Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[CH:22]=[C:21]2[C:10]([CH2:11][C:12]3[CH:16]=[CH:15][N:14]([CH2:17][C@@H:18](O)[CH3:19])[C:13]=32)=[CH:9][CH:8]=1.C(N(CC)CC)C.[N-:30]=[N+:31]=[N-:32].[Na+]>ClCCl.CN(C)C=O.O>[N:30]([C@H:18]([CH3:19])[CH2:17][N:14]1[CH:15]=[CH:16][C:12]2[CH2:11][C:10]3[C:21]([C:13]1=2)=[CH:22][C:7]([Cl:6])=[CH:8][CH:9]=3)=[N+:31]=[N-:32]
Reactant: C[C@H](O)Cn1ccc2c1-c1cc(Cl)ccc1C2
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@H](Cn1ccc2c1-c1cc(Cl)ccc1C2)N=[N+]=[N-]
Yield: 48.8 %

Procedure:
0.97 ml of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 1.55 g of (S)-1-(7-chloro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 3.5 ml of triethyl-amine in 40 ml of diohloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 200 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed to 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 30 ml of anhydrous dimethylformamide, treated with 815 mg of sodium azide and the reaction mixture was heated to 60° for 17 hours while stirring. After cooling, the solution was poured into 140 ml of water and extracted twice with 140 ml of ethyl acetate each time. The combined organic phases were washed once with 140 ml of water and once with 140 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (toluene). 833 mg (49%) of (R)-1-(2-azido-propyl)-7-chloro-1,4-dihydro-indeno[1,2-b]pyrrole were obtained as an oil.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[N:14]O)[CH3:13])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[H][H].C([O-])(O)=O.[Na+]>[Pd].CO.Cl>[CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: [H][H]
Reactant: CC(=NO)c1ccc(NS(C)(=O)=O)cc1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Product: CC(N)c1ccc(NS(C)(=O)=O)cc1
Yield: 99 %

Procedure:
A suspension of 4′-(Methylsulfonylamino)acetophenone oxime (13-8, 5 mmol) and 10% palladium on carbon (150 mg) in MeOH (25 mL) was treated with concentrated hydrochloric acid (10 drops) was hydrogenated under a balloon of hydrogen for 6 h. The reaction mixture was neutralized with solid NaHCO3, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using CH2Cl2:MeOH as eluant to afford 1-[4-(Methylsulfonylamino)phenyl]ethyl amine (13-11, LJO-302).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16](=[O:20])(=[O:19])[NH:17][CH3:18])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21]1([C:27]2[N:31]=[C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:29][N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([NH:17][CH3:18])(=[O:20])=[O:19])=[CH:12][C:8]=2[C:9]([N:35]2[CH2:36][CH2:37][N:32]([C:30]3[S:29][N:28]=[C:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:31]=3)[CH2:33][CH2:34]2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: CNS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1
Product: CNS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)c1
Yield: 72 %

Procedure:
Prepared in analogy to example 1 (b) from 2-cyclopentyloxy-5-methylsulfamoyl-benzoic acid (Example A29) and 3-phenyl-5-piperazino-1,2,4-thiadiazole. The crude material was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as an off-white solid (yield 72%). MS (m/e): 528.5 (M+H+, 100%).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][NH:10][CH2:9][C@H:8]2[NH:12]C(=O)[O-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].FC(F)(F)S(O[CH2:24][C:25]([F:28])([F:27])[F:26])(=O)=O>CN(C=O)C>[C:1]1([C@@H:7]2[CH2:11][N:10]([CH2:24][C:25]([F:28])([F:27])[F:26])[CH2:9][C@H:8]2[NH2:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])N[C@@H]1CNC[C@H]1c1ccccc1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N[C@@H]1CN(CC(F)(F)F)C[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Racemic tert-butyl (3R,4S) and (3S,4R)-4-phenylpyrrolidin-3-ylcarbamate (260 mg, 0.991 mmol) was taken up in DMF (5 ml) and cooled to 0° C. NaH (59.5 mg, 1.487 mmol) was added slowly. The reaction was allowed to stir for 10 minutes at 0° C. before adding 2,2,2-trifluoroethyl trifluoromethanesulfonate (345 mg, 1.487 mmol). The reaction continued to stir at 0° C. for 1 hour and was then allowed to reach room temperature and continue stirring for 16 hours. LC/MS in showed full conversion to desired product. Saturated NH4Cl was added slowly. EtOAc and water were added. Our products were extracted into EtOAc (3×). The combined organic layers were then washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by MPLC SNAP 25 g 0-25% EtOAc/hexanes gave racemic tert-butyl (3R,4S) and (3S,4R)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)carbamate (258 mg, 0.749 mmol, 76% yield). MS ESI calc'd. For C17H24F3N2O2 [M+1]+ 345, found 345.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:19]3([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:60][C:61]1[S:62][CH:63]=[CH:64][N:65]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[C:18][C:19]3([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:15][CH:16]=2)[C:8]([NH:60][C:61]2[S:62][CH:63]=[CH:64][N:65]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(C#CC2(O)CCCCC2)cc1
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(C#CC2(O)CCCCC2)cc1
Yield: 58.2 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(1-hydroxy-cyclohexylethynyl)-phenyl]-propionic acid (170 mg, 0.50 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (332 mg, 0.75 mmol), triethylamine (0.21 mL, 1.50 mmol) and 2-aminothiazole (86 mg, 0.75 mmol) in methylene chloride (5 mL) was stirred at 25° C. for 4 h. At this time, the reaction was diluted with methylene chloride (10 mL). This solution was washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL), a 1N aqueous hydrochloric acid solution (1×10 mL), and a half-saturated aqueous sodium chloride solution (1×10 mL). The aqueous layers were back extracted with methylene chloride (1×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-[4-(1-hydroxy-cyclohexylethynyl)-phenyl]-N-thiazol-2-yl-propionamide (123 mg, 58.3%) as a white solid: mp 172-173° C.; EI-HRMS m/e calcd for C25H30N2O2S (M+) 422.2028, found 422.2023.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:18][CH:17]([C:19](OC)=[O:20])[CH2:16][C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[CH2:7]([N:14]1[CH2:15][CH2:16][CH:17]([CH2:19][OH:20])[CH2:18]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)C1CC(=O)N(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCC1CCN(Cc2ccccc2)C1
Yield: 106 %

Procedure:
To a suspension of lithium aluminum hydride (16.2 g) in tetrahydrofuran (1 l) was added 1-benzyl-4-methoxycarbonyl-2-oxopyrrolidine (50 g) under reflux for one hour and the mixture was refluxed for 2 hours. A solution of water (15.5 ml) and tetrahydrofuran (50 ml) was added to the mixture under reflux. After cooling insoluble material was filtered off and the filtrate was concentrated under reduced pressure to give 1-benzyl-3-hydroxymethylpyrrolidine (43.45 g).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=2[C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=2[C:10]([OH:12])=[O:11])=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccccc1COc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccccc1COc1ccc(Br)cc1

Procedure:
Reflux 90 gm. of the crude methyl o-(p-bromophenoxymethyl)benzoate from Step B for 1 hour in a mixture of 500 cc. of methanol and 250 cc. of 10% aqueous sodium hydroxide. Evaporate the methanol and dilute the resulting aqueous solution with an equal volume of water. Acidify with conc. hydrochloric acid. Separate the solids by filtration, wash with water and dry in vacuo to obtain the title product (m.p. 183°-185° C.).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23](OC)=[O:24])[N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:28][C:29]([CH3:33])([CH3:32])[CH2:30][NH2:31]>>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]([NH:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH3:28])=[O:24])[N:17]=[CH:16]4)[CH:12]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)CN
Reactant: COC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)ccc3C)ccc21
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(cnn2CC(=O)NCC(C)(C)C)c1

Procedure:
Example 130 was prepared by General Method D using methyl (5-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-1H-indazol-1-yl)acetate (Example 117) and 2,2-dimethyl-1-propanamine to give the title compound (0.015 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[S:14](Cl)(=[O:17])(=[O:16])[NH2:15].C(N(CC)CC)C>C(#N)C>[CH3:13][C:6]1[C:5]2[CH:4]=[CH:3][C:2]([O:1][S:14](=[O:17])(=[O:16])[NH2:15])=[CH:11][C:10]=2[O:9][C:8](=[O:12])[CH:7]=1
Reactant: Cc1cc(=O)oc2cc(O)ccc12
Reactant: NS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(=O)oc2cc(OS(N)(=O)=O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
A slurry of 7-hydroxy-4-methylcoumarin (17.6 g, 0.10 mole) in acetonitrile (100 ml) was treated with a total of 84 ml of 3M sulfamoyl chloride (0.255 mole) in acetonitrile. The mixture was then treated dropwise with triethylamine (25.8 g, 0.255 mole). The reaction temperature was allowed to rise to 45° without any cooling. The mixture was stirred overnight at ambient temperature. The precipitate was collected, triturated with water, and dried in a vacuum oven at 70° C. for 15 hr to give 10.5 g (41%) of white powder, mp 161°-164° C.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH:8]2[CH2:20][NH2:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][S:23]([NH:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)(=[O:25])=[O:24]>>[CH3:22][S:23]([NH:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:21][CH2:20][CH:8]2[CH2:9][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][CH2:12][N:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:32])=[CH:29][CH:28]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: NCC1CN(Cc2ccccc2)CCN1c1ccccc1
Product: CS(=O)(=O)Nc1ccc(C(=O)NCC2CN(Cc3ccccc3)CCN2c2ccccc2)cc1

Procedure:
In a manner similar to Preparation 3, react 1-phenyl-4-(phenylmethyl)-2-piperazinemethanamine (11.1 g, 40 mmol) with 4-[(methylsulfonyl)amino]benzoyl chloride (10.1 g, 43 mmol) to obtain the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1.S(Cl)([Cl:13])=O>ClCCl>[Cl:13][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: CSc1ccc(CO)cc1
Solvent: ClCCl
Product: CSc1ccc(CCl)cc1
Temperature: 25 °C

Procedure:
4-Methylsulfanylbenzyl alcohol (30.5 g; 0.2 mol) was dissolved in dichloromethane (180 ml). A solution of thionyl chloride (23.8 g; 0.2 mol) in dichloromethane (120 ml) was added dropwise to the initial charge, which was kept under reflux. The reaction mixture was stirred under reflux for a further 2 h. The solution was cooled to room temperature, washed with H2O (2×250 ml), dried over Na2SO4 and concentrated. The oily residue (6) was purified by column chromatography (Al2O3, CH2Cl2).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.O.NN.Cl>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Agent: Cl
Agent: NN
Solvent: O
Product: Cc1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.5 %

Procedure:
A solution of 5-methylisatin (15.0 g) and hydrazine hydrate (60 mL) was heated to 140-160° C. for 4 hours. The reaction mixture was cooled to room temperature, poured into 300 mL of ice water and acidified to pH 2 with 6 N hydrochloric acid. After standing at room temperature for 2 days the precipitate was collected by vacuum filtration, washed with water and dried under vacuum to give 6.5 g (47% yield) of 5-methyl-2-oxindole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1[O:10][C:9]([CH:11]2OCC[O:12]2)=[CH:8][CH:7]=1.O1CCOC1C1OC=CC=1.C(O)(=O)C(O)=O.O>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1[O:10][C:9]([CH:11]=[O:12])=[CH:8][CH:7]=1
Reactant: Fc1cccc(Cc2ccc(C3OCCO3)o2)c1
Agent: O=C(O)C(=O)O
Agent: c1coc(C2OCCO2)c1
Solvent: CO
Solvent: O
Product: O=Cc1ccc(Cc2cccc(F)c2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a solution of a mixture of 2-(5-(3-fluoro-benzyl)-furan-2-yl)-[1,3]dioxolane and 2-(1,3-dioxolan-2-yl)furan (8033 mg) in methanol (80 mL) was added an aqueous solution of oxalic acid (22 g, 115 mmol) (80 mL), and the solution was stirred at room temperature for 1 hour. Water was added to the reaction mixture, which extracted with diethyl ether, the organic layer was sequentially washed with an aqueous solution of saturated sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate, and then, concentrated in vacuo. The resulting residue was purified by silica gel chromatography (hexane-ethyl acetate), and the title compound (4084 mg, 20.0 mmol, 34%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[O:14][CH2:15][C:16]3[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:17]=3[N:18]=1)[CH2:9][CH2:8]2.[CH:24]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[O:14][CH2:15][C:16]3[CH:22]=[C:21]([NH:23][S:27]([CH:24]4[CH2:26][CH2:25]4)(=[O:29])=[O:28])[CH:20]=[CH:19][C:17]=3[N:18]=1)[CH2:9][CH2:8]2
Reactant: COc1cccc2c1C(NC1=Nc3ccc(N)cc3CO1)CC2
Reactant: O=S(=O)(Cl)C1CC1
Product: COc1cccc2c1C(NC1=Nc3ccc(NS(=O)(=O)C4CC4)cc3CO1)CC2
Yield: 61.4 %

Procedure:
Prepared from rac-N2-(7-methoxy-indan-1-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 10) (155 mg, 0.50 mmol, HPLC 0.776 min) and cyclopropanesulfonyl chloride (77 mg, 0.55 mmol) according to the procedure described for Example 27. Obtained the title compound as a light brown solid (127 mg, 61%, HPLC 1.366 min), MS (ISP) m/e=414.2 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([O:21]C)=O)[C:5]([O:7][CH3:8])=[O:6].C[Al](C)C>C(Cl)Cl>[O:21]=[C:19]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][C:11]2[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[NH:1]1
Reactant: COC(=O)c1ccc(Oc2ccccc2C(=O)OC)c(N)c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)NC(=O)c1ccccc1O2
Yield: 35.3 %

Procedure:
A solution of compound 547 (3.2 g, 10.62 mmol) and AlMe3 (6.37 mL, 12.75 mmol) in DCM (40 mL) was stirred at 45° C. for 16 h and quenched with water. The reaction was diluted with AcOEt, washed with water and 1M HCl. The organic layer was separated, dried with Na2SO4, filtered and concentrated via rotary evaporation. The residue was triturated with AcOEt, filtered, washed with AcOEt and was purified via Isco employing a 0 to 50% AcOEt in hexanes solvent gradient to afford the title compound 548 (1.01 g, 35%) as a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:7][N:6]=[C:5]([CH3:8])[CH:4]=1.N1C=CC=CC=1.[Cl:15][C:16]([Cl:23])([Cl:22])[CH2:17][O:18][C:19](Cl)=[O:20]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:8][C:5]1[CH:4]=[C:3]([NH:2][C:19](=[O:20])[O:18][CH2:17][C:16]([Cl:23])([Cl:22])[Cl:15])[S:7][N:6]=1
Reactant: Cc1cc(N)sn1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(NC(=O)OCC(Cl)(Cl)Cl)sn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cold (−78° C.) solution of 5-amino-3-methylisothiazole hydrochloride (21.2 g, 127 mmol), pyridine (68 mL, 841 mmol) and DMAP (4.62 g, 38 mmol) in CH2Cl2 (420 mL) was slowly added trichloroethylchloroformate (31 mL, 224 mmol) over a period of 15 min. The reaction mixture was stirred at −78° C. for 30 min and then warmed to room temperature for 1 h. The mixture was partitioned between EtOAc and water, the organic layer was dried over MgSO4 and concentrated in vacuo. The crude product was disolved in Et2O (800 mL), charcoal was added and the resulting black suspension was boiled for 15 min and allowed to stand at room temperature for 18 h. The charcoal was removed by filtration on a pad of celite and the filtrate was concentrated in vacuo. The crude product was crystallized from a hot mixture of Et2O/hexane (1:1, 600 mL) to yield 2,2,2-trichloroethyl 3-methylisothiazol-5-ylcarbamate as a light yellow solid.
Reaction SMILES: [C:1](OC)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]CC>CCCCCC>[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCCC(=O)OC
Solvent: CCCCCC
Product: C=CCCCCCCCCCCCC

Procedure:
Irradiation of methyl palmitate. Methyl palmitate was dissolved in a small amount of hexane and irradiated in a quartz container (UV cuvette) at 253.7 nm in the Rayonet reactor. After 7 hours a small amount of 1-tetradecene was formed. After 24 hours a larger amount of 1-tetradecene and a corresponding isomer (to be identified but likely 2-tetradecene (CH3CH═CHCH2(CH2)9CH3) was obtained.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:12])[CH3:11])=[CH:6][CH:5]=1.[OH-].[K+]>C1COCC1.CO.Cl>[OH:12][CH:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:13])=[O:2])=[CH:5][CH:6]=1)[CH3:11]
Reactant: COC(=O)c1ccc(C(C)O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl-4-(1-hydroxyethyl)benzoate (2.00 g, 11.10 mmol) in a mixture of THF (20 mL) and MeOH (10 mL) was added 1 M KOH (13.32 mL, 13.32 mmol). After stirring at room temperature overnight, the solution was diluted with 2 N HCl and extracted with EtOAc (4×). The combined organic layers were dried (MgSO4) and evaporated to give 4-(1-hydroxyethyl)benzoic acid as a colorless solid. 1H NMR (DMSO-d6, 600 MHz) δ 7.86 (d, J=8.6 Hz, 2H), 7.43 (d, J=8.3 Hz, 2H), 4.75 (q, J=6.5 Hz, 1H), 1.30 (d, J=6.6 Hz, 3H). MS: cal'd 167 (MH+), exp 167 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl:11][C:12]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[C:13]=1[O:14][CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][NH:17]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[C:3]([C:4]([N:17]2[CH2:18][CH2:19][CH2:20][C@H:16]2[CH2:15][O:14][C:13]2[C:21]([Cl:26])=[CH:22][C:23]([Cl:25])=[CH:24][C:12]=2[Cl:11])=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Clc1cc(Cl)c(OC[C@@H]2CCCN2)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccnc1Cl)N1CCC[C@H]1COc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.9 %

Procedure:
At a temperature of 0° C., a solution of 2-chloro-nicotinoyl chloride (0.313 g; 1.78 mmol) in dichloromethane (5 ml) was added dropwise to a stirred solution of (S)-2-(2,4,6-trichloro-phenoxymethyl)-pyrrolidine (0.30 g; 1.78 mmol), which was prepared as described in example P13, and triethylamine (0.50 ml; 3.56 mmol) in dichloromethane (10 ml). The ice bath was removed and reaction mixture was allowed stirring for 16 hours at ambient temperature. Dichloromethane (40 ml) was added to the mixture. The reaction mixture was washed with 2M HCl (40 ml), 1M NaOH (50 ml) and saturated NaCl (50 ml) and then dried over Na2SO4. After removal of the solvent, the residue (0.21 g in the form of an oil) was purified by flash chromatography over silica gel (eluent:cyclohexane/ethyl acetate 1:1). 0.134 g (17.9% of theory) of (2-chloro-pyridin-3-yl)-[(S)-2-(2,4,6-trichloro-phenoxymethyl)-pyrrolidin-1-yl]-methanone was obtained in form of an oil. 1H NMR (400 MHz, CDCl3): δ 1.88-1.97 (m, 1H), 2.10-2.28 (m, 2H), 2.47-2.54 (m, 1H), 3.30-3.41 (m, 2H), 4.21-4.24 (m, 1H), 4.44 (m, 1H), 4.60-4.65 (m, 1H), 7.26 (s, 2H, Ar—H), 7.30-7.34 (m, 1H, Py-H), 7.68-7.72 (m, 1H, Py-H), 8.42-8.44 (m, 1H, Py-H). MS [M+H]+ 419/421/423/425.
Reaction SMILES: CS([Cl:5])(=O)=O.[CH3:6][S:7]([C:10]1[CH:11]=[C:12]([CH2:16]O)[CH:13]=[CH:14][CH:15]=1)(=[O:9])=[O:8].C(N(CC)CC)C.O>ClCCl>[Cl:5][CH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([S:7]([CH3:6])(=[O:9])=[O:8])[CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)c1cccc(CO)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1cccc(CCl)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
0.267 ml (3.45 mmol) methanesulphonyl-chloride is added to o a solution of 584 mg (3.14 mmol) (3-methanesulphonyl-phenyl)-methanol and 0.66 ml (4.71 mmol) triethylamine in 6 ml dichloromethane. This reaction mixture is stirred at room temperature for 1 h and at 50° C. for additional 3 h. The reaction mixture is then poured into water and extracted twice with dichloromethane. The combined organic layers are washed with water and brine, dried, filtered and concentrated in vacuo to afford the title compound, which is used in the next step without further purification.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]2[N:15]=[C:14]3[C:10]([N:11]=[C:12]([O:22]C)[N:13]3[CH2:16][CH:17]3[CH2:21][CH2:20][O:19][CH2:18]3)=[C:9]([NH2:24])[N:8]=2)[CH2:3][CH2:2]1.Cl.[OH-].[Na+]>CO.O1CCOCC1>[NH2:24][C:9]1[N:8]=[C:7]([NH:6][CH2:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:22])[N:13]2[CH2:16][CH:17]1[CH2:21][CH2:20][O:19][CH2:18]1
Reactant: COc1nc2c(N)nc(NCCC3CC3)nc2n1CC1CCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: Nc1nc(NCCC2CC2)nc2c1[nH]c(=O)n2CC1CCOC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.5 %

Procedure:
To a solution of N2-(2-cyclopropylethyl)-8-(methoxy)-9-(tetrahydro-3-furanylmethyl)-9H-purine-2,6-diamine (209 mg) in methanol (21 ml) at room temperature was added 4.0M hydrogen chloride in 1,4-dioxane (3.93 ml) to give a colorless solution. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was neutralised with 2M NaOH and concentrated in vacuo. The resultant solid was taken up in water (50 ml) and filtered off to give a white solid. This solid was recrystallised from ethanol:water (1:1) and filtered to afford an off-white crystalline solid (105 mg).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=3[O:17][CH3:18])[NH:9][C:5]=2[CH:4]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:12][C:11]=3[O:17][CH3:18])[NH:9][C:5]=2[CH:4]=1
Reactant: COc1cc(O)ccc1-c1nc2ccc(C(F)(F)F)cc2[nH]1
Reactant: CS(=O)(=O)Cl
Product: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ccc(C(F)(F)F)cc2[nH]1

Procedure:
Prepared analogously to Example 1 from 5-trifluoromethyl-2-(2'-methoxy-4'-hydroxy-phenyl)-benzimidazole and methanesulfonic acid chloride.