Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[C:21]([C:23]4[O:24][C:25]([CH3:28])=[N:26][N:27]=4)[CH:20]=[CH:19][C:18]=3[CH3:29])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.[CH:32]1([CH2:35]Br)[CH2:34][CH2:33]1>>[CH:32]1([CH2:35][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:31][CH:30]=2)[C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[C:21]([C:23]4[O:24][C:25]([CH3:28])=[N:26][N:27]=4)[CH:20]=[CH:19][C:18]=3[CH3:29])=[CH:15][CH:16]=2)=[O:10])[CH2:34][CH2:33]1
Reactant: BrCC1CC1
Reactant: COc1ccc(CNC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1
Product: COc1ccc(CN(CC2CC2)C(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1

Procedure:
N-(Cyclopropylmethyl)-N-(4-methoxybenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from N-(4methoxybenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide and cyclopropylmethyl-bromide using method L. LCMS; retention time 3.70 min, MH+ 468.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](Cl)=[O:39])=[CH:33][CH:32]=1>C(Cl)Cl>[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=2)=[O:39])=[CH:33][CH:32]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(F)cc1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1

Procedure:
To a solution of 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.36 mmol, example 9 (step 3) and DIEA (63 μL, 0.36 mmol) in DCM (2 mL) was added 4-fluorophenylacetyl chloride (62 μL, 0.36 mmol). The resulting mixture was reacted under the same conditions as described for example 10 give the title compound as a white oil. MS (ESI, positive ion) m/z: 414 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:6][C:5]([NH2:17])=[C:4]([N+:18]([O-])=O)[CH:3]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([NH2:17])=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Nc1cc(OCCN2CCCCC2)c(F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cc(F)c(OCCN2CCCCC2)cc1N
Yield: 95.9 %

Procedure:
443 mg of 4-fluoro-2-nitro-5-(2-piperidin-1-ylethoxy)-phenylamine in solution in 20 mL of methanol are hydrogenated under 1 bar of hydrogen pressure in the presence of 44 mg of palladium-on-charcoal at 25° C. for 10 hours. The reaction crude is filtered through celite and the filtrate is concentrated under vacuum in a rotary evaporator. 380 mg of 4-fluoro-5-(2-piperidin-1-ylethoxy)benzene-1,2-diamine are obtained in the form of a black lake. The compound is used without any other purification.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:15]4=[O:22])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([O:21][CH2:20][C:17]2[CH:18]=[CH:19][N:14]([C:11]3[CH:12]=[CH:13][C:6]4[N:5]=[C:4]([CH:1]5[CH2:2][CH2:3]5)[N:8]([CH3:9])[C:7]=4[CH:10]=3)[C:15](=[O:22])[CH:16]=2)=[CH:26][CH:25]=1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(CO)cc3=O)cc21
Reactant: Oc1ccc(Cl)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(COc4ccc(Cl)cc4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 21.8 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-(hydroxymethyl)pyridin-2(1H)-one (150 mg), 4-chlorophenol (130 mg) and tributylphosphine (514 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (641 mg), and the mixture was stirred at 60° C. for 4 h. The mixture was concentrated in vacuo, and diluted with DCM. The mixture was washed with water and brine successively, dried over Na2SO4, concentrated in vacuo and purified by column chromatography (MeOH/DCM) to afford the title compound (45 mg) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH3:15])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[O:16]1[C@:18]2([CH2:23][CH2:22][CH2:21][C@H:20]([CH2:24][N:25]3[C:29]4[CH:30]=[C:31]([C:34]#[N:35])[CH:32]=[CH:33][C:28]=4[N:27]=[CH:26]3)[CH2:19]2)[CH2:17]1>C(O)(C)C>[C:34]([C:31]1[CH:32]=[CH:33][C:28]2[N:27]=[CH:26][N:25]([CH2:24][C@H:20]3[CH2:21][CH2:22][CH2:23][C@:18]([CH2:17][NH:1][CH2:2][C:3]4([CH3:15])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]4)([OH:16])[CH2:19]3)[C:29]=2[CH:30]=1)#[N:35]
Reactant: CC1(CN)CCN(C(=O)OC(C)(C)C)C1
Reactant: N#Cc1ccc2ncn(C[C@H]3CCC[C@@]4(CO4)C3)c2c1
Solvent: CC(C)O
Product: CC1(CNC[C@]2(O)CCC[C@H](Cn3cnc4ccc(C#N)cc43)C2)CCN(C(=O)OC(C)(C)C)C1
Yield: 62.4 %

Procedure:
A solution of 1,1-dimethylethyl 3-(aminomethyl)-3-methyl-1-pyrrolidinecarboxylate (0.677 g, 3.16 mmol) and 1-[(3S,5S)-1-oxaspiro[2.5]oct-5-ylmethyl]-1H-benzimidazole-6-carbonitrile (0.844 g, 3.16 mmol) in isopropanol (5 mL) was heated at 102° C. overnight. The reaction mixture was concentrated and purified via silica gel chromatography (ISCO, 40 g silica gel column. Solvent A: DCM; B: MeOH; 0-10% B: 15 min; 10% B: 10 min) to give 1,1-dimethylethyl 3-{[({(1S,3S)-3-[(6-cyano-1H-benzimidazol-1-yl)methyl]-1-hydroxycyclohexaneyl}methyl)amino]methyl}-3-methyl-1-pyrrolidinecarboxylate (950 mg, 62.4% yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH3:11]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:11])=[O:7])=[CH:4][CH:3]=1
Reactant: N
Reactant: O=C(Cl)c1ccc(Br)cc1
Product: NC(=O)c1ccc(Br)cc1
Yield: 89.8 %

Procedure:
On an ice water bath, 108 g (0.49 mol) of 4-bromobenzoic acid chloride was added drop-wise over 30 minutes to 330 cm3 (4.9 mol) of concentrated aqueous ammonia while vigorously stirring. The resultant crystals were filtered out, washed with water and recrystallized from acetone to yield 88 g (0.44 mol) of 4-bromobenzoic acid amide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]3[CH:17]=[C:16]([O:18][CH2:19][CH3:20])[CH:15]=[CH:14][N:13]3[C:21]=2[CH3:22])=[CH:4][C:3]=1[OH:23].[N:24]#[C:25]Br>C(O)C>[CH2:19]([O:18][C:16]1[CH:15]=[CH:14][N:13]2[C:21]([CH3:22])=[C:10]([CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]4[N:1]=[C:25]([NH2:24])[O:23][C:3]=4[CH:4]=3)[N:11]=[C:12]2[CH:17]=1)[CH3:20]
Reactant: N#CBr
Reactant: CCOc1ccn2c(C)c(CCc3ccc(N)c(O)c3)nc2c1
Solvent: CCO
Product: CCOc1ccn2c(C)c(CCc3ccc4nc(N)oc4c3)nc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.8 %

Procedure:
A mixture of 2-[2-(4amino-3-hydroxyphenyl)ethyl]-7-ethoxy-3-methylimidazo[1,2-a]pyridine (1.6 g) and cyanogen bromide (0.7 g) in ethanol (24 ml) was stirred for 1.5 hours at ambient temperature. The solvent was evaporated in vacuo. To the residue was added a mixture of tetrahydrofuran, ethyl acetate and water, and the mixture was adjusted to pH 8 with 20% aqueous potassium carbonate solution. The separated organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated and the residue was triturated with a solution of diethyl ether and ethyl acetate and precipitate was collected by filtration to give 6-[2-(7-ethoxy-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]-2-aminobenzoxazole (1.12 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([N:11]=[C:12]=[O:13])([CH3:10])[CH3:9])[CH:3]=1.[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12](=[O:13])[O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH3:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(N=C=O)c1cccc(Br)c1
Reactant: OCc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(NC(=O)OCc1ccccc1)c1cccc(Br)c1
Temperature: 100 °C

Procedure:
To solution of A6.1c (11 g, 0.045 mol) in dichloromethane (110 ml) was added triethylamine (5.85 g, 0.057 mol) and cooled to 0° C. under N2. Ethylchloroformate (5.65 g, 0.05 mol) was added drop wise and stirred at 0° C. for 1 h. Sodium azide (3.24 g, 0.049 mol) was added and the mixture was stirred at RT over night. Reaction mixture was filtered to remove triethylamine-hydrochloride salt. The organic layer was concentrated to provide 1-azido-2-(3-bromophenyl)-2-methylpropan-1-one which was dissolved in toluene (60 mL) and heated to 100° C. for 30 min. The toluene was removed under vacuum to provide 1-bromo-3-(2-isocyanatopropan-2-yl)benzene. A mixture of 1-bromo-3-(2-isocyanatopropan-2-yl)benzene, pyridine (30 ml) and benzyl alcohol (12.2 g, 0.113 mol) was heated to 100° C. for 2 h under nitrogen. The reaction mixture was cooled to RT, quenched with 1.5 N HCl and extracted with ethyl acetate (3×50 ml). The combined organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated. Product was purified by column chromatography to give 7 g (45%) of A6.1d. 1H NMR (300 MHz, CDCl3) 1.65 (s, 6H), 5.03 (s, 2H), 5.1 (bs, 1H), 7.2 (dd, 1H), 7.35 (m, 6H), 7.54 (s, 1H). LCMS (M−H)+=350.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH:15](/B(O)O)=[CH:16]\[CH3:17].[F-].[Cs+]>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2](/[CH:15]=[CH:16]/[CH3:17])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(Br)c([N+](=O)[O-])c1
Reactant: C/C=C/B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Product: C/C=C/c1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A mixture of 2-bromo-5-methylsulfonylnitrobenzene (1.50 g; 5.36 mmol), trans-propenylboronic acid (690 mg; 8.03 mmol), caesium fluoride (2.44 g; 16.1 mmol) and bis(triphenylphosphine)palladium(II) chloride (376 mg; 0.54 mmol) was degassed with nitrogen, then treated with dioxane (30 ml) and water (15 ml). The resulting reaction mixture was heated at 80° C. for 2 hours, taken up in EtOAc and washed with water and brine. The organic phase was dried on MgSO4, filtered and concentrated under reduced pressure to give a residue which was purified by by flash column chromatography, eluting with cyclohexane containing increasing amounts of EtOAc. The title compound was obtained as an off-white solid (1.10 g, 85%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH:25]2OCCCO2)=[CH:18][CH:17]=1.[O:31]1[CH2:35][C:34](=[O:36])[NH:33][C:32]1=[O:37].N1CCCCC1>C(O)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH2:24][CH:25]=[C:35]2[O:31][C:32](=[O:37])[NH:33][C:34]2=[O:36])=[CH:20][CH:21]=1
Reactant: O=C1COC(=O)N1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCCC2OCCCO2)cc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCCC=C2OC(=O)NC2=O)cc1
Yield: 25.9 %

Procedure:
A mixture of 2-[3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propyl]-1,3-dioxane (2.0 g), 2,4-oxazolidinedione (0.99 g), piperidine (0.21 g) and acetic acid (50 ml) was heated for 24 hours under reflux. The reaction mixture was concentrated under reduced pressure, to which was added ethyl acetate. The ethyl acetate layer was washed with an aqueous solution of sodium hydrogencarbonate, 2N HCl and water, successively, which was then dried (MgSO4), followed by concentration. The concentrate was purified by means of a silica gel column chromatography. From the fractions eluted with chloroform--ethyl acetate (5:1), 5-[4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]butylidene]-2,4-oxazolidinedione (0.55 g, 26%) was obtained. Recrystallization from ethyl ether - methanol gave colorless needles, m.p.152°-153° C.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:25]([F:28])([F:27])[F:26])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:30][OH:31].O.O.O.C([O-])(=O)C.[Na+]>CCO.O>[C:1]1(/[C:7](/[C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:25]([F:28])([F:27])[F:26])=[N:30]\[OH:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O/N=C(\c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Reaction time: 8 h
Yield: 75.2 %

Procedure:
Phenyl[4-phenyl-8-(trifluoromethyl)quinolin-3-yl]methanone (Example 1, 0.128 g, 0.339 mmol) was taken into EtOH/H2O (7 mL, 7:3 mixture) along with hydroxylamine hydrochloride (0.028 g, 0.407 mmol) and sodium acetate trihydrate (0.061 g, 0.447 mmol) and this mixture was refluxed for 1.5 hours. TLC and LC-MS showed no reaction. Therefore, excess quantities of hydroxylamine hydrochloride and sodium acetate trihydrate were added and refluxing was continued overnight. The reaction was concentrated and the resulting material was taken up into CH2Cl2/H2O. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organics were dried over sodium sulfate and concentrated. The product was purified via column chromatography using 15% ethyl acetate in hexane as the eluent to afford 0.100 g of desired product as a white solid. MS (ESI) m/z 393 ([M+H]+);
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12].[CH2:14]([OH:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20]>>[CH2:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][OH:21])[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: OCCCCCCO
Reactant: CC(C)CCOCCCCCCBr
Product: CC(C)CCOCCCCCCOCCCCCCO

Procedure:
The above compound may be produced in analogous manner to that described in Example 13, but using 1-bromo-6-isopentyloxy hexane and 1,6-hexandiol.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[N:9]([CH3:18])[CH2:8][C:7]=12)#[N:2].Cl.[NH2:20][OH:21].C(O)C.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:18][N:9]1[C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:6]2[CH:5]=[N:4][C:3]([C:1](=[N:20][OH:21])[NH2:2])=[C:7]2[CH2:8]1
Reactant: CN1Cc2c(C#N)ncn2-c2ccccc2C1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CN1Cc2c(C(N)=NO)ncn2-c2ccccc2C1=O

Procedure:
A mixture of 0.0125 mole 3-cyano-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine, 1.1 g of hydroxylamine hydrochloride, 200 ml of 99% ethanol and 5.2 ml of a 20% potassium carbonate solution in water was refluxed for 22 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was treated with 100 ml of water and the crystalline solid was filtered off and was washed with water.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.CS(O[CH:15]1[CH2:18][N:17]([C:19]([C:21]2[O:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:24][N:25]=2)=[O:20])[CH2:16]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C>[OH:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][CH:15]2[CH2:16][N:17]([C:19]([C:21]3[O:22][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[N:24][N:25]=3)=[O:20])[CH2:18]2)=[CH:3][CH:4]=1
Reactant: OCc1ccc(S)cc1
Reactant: CS(=O)(=O)OC1CN(C(=O)c2nnc(-c3ccccc3)o2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1nnc(-c2ccccc2)o1)N1CC(Sc2ccc(CO)cc2)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
(4-Mercaptophenyl)methanol (2.38 g, 17.0 mmol) and 1C (5.00 g, 15.5 mmol) were mixed in DMF (80 mL). Cs2CO3 (6.05 g, 18.56 mmol) was added. The mixture was stirred at 90° C. overnight and then cooled room temperature. Ethyl acetate (150 mL) was added and the mixture was washed with water (50 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The organic phases were combined, dried (MgSO4) and evaporated to dryness. The residue was purified by column chromatography eluting with ethyl acetate/heptane (20:80, 40:60 and then 60:40). There was obtained 3.5 g (61%) of 5A as a solid. 1H NMR (500 MHz, CDCl3): δ 4.19 (m, 2H), 4.64 (m, 2H), 4.69 (s, 2H), 5.10 (m, 1H), 7.34 (m, 4H), 7.53 (t, 2H), 7.59 (t, 1H), 8.15 (d, 2H), MS (APCI+) m/z 368 [M−H]−.
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]CC)=O)[CH:5]=[N:4][C:3]1=2.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:18][CH2:19][CH2:20][CH2:21][N:22]3[CH:26]=[CH:25][N:24]=[CH:23]3)=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: NCCCn1ccnc1
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NCCCn1ccnc1
Yield: 59.8 %

Procedure:
250 mg (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl) propionic acid, ethyl ester (AIT-0027) was heated with 500 mg (3.99 mmol) of 1-(3-aminopropyl)-imidazole in a 10 ml round bottom flask at 120° C. for two hours with stirring. The resulting viscous yellow oil was chromatographed on 15 g of silica gel, eluting with 60% methanol/40% ethyl acetate, which yielded a highly viscous colorless oil after evaporation of the solvent. The oil was dissolved in approximately 50 ml of ethyl ether and then methanol was added slowly until a white precipitate formed. The precipitate was collected by vacuum filtration and washed with ethyl ether. The material was dried to yield 200 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-[3-(1-imidazolyl)propyl]propanamide (AIT-0037) as a white solid. Yield 66%.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[Br:12][C:13]1[S:17][C:16]([C:18](O)=[O:19])=[CH:15][CH:14]=1.S(Cl)(Cl)=O>ClCCl>[Br:12][C:13]1[S:17][C:16]([C:18]([NH:2][C:3]2([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]2)=[O:19])=[CH:15][CH:14]=1
Reactant: COC(=O)C1(N)CCCC1
Reactant: O=C(O)c1ccc(Br)s1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C1(NC(=O)c2ccc(Br)s2)CCCC1

Procedure:
Prepared analogously to Example 37a from methyl 1-amino-cyclopentane-1-carboxylate hydrochloride and 5-bromo-thiophene-2-carboxylic acid with thionyl chloride in dichloromethane with TEA.
Reaction SMILES: [Li+].[BH4-].CO.C([O:7][C:8]([C:10]1[CH:18]=[C:13]2[CH2:14][S:15][CH2:16][CH2:17][N:12]2[N:11]=1)=O)C>C1COCC1>[N:11]1[N:12]2[C:13]([CH2:14][S:15][CH2:16][CH2:17]2)=[CH:18][C:10]=1[CH2:8][OH:7]
Reactant: CCOC(=O)c1cc2n(n1)CCSC2
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cc2n(n1)CCSC2
Temperature: 40 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
LiBH4 (cont. 90%) (536 mg) and MeOH (0.9 mL) was added to the THF (59 mL) solution of 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]thiazine-2-carboxylic acid ethyl ester (3.13 g) under a nitrogen atmosphere at room temperature and stirred for 3 h at 40° C. The mixture was quenched with 1 mol/L HCl at pH 1 and stirred for 1 h at room temperature. Solid K2CO3 was added to the solution to adjust pH to 8 and the mixture was extracted with AcOEt. The organic layer was dried (K2CO3) and filtered. The filtrate was concentrated under reduced pressure to afford titled compound as pale yellow oil (2.51 g, quant.).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1)[CH:8]=O.[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)(=[O:17])[CH3:16]>O.CO>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1)[CH:8]=[C:23]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]1[C:15](=[O:17])[CH3:16]
Reactant: CC(=O)c1ccccn1
Reactant: COc1cc(C=O)cc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C=C2C=CC=NC2C(C)=O)cc(OC)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a well stirred solution of NaOH (12 g, 0.3 mmole) in H2O (125 ml) and methanol (250 ml) at 0° C. was added 3,5-dimethoxy benzaldehyde (19 g, 0.11 mmole) followed by a solution of 2-acetylpyridine (14.4 g, 0.12 mmole) in MeOH. The reaction was stirred at 0° C. for 1 hour and at room temperature for 16 hours. The precipitate was filtered and recrystallized from MeOH (Yield: 18 mg, 57%). The preparation scheme is shown below:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[C:28]([O:37][CH3:38])(=[O:36])[C:29]1[C:30](=[CH:32][CH:33]=[CH:34][CH:35]=1)O.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:38][O:37][C:28](=[O:36])[C:29]1[CH:30]=[CH:32][CH:33]=[CH:34][C:35]=1[O:15][CH2:14][CH:13]([N:12]1[C:11]2[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=2[N:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COC(=O)c1ccccc1O
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: COC(=O)c1ccccc1OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and methyl salicylate (commercially available) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. White solid (50%). MS (Turbo Spray): m/z=525.0 [M+H].
Reaction SMILES: OO.C([C:6]1[CH:18]=[CH:17][C:9]([O:10][C@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=1)(=O)C.S([O-])([O-])=O.[Na+].[Na+]>O.C(O)=O>[C:12]([O:14][C:6]1[CH:7]=[CH:8][C:9]([O:10][C@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:17][CH:18]=1)(=[O:13])[CH3:11]
Reactant: COC(=O)[C@@H](C)Oc1ccc(C(C)=O)cc1
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: COC(=O)[C@@H](C)Oc1ccc(OC(C)=O)cc1
Temperature: 35 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
54.4 g (0.48 mol) of a 30% strength solution of hydrogen peroxide in water was added dropwise to the solution of 88.93 g (0.4 mol) of methyl (R)-2-(4-acetylphenoxy)propionate in 356 g of formic acid at 35° C. over the course of 1 h. After stirring at 35° C. for 5 hours, the excess hydrogen peroxide was decomposed with 5 g of sodium sulfite. The mixture was finally concentrated under reduced pressure and subjected to a short-path distillation at 150°-160° C. under 0.5 mbar. Yield: 96% (94-95% enantiomeric excess).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1.[CH3:16][CH:17]1[CH2:21][CH2:20][CH2:19][NH:18]1>CN1C(=O)CCC1>[CH3:16][CH:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1
Reactant: CC1CCCN1
Reactant: Cc1nc(C#Cc2ccc(Cl)nc2)cs1
Solvent: CN1CCCC1=O
Product: Cc1nc(C#Cc2ccc(N3CCCC3C)nc2)cs1
Temperature: 180 °C

Procedure:
200 mg (0.85 mmol, 1 eq) 2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine, 0.30 mL (2.5 mmol, 3 eq) 2-methylpyrrolidine and 2 mL NMP were combined. The reaction mixture was heated in the microwave at 180° C. for 30 min, quenched with pH 10 PBS, extracted with DCM. Silica gel chromatography (gradient 10% to 50% EtOAc/Hexanes) gave 2-(2-methylpyrrolidin-1-yl)-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (L-001 120970). The mono HCl salt was made by dissolving the free base into diethyl ether, adding 1 eq of HCl, and isolated by filtration. LC-MS calculated for C16H17N3S 283, observed m/e 284.0 (M+H)30.