Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)=[O:9].O>CN(C)C=O>[N:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)=[O:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(CCl)c1ccc(CCc2ccccc2)cc1
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cn1ccnc1)c1ccc(CCc2ccccc2)cc1
Yield: 77.4 %

Procedure:
To a solution containing 3.4 g of imidazole in 5 ml of dimethylformamide, stirred at 0/+5° C., 2.58 g of 4-chloroacetyl-bibenzyl were slowly added. The reaction mixture was stirred for few minutes, then allowed to stand and then poured into water. The product thus formed was filtered off, purified by silica gel column chromatography (eluant: benzene/acetone) and then crystallized from ethyl acetate to give 2.24 g of the title compound melting at 134°-6° C. Yield 77%.
Reaction SMILES: [F:1][CH:2]([F:21])[CH2:3][NH:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=1[O:19][CH3:20].[F:22][C:23]([F:38])([F:37])[C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[N:32]=1)[C:27](O)=[O:28]>>[F:21][CH:2]([F:1])[CH2:3][N:4]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=1[O:19][CH3:20])[C:27](=[O:28])[C:26]1[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[N:32]=[C:24]([C:23]([F:38])([F:22])[F:37])[CH:25]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: COc1cc(F)c(F)cc1-c1ccncc1NCC(F)F
Product: COc1cc(F)c(F)cc1-c1ccncc1N(CC(F)F)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from (2,2-difluoro-ethyl)-[4-(4,5-difluoro-2-methoxy-phenyl)-pyridin-3-yl]-amine and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 66 hours. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Light brown solid (66%). MS (ESI): m/z=542.09 [M+H]+.
Reaction SMILES: [C:1]([C@@H:6]([NH:10][C@H:11]([C:13]([OH:15])=[O:14])[CH3:12])[CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2].F[P-](F)(F)(F)(F)F.[N:23]1(OC(N(C)C)=[N+](C)C)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2N=N1>C(#N)C.[Cl-].[Na+].O>[CH2:4]([O:3][C:1]([C@@H:6]([NH:10][C@@H:11]([CH3:12])[C:13]([O:15][C:1]([CH:6]1[CH2:7][CH:26]2[CH:27]([CH2:28][CH2:29][CH2:30][CH2:31]2)[NH:23]1)=[O:2])=[O:14])[CH2:7][CH2:8][CH3:9])=[O:2])[CH3:5]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCC[C@H](N[C@@H](C)C(=O)OC(=O)C1CC2CCCCC2N1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 9.54 g of (2S,3aS,7aS)-2-carboxyperhydroindole benzyl ester, 7.26 g of N-((S)-1-carbetoxybutyl)-(S)-alanine and 12.7 g of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate in 225 ml of acetonitrile is stirred at room temperature for 30 min, then 560 ml of brine is added. The product is extracted twice with 400 ml of ethyl acetate, combined extracts are washed first with 800 ml of water, acidified with concentrated hydrochloric acid and then with 1.5 l of water. Organic phase is dried over anhydrous sodium sulphate and evaporated at 40° C. in vacuo to yield 13.5 g (88%) of benzyl (2S,3aS,7aS)-((2-(1-(ethoxycarbonyl)-(S)-butylamino)-(S)-propionyl)octahydroindole-2-carboxylate (benzyl ester of perindopril).
Reaction SMILES: [CH2:1]([N:8]=[N+:9]=[N-:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][C:12]([OH:16])([C:14]#[CH:15])[CH3:13]>C[C-]1C(C)=C(C)C(C)=C1C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru+].C1C=CC=CC=1>[CH2:1]([N:8]1[C:14]([C:12]([OH:16])([CH3:13])[CH3:11])=[CH:15][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#CC(C)(C)O
Agent: Cl[Ru+]
Agent: Cc1c(C)c(C)[c-](C)c1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)(O)c1cnnn1Cc1ccccc1

Procedure:
Benzyl azide (0.400 g, 3.00 mmol), 2-methyl-3-butyn-2-ol (0.290 ml, 3.00 mmol), Cp*RuCl(PPh3)2 (25 mg, 0.031 mmol). Solvent, benzene; reaction temperature, 80° C.; reaction time, 2.5 hours; yield, 0.63 g (96%). EI-MS: m/z 218 [M+1 ].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[CH2:26][C:25](=[N:28][OH:29])[CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.Br[CH2:31][CH2:32][CH2:33][CH2:34][N:35]([CH2:42][CH2:43][S:44]([CH3:47])(=[O:46])=[O:45])[C:36](=[O:41])[C:37]([F:40])([F:39])[F:38].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[CH2:26][C:25](=[N:28][O:29][CH2:31][CH2:32][CH2:33][CH2:34][N:35]([CH2:42][CH2:43][S:44]([CH3:47])(=[O:45])=[O:46])[C:36](=[O:41])[C:37]([F:39])([F:38])[F:40])[CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CS(=O)(=O)CCN(CCCCBr)C(=O)C(F)(F)F
Reactant: ON=C1C=Cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)CCN(CCCCON=C1C=Cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2C1)C(=O)C(F)(F)F
Temperature: 60 °C
Reaction time: 1.3 h
Yield: 29.9 %

Procedure:
In N,N-dimethylacetamide (1.5 ml) were dissolved 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(hydroxyimino)quinazoline (V-2, 84 mg) and N-(4-bromobutyl)-N-(2-methanesulfonylethyl)-2,2,2-trifluoroacetamide (71 mg), and potassium carbonate (41 mg) was added, followed by stirring at 60° C. for 1.3 hours with heating. Thereafter, the reaction mixture was poured into 0.5 M citric acid, followed by extraction with ethyl acetate. The organic layer was washed with water and aqueous sodium chloride solution, and dried over magnesium sulfate. The crude product was purified by silica gel chromatography (eluting with hexane:ethyl acetate=1:4) to obtain 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(4-(N-(2-(methanesulfonyl)ethyl)-2,2,2-trifluoroacetamido)butyloxyimino)quinazoline (V-14, 41 mg) as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:15]([OH:17])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:18][C:19](=[CH2:21])[CH3:20]>C1COCC1.S(=O)(=O)(O)O>[C:19]([O:16][C:15]([C:10]1([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:17])([CH3:21])([CH3:20])[CH3:18]
Reactant: C=C(C)C
Reactant: O=C(O)C1(c2ccc([N+](=O)[O-])cc2)CCCC1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(c2ccc([N+](=O)[O-])cc2)CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 1-(4-nitro-phenyl)-cyclopentanecarboxylic acid (as prepared in the previous step) in THF at −78° C. in a pressure bottle is treated with 2 drops of concentrated sulfuric acid, and isobutylene gas is condensed into the mixture. The mixture is stirred 24 h at RT, cooled to −78° C. and quenched with satd aq NaHCO3. The mixture is warmed to RT and extracted with EtOAc. The organic layer is dried (MgSO4) and concentrated in vacuo. The residue is purified by silica gel chromatography with an appropriate solvent to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[CH3:15][C:16]1[CH:25]=[CH:24][C:19]([C:20](=[O:23])[CH2:21]Cl)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:3]1[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]=2[CH:13]=[CH:14][C:2]=1[O:1][CH2:21][C:20]([C:19]1[CH:24]=[CH:25][C:16]([CH3:15])=[CH:17][CH:18]=1)=[O:23]
Reactant: Oc1ccc2oc3ccccc3c2c1
Reactant: Cc1ccc(C(=O)CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)COc2ccc3oc4ccccc4c3c2)cc1

Procedure:
Following the procedure given in Example 13a 2-hydroxydibenzofuran was interacted with 4-methylphenacylchloride in the presence of anhydrous potassium carbonate in acetone to give ω-(2-dibenzofuranyloxy)-p-methylacetophenone. Following recrystallization from 2-ethoxyethanol, this compound melted at 162°-164° C.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([NH:21][C:22]3[CH:23]=[N:24][C:25](Cl)=[CH:26][C:27]=3[CH3:28])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([NH:21][C:22]3[CH:23]=[N:24][C:25]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:26][C:27]=3[CH3:28])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: Cc1cc(Cl)ncc1Nc1ncnc(OC2CCN(C(=O)OC(C)C)CC2)c1C
Product: Cc1cc(N2CCOCC2)ncc1Nc1ncnc(OC2CCN(C(=O)OC(C)C)CC2)c1C
Yield: 74 %

Procedure:
A solution of 4-[6-(6-chloro-4-methyl-pyridin-3-ylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (223 mg, 0.53 mmol) in 4.5 mL morpholine was reacted under microwave irradiation at 180° C. for 16 hours. Mixture was concentrated and purified by HPLC to give Compound A102 as a white solid (200 mg, 74%). 1H NMR (MeOH-d4, 400 MHz) δ 1.16-1.18 (d, 6H), 1.64-1.71 (m, 2H), 1.89-1.98 (m, 2H), 2.10 (s, 3H), 2.28 (s, 3H), 3.31-3.38 (m, 2H), 3.61-3.69 (m, 6H), 3.78-3.80 (m, 4H), 4.77-4.82 (m, 1H), 5.28-5.35 (m, 1H), 7.34 (s, 1H), 7.98 (s, 1H), 8.16 (s, 1H). Exact mass calculated for C24H34N6O4 470.26, found 471.4 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH:14]([CH3:15])[CH2:13][O:12][CH2:11][CH:10]2[CH3:16])[N:3]=1.[CH3:17][NH:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=1)=[O:20]>>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[CH:14]([CH3:15])[CH2:13][O:12][CH2:11][CH:10]2[CH3:16])[N:3]=[C:2]([C:25]2[CH:24]=[CH:23][C:22]([NH:21][C:19]([NH:18][CH3:17])=[O:20])=[CH:27][CH:26]=2)[N:7]=1
Reactant: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CC1COCC(C)N1c1nc(Cl)nc(Cl)n1
Product: CNC(=O)Nc1ccc(-c2nc(Cl)nc(N3C(C)COCC3C)n2)cc1
Yield: 16 %

Procedure:
The title compound was prepared by following the procedure of example 462 step 4 using 4-(4,6-dichloro-1,3,5-triazin-2-yl)-3,5-dimethylmorpholine and 1-methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea. Yield 1.15 g, 16% yield.
Reaction SMILES: C[O:2][C:3](=[O:30])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C@H:22]3[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]3)=[CH:17][CH:16]=2)=[CH:11][C:10]1=[O:29])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1.O>[CH3:28][C:24]1([CH3:27])[O:23][C@@H:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][C:12]3[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:30])=[O:2])[C:10](=[O:29])[CH:11]=3)=[CH:16][CH:17]=2)[CH2:26][O:25]1
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2ccc(C[C@H]3COC(C)(C)O3)cc2)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2ccc(C[C@H]3COC(C)(C)O3)cc2)=CC1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
A solution of (S)-2-{4-[4-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid methyl ester (0.198 g, 0.47 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was treated with lithium hydroxide monohydrate (0.022 g 0.51 mmol) and stirred at room temperature for 1.5 h. The mixture was partitioned between ethyl acetate and water and the layers separated. The aqueous phase was acidified with 1N aqueous hydrochloric acid (pH=1) and extracted with ethyl acetate. The combined organic layers from extraction of the acidic aqueous layer were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was treated with dichloromethane/hexanes and the precipitate isolated by filtration to afford (S)-2-{4-[4-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid (148 mg, 77%), as a white solid.
Reaction SMILES: N1C2C(=NC=CC=2)N([N:10]2[C:14](/[CH:15]=[C:16]3\[C:17](=[O:26])[NH:18][C:19]4[C:24]\3=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[C:13]([CH3:27])[C:12]([C:28]([O-])=[O:29])=[C:11]2[CH3:31])N=1.CN([CH:35]=[O:36])C>>[O:36]=[C:35]1[CH2:16][CH2:15][CH:14]([NH:10][C:28]([C:12]2[C:13]([CH3:27])=[C:14](/[CH:15]=[C:16]3\[C:17](=[O:26])[NH:18][C:19]4[C:24]\3=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[NH:10][C:11]=2[CH3:31])=[O:29])[CH2:13][CH2:12]1
Reactant: CN(C)C=O
Reactant: Cc1c(C(=O)[O-])c(C)n(-n2nnc3cccnc32)c1/C=C1\C(=O)Nc2ccc(F)cc21
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NC1CCC(=O)CC1
Temperature: 25 °C
Yield: 26 %

Procedure:
To the solution of (Z)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl-5-[(5-fluoro-2-oxoindolin-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxylate (A4) (0.2 g, 0.48 mmol) in 25 mL of DMF solution was added compound 7b (0.13 g, 0.58 mmol), the reaction mixture was stirred at room temperature for several hours. LC/MS detection was applied to determine completion of the reaction. DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine/methanol (25 mL) under sonication. The solid was collected by filtration and washed with methanol (5 mL*2), dried under vacuum to provide the title compound (50 mg, 26% yield) as orange solid. 1H NMR (300 MHz, DMSO-d6): δ=13.68 (s, 1H), 10.89 (s, 1H), 7.70-7.78 (m, 3H), 6.82-6.93 (m, 2H), 4.21-4.28 (m, 1H), 2.41-2.49 (m, 8H), 2.28-2.31 (m, 2H), 2.07-2.13 (m, 2H), 1.76-1.80 (m, 2H). LC/MS: 394.3 [M−H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:20][CH3:21])[CH:12]2[N:7]([CH2:8][CH2:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:11]=32)[CH2:6][CH2:5][CH2:4]1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:22]([O:1][CH2:2][C:3]1([CH2:20][CH3:21])[CH:12]2[N:7]([CH2:8][CH2:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:11]=32)[CH2:6][CH2:5][CH2:4]1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CCC1(CO)CCCN2CCc3c([nH]c4ccccc34)C21
Solvent: c1ccncc1
Product: CCC1(COC(C)=O)CCCN2CCc3c([nH]c4ccccc34)C21
Reaction time: 72 h
Yield: 61.2 %

Procedure:
2.50 g. (8.82 mmoles) of 1-hydroxymethyl-1-ethyl-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a]quinolizine are dissolved in 15 ml. of absolute pyridine. 15 ml. of acetic anhydride are added to the solution, and the mixture is allowed to stand at room temperature for three days. Thereafter the solution is evaporated in vacuo, and the oily residue is stirred with a 5% sodium hydrocarbonate solution. The separated solid substance is filtered off, washed with water, dried, and recrystallized first from aqueous methanol and then from methanol. 1.75 g. (61.2%) of the title compound are obtained in the form of shiny crystals melting at 96°-97° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[CH2:5][NH2:6].[I:11]Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([I:11])[C:9]=1[NH2:10])[CH2:5][NH2:6]
Reactant: NCc1ccc(N)c(Cl)c1
Reactant: ClI
Solvent: CO
Product: NCc1cc(Cl)c(N)c(I)c1
Reaction time: 1 h
Yield: 41.5 %

Procedure:
To 3-Chloro-4-aminobenzylamine (200 mg, 1.28 mmol) in methanol (5 mL) was added Iodine monochloride (230 mg, 1.42 mmol). The mixture was stirred for 1 hour, then purified by HPLC to give 3-chloro-4-amino-5-iodobenzylamine (150 mg, 42%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]#[N:11].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[F:1][C:2]1[C:7]([N+:12]([O-:14])=[O:13])=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]#[N:11]
Reactant: N#CCc1c(F)cccc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: N#CCc1c(F)ccc([N+](=O)[O-])c1F
Yield: 98.8 %

Procedure:
To a solution of (2,6-difluorophenyl)acetonitrile (5 g, 32.7 mmol) in conc. Sulphuric acid (15 mL) at −78° C. was added dropwise a solution of nitric acid (65%, 2.25 mL, 32.7 mmol) in conc. sulphuric acid (5 mL). On completion of addition the reaction mixture was poured onto ice and the precipitate that formed collected by filtration, washed with water and dried in vacuo to give the title product as a white solid (6.4 g, 100%). 1H NMR 400 MHz δ (CDCl3): 8.24-8.16 (1H, m), 7.17 (1H, ddd, J=9.6, 7.8, 1.9 Hz), 3.84 (2H, t, J=1.2 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])=[C:4]([NH2:20])[N:3]=1.[H-].[Na+].BrCCCC[C:28]1[NH:29][CH:30]=[CH:31][N:32]=1>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]2[O:13][CH2:11][CH2:12][CH2:14][CH2:16][N:29]2[CH:30]=[CH:31][N:32]=[CH:28]2)=[C:4]([NH2:20])[N:3]=1
Reactant: BrCCCCc1ncc[nH]1
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3OCCCCn3ccnc3)c2n1
Reaction time: 8 h

Procedure:
2,6-Diamino-(9-β-D-ribofuranosyl)purine (5.0 g) in DMF (400 ml) was treated with sodium hydride (0.78 g). After stirring an additional 30 min a further portion of sodium hydride (2.6 g) was added immediately followed by bromobutylimidazole (9.9 g) in DMF (25 ml). The reaction mixture was stirred overnight and quenched with H2O. The reaction mixture was filtered through celite and evaporated to yield an oily product. TLC showed a mixture of isomers.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:50])[CH2:30][CH2:31][N:32]([C:43]1[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=1)[C:33](=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][CH3:41]>>[CH3:50][N:29]([CH3:28])[CH2:30][CH2:31][N:32]([C:43]1[CH:44]=[CH:45][C:46]([NH:47]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:48][CH:49]=1)[C:33](=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][CH3:41]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: COc1ccccc1C(=O)N(CCN(C)C)c1ccc(N)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCN(C)C)C(=O)c2ccccc2OC)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-(2-dimethylamino-ethyl)-N-(2-methoxy-benzoyl)-amino)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C35H34N4O5
Reaction SMILES: [C:1]([O:5]O)(C)([CH3:3])[CH3:2].[CH3:7][C:8]([CH3:28])([CH3:27])[C:9]([O:11][CH2:12][C:13]1[NH:22][C:21](=[O:23])[C:20]2[C:15](=[CH:16][C:17]3CCC[C:18]=3[CH:19]=2)[N:14]=1)=[O:10]>C(Cl)Cl>[CH3:7][C:8]([CH3:28])([CH3:27])[C:9]([O:11][CH2:12][C:13]1[NH:22][C:21](=[O:23])[C:20]2[C:15](=[CH:16][C:17]3[CH2:18][CH2:3][C:1](=[O:5])[C:2]=3[CH:19]=2)[N:14]=1)=[O:10]
Reactant: CC(C)(C)C(=O)OCc1nc2cc3c(cc2c(=O)[nH]1)CCC3
Reactant: CC(C)(C)OO
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCc1nc2cc3c(cc2c(=O)[nH]1)C(=O)CC3
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of (Ph3SiO)2CrO2 (L. M. Baker and W. L. Carrick, J. Org. Chem. 1970, 35, 774) (10.6 mg, 0.017 mmol) in CH2Cl2 (5 ml) was added sequentially aqueous 70% tert-butyl hydroperoxide (0.18 ml, 1.3 mmol) and 2-(2,2-dimethylpropionyloxymethyl)-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4-one (0.1 g, 0.33 mmol). The mixture was stirred at room temperature with protection from the light for 24 h. The solvents were removed in vacuo and the residue purified by column chromatography (20 g of silica gel) eluting with a gradient of 10-30% EtOAC in CHCl3 to yield 2-(2,2-dimethylpropionyloxymethyl)-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4,6-dione as a while solid (47 mg, 45%); m.p. 185-190° C.; 1H-NMR (DMSO-d6) δ 1.23 (s, 9H, CMe3), 2.72 (m, 2H, 7-H), 3.25 (m, 2H, 8-H), 5.00 (s, 2H, 2-CH2), 7.70 (s, 1H, 9-H), 8.29 (s, 1H, 5-H), 12 20 (br, 1H, NH); MS (FAB, m/z): Found 315 [(M+H)+, 100%], 337 [(M+Na)+, 75%]; HRMS: measured 315.1360; calculated for C17H19N2O4 (M+H)+: 315.1345. Found C, 64.18; H, 5.72; N, 8.81, C17H18N2O4.0.2H2O requires C, 64.23; H, 5.79; N, 8.82%.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([OH:13])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[CH3:19]O>>[CH3:19][O:12][C:11]([C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([CH3:1])[CH:10]=2)=[O:13]
Reactant: CO
Reactant: Cc1ccc2cc(C(=O)O)[nH]c2c1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc2ccc(C)cc2[nH]1

Procedure:
A solution of 6-methylindole-2-carboxylic acid (38.2 g.) in methanol (400 ml.) containing phosphorus oxychloride (5 ml.) was heated under reflux for 4 hours and then evaporated. The residue was dissolved in chloroform and the solution was washed successively with water and sodium bicarbonate solution and then dried (Na2SO4). Evaporation of the solvent gave a solid which was crystallized from methanol to give 6-methylindole-2-carboxylic acid methyl ester (28.1 g.), m.p. 128°-131° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]#[N:22])[CH:5]=[C:6]([CH3:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=1.[Cl-].[NH4+].[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=1)[CH2:20][C:21]1[NH:27][N:26]=[N:25][N:22]=1
Reactant: Cc1cc(CC#N)cc(C)c1Oc1ccc(O)c(C(C)C)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Cc2nnn[nH]2)cc(C)c1Oc1ccc(O)c(C(C)C)c1
Yield: 38.5 %

Procedure:
To a stirred solution of 3,5-dimethyl-4-(4-hydroxy-3-isopropylphenoxy)-phenylacetonitrile (154 mg) in 6.3 ml of dimethyl formamide, ammonium chloride (297 mg, 5.21 mmol) and sodium azide (339 mg, 5.21 mmol) was added at reflux. After 4.5 hours the reaction mixture was concentrated, treated with 6 M hydrochloric acid and extracted several times with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered and concentrated. The residue was purified by column chromatography (silica gel, 96:4:1 chloroform/methanol/acetic acid) to give 68 mg (37%) of the title compound.
Reaction SMILES: [O:1]=[CH:2][CH:3]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([O:16][CH3:17])[CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[BH4-].[Na+].O>CO>[OH:1][CH2:2][CH:3]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([O:16][CH3:17])[CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C=O)c1cc(C)cc(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)C(CO)c1cc(C)cc(OC)c1
Temperature: -10 °C
Reaction time: 3 h
Yield: 103.6 %

Procedure:
A stirred solution of ethyl 3-oxo-2-(3-methoxy-5-methylphenyl)propionate (1.9 g; 8.1 mmol; from step (v) above) in MeOH (50 mL) was cooled to −15° C. NaBH4 (0.61 g; 16 mmol) was then added in portions. The mixture was stirred for 3 hours at −15 to −5° C. Water was then added, and resultant mixture concentrated. The aqueous phase was extracted with EtOAc, the organic phase was washed with water, dried (Na2SO4) and evaporated to yield 2.0 g (59%) of sub-title compound.