min at reflux. Then, within 2 min, a solution of 6.8 ml 1-bromopentane in 20 ml of acetone is added and the suspension is stirred for additional 22 h at reflux. Conventional workup and subsequent chromatography affords naphthalen-1-yl-(4-pentyloxy-naphthalen-1-yl)-methanone.
Reaction SMILES: [C:1]([C:5]1[O:9][NH:8][N:7]([C:10]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](Cl)=[O:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]1[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:22]=1[NH2:23].C(N(CC)CC)C.O>O1CCCC1>[C:1]([C:5]1[O:9][NH:8][N:7]([C:10]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:23][C:22]2[CH:24]=[CH:25][C:26]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:27][C:21]=2[CH3:20])=[O:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(OC(F)(F)F)ccc1N
Reactant: CC(C)(C)C1=CN(c2c(Cl)cccc2C(=O)Cl)NO1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(OC(F)(F)F)ccc1NC(=O)c1cccc(Cl)c1N1C=C(C(C)(C)C)ON1
Reaction time: 1 h
Yield: 29 %

Procedure:
0.5 Gram of 2-(5-t-butyloxadiazol-3-yl)-3-chlorobenzoyl chloride was dissolved in 30 ml of tetrahydrofuran, and 0.3 g of 2-methyl-4-trifluoromethoxyaniline and 0.2 g of triethylamine were added thereto, the reaction was carried out for 1 hour under stirring. After completion of the reaction, the reaction mixture was poured into water, after extraction of the objective product with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure, the residue thus obtained was purified by a silica gel column chromatography to obtain 0.22 g (yield: 29%) of the objective product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](N)=[O:7])#[N:2].N([N+]([O-])=O)=[O:13].CC1OC(OC2C(O)CC(OC3C(O)CC(OC4CC5CCC6C7(O)CC(OC(C)=O)C(C8COC(=O)C=8)C7(C)CCC6C5(C)CC4)OC3C)OC2C)CC(O)C1O>S(=O)(=O)(O)O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:13])=[O:7])#[N:2]
Reactant: N#Cc1cccc(C(N)=O)c1
Reactant: O=N[N+](=O)[O-]
Agent: CC(=O)OC1CC2(O)C3CCC4CC(OC5CC(O)C(OC6CC(O)C(OC7CC(O)C(O)C(C)O7)C(C)O6)C(C)O5)CCC4(C)C3CCC2(C)C1C1=CC(=O)OC1
Agent: O=S(=O)(O)O
Product: N#Cc1cccc(C(=O)O)c1
Yield: 92 %

Procedure:
m-Cyanobenzamide (2.92 g) was added to a 70 wt. % aqueous sulfuric acid solution (100 ml), and the mixture was stirred under cooling with ice. The mixture was allowed to react while dinitrogen trioxide gas was introduced thereto at 336 N ml/hour for two hours. The precipitated crystals were collected through filtration, washed with water, and dried, to thereby obtain 2.68 g of m-cyanobenzoic acid (yield 92%, based on m-cyanobenzamide). The m-cyanobenzoic acid obtained had a purity of 99% or more.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][O:11][C:10](=[O:13])[NH:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[Br:16][C:17]1[CH:18]=[N:19][N:20]2[CH:25]=[CH:24][C:23](Cl)=[N:22][C:21]=12.O>CN(C=O)C>[Br:16][C:17]1[CH:18]=[N:19][N:20]2[CH:25]=[CH:24][C:23]([N:9]3[C@@H:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:12][O:11][C:10]3=[O:13])=[N:22][C:21]=12
Reactant: Clc1ccn2ncc(Br)c2n1
Reactant: O=C1N[C@@H](c2ccc(F)cc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1OC[C@H](c2ccc(F)cc2)N1c1ccn2ncc(Br)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
To a solution of (S)-4-(4-fluorophenyl)oxazolidin-2-one (0.43 g, 2.4 mmol) in DMF (10 mL) was added sodium hydride (0.095 g, 2.4 mmol) and the reaction stirred at ambient temperature for 30 minutes. 3-Bromo-5-chloropyrazolo[1,5-a]pyrimidine (0.50 g, 2.2 mmol) was added and the reaction was stirred for 2 hours at ambient temperature. The reaction mixture was poured into water (100 mL) and extracted into ether (2×100 mL). The organic layer was washed with brine (2×20 mL), dried over MgSO4 and concentrated under vacuum. The crude material was purified by silica gel chromatography, eluting with 2% EtOAc/DCM to yield (S)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-4-(4-fluorophenyl)oxazolidin-2-one (0.35 g, 43%).
Reaction SMILES: [CH2:1]([C:5]1([CH:9]([OH:12])C#C)[CH2:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].N1C=CN=C1.[Si](Cl)(C(C)(C)C)(C)C.CN(C=[O:30])C>>[CH2:1]([C:5]1([C:9]([OH:12])=[O:30])[CH2:6][CH2:7][CH2:8]1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)C=O
Reactant: C#CC(O)C1(CCCC)CCC1
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: CCCCC1(C(=O)O)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To 6.26 g (37.6 mmol) of crude 1-(1-butylcyclobutyl)prop-2-yn-1-ol in DMF (20 mL) were added imidazole (3.1 g, 45.2 mmol) and tert-butyldimethylsilyl chloride (6.8 g, 45.2 mmol). The reaction mixture was stirred at RT overnight, then concentrated to remove DMF, diluted with 100 ml of EtOAc, and added 100 mL of sat. aq. NH4Cl. After separation, the aq. phase was extracted with EtOAc (2×100 mL). The combined organic phase was washed with 50 mL of brine, dried (Na2SO4), concentrated. Flash chromatography over silica gel of the crude product (eluted with hexanes) afforded the title intermediate (6.82 g, 58% 3 steps) as colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[CH3:1][N:2]1[CH:6]=[C:5]([N+:12]([O-:14])=[O:13])[N:4]=[C:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1nccn1C
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1nc([N+](=O)[O-])cn1C
Temperature: 0 °C

Procedure:
Ethyl 1-methylimidazole-2-carboxylate was carefully dissolved in 1000 mL of concentrated sulfuric acid cooled to 0° C. 90% nitric acid (1 L) was slowly added maintaining a temperature of 0° C. The reaction was then refluxed with an efficient condenser (−20° C.) in a well ventilated hood for 50 min. The reaction was cooled with an ice bath, and quenched by pouring onto 10 L ice. The resulting blue solution was then extracted with 20 L DCM, the combined extracts dried (sodium sulfate) and concentrated in vacuo to yield a tan solid which was recrystallized from 22 L of 21:1 carbon tetrachloride/ethanol. The resulting white crystals are collected by vacuum filtration.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[CH3:7])=[O:5].[H-].[Na+].[C:18]([N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[C:18]([N:26]1[CH2:31][CH2:30][C:29](=[C:6]([CH3:7])[C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH2:28][CH2:27]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=C1CCN(C(=O)c2ccccc2)CC1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
A solution of triethyl 2-phosphonopropionate (50.0 g) in dry tetrahydrofuran (75 ml) was added dropwise to a stirred suspension of sodium hydride (60% in mineral oil, 8.0 g) in dry tetrahydrofuran (275 ml) under nitrogen and stirred at 20° C. for 10 minutes until a clear solution was formed. 1-Benzoyl-4-piperidone (34.5 g) in dry tetrahydrofuran (75 ml) was added dropwise to the clear solution and the reaction mixture heated under reflux for 16 hours. After quenching the reaction mixture with 5M hydrochloric acid (20 ml), the resulting solid was removed by filtration. Excess ether was added to the filtrate, the aqueous layer separated off and the ethereal layer washed (water), dried, filtered and concentrated to give ethyl 2-(1-benzoyl-4-piperidylidene)propionate as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]([F:26])([F:25])[C:14]([N:16]([F:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:8][CH2:7]2)([O-])=O>C1COCC1.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]([F:26])([F:25])[C:14]([N:16]([F:24])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])[CH2:8][CH2:7]2
Reactant: O=C(N(F)Cc1ccccc1)C(F)(F)C1CCc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc2c(c1)CCC2C(F)(F)C(=O)N(F)Cc1ccccc1
Reaction time: 1 h

Procedure:
To a stirred solution of 2-(5-nitroindanyl)-N-(phenylmethyl)trifluoroacetamide (1.17g, 3.21 mmol) in THF/MeOH (100 ml, 1:1) was added a catalytic amount of 10% Pd/C. The mixture was hydrogenated at 50 psi for 1 hr, filtered through celite, and concentrated to give 2-(5-aminoindanyl)-N-(phenylmethyl)trifluoroacetamide which was homogeneous by TLC and used immediately in step (f).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:22][CH2:21][C@@:12]34[C:13]5[CH:14]=[C:15]([OH:20])[CH:16]=[CH:17][C:18]=5[CH2:19][C@@H:6]2[C@:7]3([OH:23])[CH2:8][CH2:9][O:10][CH2:11]4)[CH2:3][CH2:2]1.[C:24](Cl)(=[O:26])[CH3:25].N1C=CC=CC=1>C(Cl)Cl>[C:24]([O:20][C:15]1[CH:16]=[CH:17][C:18]2[CH2:19][C@H:6]3[N:5]([CH2:4][CH:1]4[CH2:2][CH2:3]4)[CH2:22][CH2:21][C@@:12]4([C:13]=2[CH:14]=1)[C@@:7]3([OH:23])[CH2:8][CH2:9][O:10][CH2:11]4)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: Oc1ccc2c(c1)[C@]13CCN(CC4CC4)[C@H](C2)[C@]1(O)CCOC3
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(c1)[C@]13CCN(CC4CC4)[C@H](C2)[C@]1(O)CCOC3

Procedure:
Equimolar quantities of 17-cyclopropylmethyl-3,14β-dihydroxy-6-oxamorphinan (XVI), acetyl chloride and pyridine are mixed together in dry methylene chloride and the resultant mixture is heated at reflux for several hours to produce the title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[C:14]1[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=1.[Br:20]N1C(=O)CCC1=O>CN(C=O)C>[Br:20][C:15]1[CH:16]=[N:17][N:18]([CH3:19])[C:14]=1[C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][Br:1]
Reactant: Cn1nccc1-c1cc([N+](=O)[O-])ccc1OCCBr
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Cn1ncc(Br)c1-c1cc([N+](=O)[O-])ccc1OCCBr
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 80.9 %

Procedure:
A mixture of 5-[2-(2-bromo-ethoxy)-5-nitro-phenyl]-1-methyl-1H-pyrazole (200 mg, 0.61 mmole), and N-bromosuccinimide (0.61 mmole, 1.0 eq) in 2 mL of DMF was stirred at 100° C. for 10 minutes in the Microwave. The mixture was quenched with water, extract with ethyl acetate, and dried in vacuo give the title compound as a yellow solid (200 mg, 81%). 1H NMR (400 MHz, CDCl3) δ3.53-3.64 (m, 2H), 3.78 (s, 3H), 4.38-4.49 (m, 2H), 7.11 (d, 1H), 7.57 (s, 1H), 8.23 (s, 1H), 8.39 (d, 1H). Exact mass calculated for C12H11Br2N3O3 402.9. found 406.1 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=1[CH3:18])([O-])=O.CO.[H][H]>[Pt].ClCCl>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=1[CH3:18]
Reactant: [H][H]
Reactant: Cc1cc(Br)ccc1Nc1ccccc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(Br)ccc1Nc1ccccc1N

Procedure:
A suspension of 5.34 g (17.4 mmol) of N-(2-nitrophenyl)-4-bromo-2-methyl-aniline and 1.7 g of platinum on charcoal is stirred in 100 ml of dichloromethane and 100 ml of methanol at a hydrogen pressure of 3 bar for 1 hour. Then the catalyst is filtered off and the filtrate is evaporated down.
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][NH:9][CH2:10][CH2:11][C@@H:12]([CH3:24])[O:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:31][C:32]([F:42])([F:41])[C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=O.COC(=O)C.[Cl:48]C1C(C(F)(F)F)=CC=CC=1C=O.Cl.CCOCC>CCOCC>[ClH:48].[F:31][C:32]([F:41])([F:42])[C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36][N:9]([CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:10][CH2:11][C@@H:12]([CH3:24])[O:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Reactant: C[C@H](CCNCC(c1ccccc1)c1ccccc1)Oc1cccc(CC(=O)O)c1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCOCC
Solvent: COC(C)=O
Product: C[C@H](CCN(Cc1cccc(C(F)(F)F)c1)CC(c1ccccc1)c1ccccc1)Oc1cccc(CC(=O)O)c1

Procedure:
Following the procedure of Example 7(d) except (R)-2-(3-{3-[(2,2-diphenylethyl)amino]-1-methyl-propoxy}-phenyl)acetic acid and 3-trifluoromethylbenzaldehyde were used instead of (R)-2-(3(3-(2,2-diphenylethyl)amino]-3-methyl-propoxy}-phenyl)acetic acid methyl ester and 2-chloro-3-trifluoromethylbenzaldehyde in step (d) the corresponding carboxylic acid was obtained. The crude product was purified by preparative HPLC (TMC CombiPrep PDS, 75×30 mm, 25 mL/min, acetonitrile: H2O, UV detection at 254 nm) to afford the free base. The resulting amine/carboxylic acid was dissolved in Et2O (diethylether) and acidified with 1.0 M HCl/Et2O. The reaction mixture was concentrated in vacuo and dried under reduced pressure to give the title compound as a white solid, 75 mg (72%). MS (ESI) 562.2 (M+H+).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][O:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.[OH-].[Na+].O>CO.O1CCOCC1>[NH2:26][C:8]1[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][O:20][CH2:19]1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CCCC3CCCOC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: CCCCNc1nc(N)c2[nH]c(=O)n(CCCC3CCCOC3)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.3 %

Procedure:
To a solution of N2-butyl-8-(methoxy)-9-[3-(tetrahydro-2H-pyran-3-yl)propyl]-9H-purine-2,6-diamine (198 mg) in dry methanol (20.8 ml) was added 4.0M hydrochloric acid in 1,4-dioxane (3.6 ml) in one go. The reaction was left to stir at room temperature for 4 hours. The reaction was neutralised by the addition of 2.0M sodium hydroxide solution and concentrated in vacuo. to give an off-white solid. To this solid was added water, triturated, and the solid filtered under vacuum until dry. This afforded the title compound as an off-white solid (151 mg).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[CH:22][CH:21]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[C:16][CH2:17][O:18][CH3:19])[CH:10]=2)[N:3]=1>C(O)C.N1C2C(=CC=CC=2)C=CC=1.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH:27]([F:29])[F:28])=[CH:24][CH:25]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[C:11](/[CH:15]=[CH:16]\[CH2:17][O:18][CH3:19])[CH:10]=2)[N:3]=1
Reactant: COCC#Cc1cccc(C2(c3ccc(OC(F)F)cc3)N=C(N)N(C)C2=O)c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Solvent: c1ccc2ncccc2c1
Product: COC/C=C\c1cccc(C2(c3ccc(OC(F)F)cc3)N=C(N)N(C)C2=O)c1
Reaction time: 16 h
Yield: 50 %

Procedure:
A mixture of a solution of 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-methoxyprop-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one (0.1 g, 0.25 mmol) in ethanol (1.5 mL), quinoline (1 drop) and Lindlar catalyst (24 mg. 10% mol) was placed under a hydrogen filled balloon, stirred for 16 hr filtered through celite. The filtrate was concentrated in vacuo. The resultant residue was purified by flash chromatography on silica ge,l ethyl acetate as eluent, to afford the title compound as a white solid, 0.05 g (50% yield), mp 41-44° C.; 1H NMR (DMSO-d6) δ 2.95 (s, 3H); 3.2 (s, 3H); 4.0 (d, 2H); 5.7 (q, 1H) 6.5 (d, 1H); 6.6 (b, 2H); 7.1 (m, 3H); 7.3 (m, 4H); 7.4 (d, 2H); MS [(+)ESI] m/z=402 [M−H]+.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[C:7]([O:14][CH3:15])(=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10].Cl[C:17]1[CH:18]=[C:19]([N:26]([C:31]2[C:50]([CH:51]3[CH2:53][CH2:52]3)=[CH:49][C:34]3[C:35]([C:45]([NH:47][CH3:48])=[O:46])=[C:36]([C:38]4[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=4)[O:37][C:33]=3[CH:32]=2)[S:27]([CH3:30])(=[O:29])=[O:28])[CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24]>CN(C=O)C.O>[CH:51]1([C:50]2[C:31]([N:26]([C:19]3[CH:20]=[CH:21][C:22]([N+:23]([O-:25])=[O:24])=[C:17]([CH:8]([C:7]([O:14][CH3:15])=[O:13])[C:9]([O:11][CH3:12])=[O:10])[CH:18]=3)[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:32][C:33]3[O:37][C:36]([C:38]4[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=4)=[C:35]([C:45](=[O:46])[NH:47][CH3:48])[C:34]=3[CH:49]=2)[CH2:53][CH2:52]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: COC(=O)CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C(C(=O)OC)C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 68 %

Procedure:
To a stirred suspension of Cs2CO3 (17.5 g, 53.8 mmol) in DMF (20 ml) under a nitrogen atmosphere was added dimethyl malonate (2.57 mL, 22.4 mmol) at room temperature. This was followed by the addition of a sonicated solution of 6-(N-(3-chloro-4-nitrophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (10.0 g, 17.9 mmol) in DMF (50 mL) at room temperature by dropwise addition. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with water and extracted with EtOAc (3×40 mL). The organic layer was washed with water (3×50 mL), dried over sodium sulfate and evaporated to dryness. The crude product triturated with ether and the solid collected by filtration to afford the title compound in 68% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.51 (d, J=4.7 Hz, 1H), 8.19 (d, J=9.2 Hz, 1H), 8.04 (s, 1H), 7.90-8.00 (m, 2H), 7.36-7.51 (m, 3H), 7.26-7.31 (m, 1H), 7.14-7.20 (m, 1H), 5.45-5.56 (m, 1H), 3.52-3.64 (m, 9H), 2.84 (d, J=4.5 Hz, 3H), 1.88-2.03 (m, 1H), 0.82-1.00 (m, 2H), 0.69 (d, J=3.1 Hz, 1H), 0.29-0.50 (m, 1H). LCMS (m/z, ES+)=654 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[O:11][C:10]2[CH:9]=[CH:8][N:7]=[C:6]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:5]=2[CH:4]=1)=O.[C:21](/[CH:23]=[C:24](\[O-:26])/[CH3:25])#[N:22].[Na+].C(O)(=O)C.N1CCCCC1.C(=O)(O)[O-].[Na+]>ClCCl>[C:21]([C:23]([C:24](=[O:26])[CH3:25])=[CH:1][C:3]1[O:11][C:10]2[CH:9]=[CH:8][N:7]=[C:6]([NH:12][C:13](=[O:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:5]=2[CH:4]=1)#[N:22]
Reactant: C/C([O-])=C/C#N
Reactant: O=Cc1cc2c(NC(=O)c3ccccc3)nccc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(=O)C(C#N)=Cc1cc2c(NC(=O)c3ccccc3)nccc2o1
Yield: 80.4 %

Procedure:
A mixture of 1.50 g (5.63 mmol) N-(2-formylfuro[3,2-c]pyridin-4-yl)benzamide (Example 3A), 0.65 g (6.2 mmol) sodium (1Z)-1-cyanoprop-1-en-2-olate, 0.4 ml (7.04 mmol) acetic acid and 56 μl (0.56 mmol) piperidine in dry dichloromethane (35 ml) containing 4 Å molecular sieve was stirred under reflux for 1 h. After cooling, 50 ml aq. sodium bicarbonate solution were added, and the mixture was stirred for 1 h at rt. The molecular sieve was filtered off, and the filtrate was concentrated under reduced pressure. The residue was treated with ethyl acetate and saturated aq. sodium carbonate solution. The organic layer was separated, washed with water, dried, and concentrated under reduced pressure to afford the title compound (1.5 g, 80% of th.) as a pale yellow solid which was used in the next step without further purification.
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]([CH3:18])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH:16]([NH:10][C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:18])[CH3:15]
Reactant: Nc1ccccc1Oc1ccccc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)Nc1ccccc1Oc1ccccc1
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
To a solution of 2-phenoxyaniline (0.93 g, 5.0 mmol) in dichloroethane (50 ml) was added anhydrous acetone (0.73 ml, 10.0 mmol) and acetic acid (0.1 ml, 2.0 mmol). The mixture was stirred for 30 min, and sodium triacetoxyborohydride (3.18 g, 15.0 mmol) was added in one portion. The reaction mixture was stirred overnight at ambient temperature. The reaction mixture was quenched by slow addition of MeOH (10 ml) and concentrated under reduced pressure. The residue was poured into water (50 ml) and extracted with ethyl acetate (3×100 ml). Organic extracts were combined and washed with brine (2×100 ml) and dried (Na2SO4), concentrated under reduced pressure to give N-isopropyl-2-phenoxyaniline (1.05 g, 91%) as colorless oil.