Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:11])[CH2:4][CH2:3]1.[CH2:25]([Br:29])[CH2:26][CH2:27][CH3:28].C(O)(C)C.II>CO.C1(C)C=CC=CC=1>[Br-:29].[CH2:25]([N+:2]1([CH3:1])[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:11])[CH2:6][CH2:7]1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCOC(=O)CCN1CCN(C)CC1
Reactant: CCCCBr
Agent: II
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CC(C)O
Product: CCCCCCCCCCCCOC(=O)CCN1CC[N+](C)(CCCC)CC1
Product: [Br-]

Procedure:
In a 100-mL round bottom flask, 5.0 g (0.015 moles) of dodecyl 3-(4-methylpiperazine-1-yl)propanoate and 7.3 g (0.044 moles) of butyl bromide are combined with 10 mL of isopropyl alcohol. This solution is heated to reflux overnight. Thin layer chromatography (TLC) was used to monitor the progress of the reaction with 1:1 methanol/toluene as a mobile phase and iodine to reveal the components on the plate. After the reaction is complete, the solvent and excess of butyl bromide are evaporated under vacuum. Finally, the resulting solid is dried under vacuum at 120° C. 1H-NMR (300 MHz, CDCl3): δ 3.92 (t, 5.9 Hz, 2H), 3.76 (m, 2H), 3.56 (m, 4H), 3.35 (s, 3H), 2.91 (m, 6H), 2.46 (t, 6.6 Hz, 2H), 1.67 (m, 2H), 1.47 (m, 2H), 1.12 (m, 24H), 0.74 (m, 6H). 13C-NMR (75 MHz, CDCl3): δ 170.98, 64.61, 59.14, 51.84, 45.88, 31.44, 31.28, 30.81, 29.18, 29.16, 29.13, 29.08, 28.87, 28.81, 28.11, 25.50, 25.43, 22.21, 21.96, 21.60, 13.66, 13.49.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15].O>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: COCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COCCCOS(=O)(=O)c1ccc(C)cc1

Procedure:
A solution of 3-methoxy-1-propanol (6 g, 65.24 mmol), triethylamine (27.5 mL, 195.7 mmol) and tosylchloride (18.85 g, 97.9 mmol) in methylene chloride (50 mL) is stirred for 3 h at room temperature under nitrogen. The mixture is poured into H2O, and the aqueous layer extracted twice with methylene chloride. The combined organic extracts are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (hexane/EtOAc 4/1) to afford the title compound as an orange oil: MS 261.9 [M+18]; Rt (HPLC, Nucleosil C18, 10:90-100:0 CH3CN/H2O+0.1% TFA within 5 min, then 100% CH3CN+0.1% TFA): 5.21 min.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:16][CH2:15]2)[C@H:10]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:9]1)C1C=CC=CC=1.Cl.[H][H].C(N(CC)CC)C.[F:42][C:43]([F:58])([F:57])[C:44]1[CH:45]=[C:46]([CH:50]=[C:51]([C:53]([F:56])([F:55])[F:54])[CH:52]=1)[C:47](Cl)=[O:48]>CO.[Pd].O>[F:42][C:43]([F:58])([F:57])[C:44]1[CH:45]=[C:46]([CH:50]=[C:51]([C:53]([F:56])([F:55])[F:54])[CH:52]=1)[C:47]([N:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:25])[C:21]([F:24])([F:22])[F:23])[CH2:16][CH2:15]2)[C@H:10]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:9]1)=[O:48]
Reactant: [H][H]
Reactant: O=C(N1CCN([C@H]2CCN(Cc3ccccc3)C[C@H]2c2ccccc2)CC1)C(F)(F)F
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCN(C(=O)C(F)(F)F)CC2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
Rac-cis-1-[4-(1-benzyl-3-phenyl-piperidin-4-yl)-piperazin-1-yl]-2,2,2-trifluoro-ethanone (4.60 g, 10.7 mmol) was dissolved in methanol (200 mL) and concentrated hydrochloric acid (1.0 mL) and palladium on charcoal (10%, 700 mg) were added. After stirring in a hydrogen atmosphere (1 bar) at room temperature overnight the mixture was filtered and the solvent was evaporated. The crude intermediate was dissolved in dichloromethane (100 mL) and triethylamine (7.25 mL, 51.7 mmol) and 3,5-bistrifluoromethyl-benzoyl chloride (2.06 mL, 11.4 mmol) were added. The reaction mixture was stirred at room temperature overnight and than diluted with 100 mL water. The organic phase was separated and the aqueous layer was extracted twice with 100 mL dichloromethane. Organic phases were pooled, dried with magnesium sulfate and evaporated. Flash chromatography on silica gel with hexane/ethyl acetate/triethyl amine 90:10:1 gave the desired product (5.26 g, 87%) as a white foam, MS: m/e=582.0 (M+H+).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.Cl[CH2:17][C:18]1[N:22]=[C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[O:20][N:19]=1>>[S:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[C:21]1[O:20][N:19]=[C:18]([CH2:17][N:7]2[C:8]3[C:4](=[C:3]([C:2]([F:14])([F:1])[F:15])[C:11]([C:12]#[N:13])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)[N:22]=1
Reactant: ClCc1noc(-c2cccs2)n1
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cccs3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 23 using 4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-(2-thienyl)-1,2,4-oxadiazole: MS (ES) m/z 375 (M+1).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([CH:10]=[O:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[H-].[Na+].[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>C1COCC1>[S:14]([N:1]1[C:5]2=[N:6][CH:7]=[C:8]([CH:10]=[O:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: O=Cc1cnc2[nH]ccc2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(C=O)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
step2: To a solution of 1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (500 mg, 3.42 mmol) in THF (50 mL) at 0° C. was added NaH (205 mg, 60% in oil, 5.13 mmol) with vigorous stirring. After 30 min, TsCl (845 mg, 4.45 mmol) was added. The reaction mixture was stirred at RT for 18 h, and then the solvent was removed in vacuo. The residue was partitioned between DCM (300 mL) and water (100 mL). The organic layer was separated, dried (MgSO4), filtered, and concentrated to afford 580 mg (56%) of 1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde as yellow solid. MS (ESI) m/z: 301.2 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]=[O:8])=[CH:5][NH:4][N:3]=1.F[C:10]1[C:15]([C:16]#[N:17])=[CH:14][CH:13]=[CH:12][N:11]=1>>[CH:7]([C:6]1[C:2]([CH3:1])=[N:3][N:4]([C:10]2[C:15]([C:16]#[N:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=1)=[O:8]
Reactant: N#Cc1cccnc1F
Reactant: Cc1n[nH]cc1C=O
Product: Cc1nn(-c2ncccc2C#N)cc1C=O
Yield: 23 %

Procedure:
The compound of Preparation 20 is essentially prepared as described in Preparation 19 by using 3-methyl-1H-pyrazole-4-carbaldehyde and 2-fluoropyridine-3-carbonitrile. The title compound is obtained with a yield of 23%. MS (m/z): 213 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)[CH3:2].[Cl:14][C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19](Cl)[N:18]=[CH:17][N:16]=1>>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:19]2[C:20]([N+:21]([O-:23])=[O:22])=[C:15]([Cl:14])[N:16]=[CH:17][N:18]=2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Reactant: CCOC(=O)Cc1ccc(N)cc1
Product: CCOC(=O)Cc1ccc(Nc2ncnc(Cl)c2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Aminophenylacetic acid ethyl ester (0.93 g, 5.2 mmol) is added to a solution of 4,6-dichloro-5-nitropyrimidine (2 g, 10.4 mmol, 2 equiv). The resulting mixture is stirred for 2 h at rt and 4-aminophenylacetic acid ethyl ester (0.47 g, 2.6 mmol, 0.5 equiv) is added. The reaction mixture is stirred for 15 min and filtered. The filtrate is concentrated. The residue is dissolved in EtOAc and a saturated aqueous solution of sodium bicarbonate. The layers are separated. The aqueous phase is extracted with EtOAc. The combined organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. Purification of the residue by silica gel column chromatography (Hexane/EtOAc, 4:1) provides the title compound as a yellow solid: ES-MS: 335.0/337.0 [M-H]−; single peak at tR=4.73 min (System 1); Rf=0.22 (Hexane/EtOAc, 4:1).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH:31]1([NH2:34])[CH2:33][CH2:32]1>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:29])[C:15]2[O:14][CH:13]([CH2:12][NH:34][CH:31]3[CH2:33][CH2:32]3)[CH2:17][C:16]=2[CH:18]=1
Reactant: NC1CC1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4c(C)cccc4C)c3O2)cc1
Product: Cc1cccc(C)c1-c1cc(Cl)cc2c1OC(CNC1CC1)C2

Procedure:
The title compound was prepared (0.056 g, 34%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and cyclopropylamine (0.39 g, 6.77 mmol). mp 214-216° C.
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:11]([CH3:27])[C:12]([CH2:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)C1C=CC=CC=1.Cl>C(O)C>[Cl:26][C:21]1[CH:20]=[C:19]([CH:24]=[C:23]([Cl:25])[CH:22]=1)[CH2:18][C:12]1[N:11]([CH3:27])[C:10]([CH2:9][OH:8])=[N:14][C:13]=1[CH:15]([CH3:16])[CH3:17]
Reactant: CC(C)c1nc(COCc2ccccc2)n(C)c1Cc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: CCO
Product: CC(C)c1nc(CO)n(C)c1Cc1cc(Cl)cc(Cl)c1
Temperature: 110 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
In 3 ml of ethanol was dissolved 470 mg (1.17 mmol)of 2-benzyloxymethyl-5-(3,5-dichlorobenzyl)-4-isopropyl-1-methyl-1H-imidazole (58), followed by addition of 10 ml of concentrated hydrochloric acid (36% aqueous solution), and the mixture was refluxed under heating at 110° C. After 3 hours, the reaction mixture was concentrated under reduced pressure, neutralized with aqueous sodium hydroxide, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. To the crude crystals, 5 ml of diethyl ether was added, and filtered to give 350 mg of [5-(3,5-dichlorobenzyl)-4-isopropyl-1-methyl-1H-imidazol-2-yl]methanol (59a)(yield 95.9%).
Reaction SMILES: [C:1]([C:4]1[CH:21]=[CH:20][C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12][C:6]=2[CH:5]=1)(=O)[CH3:2].[Se](=O)=O.[CH2:25]([NH2:28])[CH2:26][NH2:27].[OH-].[K+]>O1CCOCC1.O.C(O)C>[C:16]([O:15][C:13]([N:10]1[CH2:9][CH2:8][C:7]2[CH:20]=[CH:21][C:4]([C:1]3[CH:2]=[N:28][CH:25]=[CH:26][N:27]=3)=[CH:5][C:6]=2[CH2:12][CH2:11]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: NCCN
Reactant: CC(=O)c1ccc2c(c1)CCN(C(=O)OC(C)(C)C)CC2
Agent: O=[Se]=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2ccc(-c3cnccn3)cc2CC1
Yield: 25.6 %

Procedure:
To a stirred solution of 7-acetyl-3-(tert-butyloxycarbonyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (12 g, 42 mmol) in dioxan (60 ml) was added selenium dioxide (4.61 g, 42 mmol) in dioxan (60 ml) and water (15 ml). The mixture was heated under reflux for 18 h., cooled and the solid residue filtered. The filtrate was evaporated in vacuo and the residue azeotroped with toluene to give an orange gum which was dissolved in ethanol and added dropwise to a stirred solution of ethylenediamine (3 g, 50 mmol) in ethanol at 0° C. After the addition was complete, KOH (2.6 g, 46 mmol) was added and the reaction heated under reflux for 3 h. The reaction mixture was then allowed to cool and evaporated in vacuo. The residue was partitioned between water and dichloromethane and the combined organic extracts dried and evaporated in vacuo to give a brown gum. Purification by silica gel chromatography (eluant 20% EtOAc:hexane) gave the title compound as a yellow oil (3.5 g).
Reaction SMILES: [F:1][CH:2]([F:19])[CH2:3][O:4][C:5]1[C:10]([C:11]2([F:15])[CH2:14][CH2:13][CH2:12]2)=[CH:9][N:8]=[C:7]([C:16]([OH:18])=O)[CH:6]=1.[NH2:20][C:21]1([CH2:27][C:28]([NH2:30])=[O:29])[CH2:24][S:23](=[O:26])(=[O:25])[CH2:22]1>>[NH2:30][C:28](=[O:29])[CH2:27][C:21]1([NH:20][C:16]([C:7]2[CH:6]=[C:5]([O:4][CH2:3][CH:2]([F:1])[F:19])[C:10]([C:11]3([F:15])[CH2:12][CH2:13][CH2:14]3)=[CH:9][N:8]=2)=[O:18])[CH2:22][S:23](=[O:25])(=[O:26])[CH2:24]1
Reactant: NC(=O)CC1(N)CS(=O)(=O)C1
Reactant: O=C(O)c1cc(OCC(F)F)c(C2(F)CCC2)cn1
Product: NC(=O)CC1(NC(=O)c2cc(OCC(F)F)c(C3(F)CCC3)cn2)CS(=O)(=O)C1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 4-(2,2-difluoroethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carboxylic acid (example 308b) and 2-(3-amino-1,1-dioxo-thietan-3-yl)acetamide (example 160d) as starting materials and isolated (11.5 mg, 14%); MS (ESI, m/z): 436.3 (M+H+).
Reaction SMILES: Cl.[CH3:2][C:3]1([NH2:7])[CH2:6][CH2:5][CH2:4]1.Cl[C:9]1[N:18]([CH3:19])[C:17](=[O:20])[C:16]2[C:11](=[C:12]([I:21])[CH:13]=[CH:14][CH:15]=2)[N:10]=1>C1COCC1.CCOC(C)=O>[I:21][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[N:10]=[C:9]([NH:7][C:3]1([CH3:2])[CH2:6][CH2:5][CH2:4]1)[N:18]([CH3:19])[C:17]2=[O:20]
Reactant: CC1(N)CCC1
Reactant: Cn1c(Cl)nc2c(I)cccc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1c(NC2(C)CCC2)nc2c(I)cccc2c1=O
Temperature: 80 °C
Yield: 85 %

Procedure:
A heterogeneous mixture of 1-methylcyclobutanamine hydrochloride (Oakwood Chemical, cat #041889; 0.69 g, 5.70 mmol) (Oakwood Chemical, cat #041889), 2-chloro-8-iodo-3-methylquinazolin-4(3H)-one (700) (0.96 g, 3.0 mmol) and TEA (2.1 mL, 15.10 mmol) in 2 mL of THF in a sealed glass tube was heated in an oil bath at 80° C. for 4 h. The reaction mixture was diluted with EtOAc, washed with water followed by brine. The organic extract was concentrated and the residue was purified on a silica gel column (25-55% EtOAc in hexanes) to afford 8-iodo-3-methyl-2-((1-methyl-cyclobutyl)amino)quinazolin-4(3H)-one (0.94 g, 2.55 mmol, 85% yield) as a yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.11 (1H, dd, J=7.4, 1.4 Hz), 7.92 (1H, dd, J=7.8, 1.4 Hz), 7.03 (1H, s), 6.87 (1H, t, J=7.7 Hz), 3.40 (3H, s), 2.20-2.46 (4H, m), 1.88 (2H, m), 1.72 (3H, s). m/z (ESI, +ve) 370.1 (M+H)+).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CO>[Br-:21].[OH:10][C:9]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([CH2:8][CH2:7]1)[CH2:2][CH2:3]2
Reactant: OC(c1cccs1)(c1cccs1)C12CCN(CC1)CC2
Reactant: BrCCc1ccccc1
Solvent: CO
Product: OC(c1cccs1)(c1cccs1)C12CC[N+](CCc3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 3792.8 %

Procedure:
Following the general procedure outlined in Example 4, 1-azabicyclo[2.2.2]oct-4-yl(di-2-thienyl)methanol (0.0658 g, 0.215 mmol) and (2-bromoethyl)benzene (0.050 mL, 0.366 mmol) in 1 MeOH/1 CHCl3 (4.0 mL) were reacted to give the desired product (0.051 4 g, 48.9%). EI-MS m/z 410 (M+) Rt (1.83 min).
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:27]=[C:28]([OH:30])[CH:29]=3)[C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=3)=[O:18])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.Br[CH:32]1[CH2:36][CH2:35][N:34]([CH3:37])[C:33]1=[O:38].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:27]=[C:28]([O:30][C@H:32]4[CH2:36][CH2:35][N:34]([CH3:37])[C:33]4=[O:38])[CH:29]=3)[C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=3)=[O:18])=[CH:9][CH:8]=2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: CN1CCC(Br)C1=O
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(Oc3ccc(C(=O)N4CCC4)nc3)c2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Temperature: 25 °C
Reaction time: 21 h
Yield: 76 %

Procedure:
3-[6-(Azetidine-1-carbonyl)pyridin-3-yl]oxy-5-hydroxy-N-(5-methylpyrazin-2-yl)benzamide (442 mg, 1.1 mmol) (Intermediate 1) and 3-bromo-1-methyl-pyrrolidin-2-one (Intermediate 4) (385 mg, 2.2 mmol) were dissolved in DMF and treated with potassium carbonate (377 mg, 2.7 mmol) and stirred at room temperature for 21 hours. The DMF was evaporated, the residue partitioned between ethyl acetate (90 mL) and water (20 mL). The organic layer was separated, washed with brine, dried (MgSO4) and evaporated to give an oil which was purified by chromatography on silica eluting with 0-6% methanol in DCM to give the racemic product (420 mg). 3-[6-(Azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-N-(5-methylpyrazin-2-yl)benzamide was separated from its enantiomer by chiral HPLC using a Merck 50 mm 20 μm Chiralcel OJ No. CE001 column eluting with methanol at a flow rate of 50 mL/min; 420 mg of racemic material was separated in 3 injections of 15 mL at 11 mg/ml in 1:1:1 acetonitrile/ethanol/methanol to afford the product (179 mg, 32%) which eluted after its enantiomer. 1H NMR δ (400 MHz, CDCl3): 2.08-2.18 (m, 1H), 2.28 (quintet, 2H), 2.47-2.57 (m, 1H), 2.48 (s, 3H), 2.86 (s, 3H), 3.29-3.37 (m, 1H), 3.42-3.48 (m, 1H), 4.18 (t, 2H), 4.64 (t, 2H), 4.86 (t, 1H), 6.91 (s, 1H), 7.14 (s, 1H), 7.32 (d, 1H), 7.39 (s, 1H), 8.05 (d, 1H), 8.07 (s, 1H), 8.26 (s, 1H), 8.37 (s, 1H), 9.45 (s, 1H); m/z 503 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.[CH2:12]([OH:19])[C:13]([NH2:18])([CH2:16][OH:17])[CH2:14][OH:15].[C:20]([C:22]1[CH:23]=[N:24][N:25]2[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][C:28]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=3)=[N:27][C:26]=12)#[CH:21].C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.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[Pd]Cl>[OH:19][CH2:12][C:13]([NH:18][S:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:21]#[C:20][C:22]2[CH:23]=[N:24][N:25]3[C:30]([C:31]([F:32])([F:34])[F:33])=[CH:29][C:28]([C:35]4[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:42])[F:43])=[CH:37][CH:36]=4)=[N:27][C:26]=23)[CH:3]=1)(=[O:10])=[O:9])([CH2:16][OH:17])[CH2:14][OH:15]
Reactant: NC(CO)(CO)CO
Reactant: O=S(=O)(Cl)c1cncc(Br)c1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S(=O)(NC(CO)(CO)CO)c1cncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1
Reaction time: 16 h
Yield: 9.7 %

Procedure:
To a solution of 5-bromo-pyridine-3-sulfonyl chloride (Example B.2, step 2) (500 mg, 2 mmol) in DMF (5 mL) at 5° C. was added Tris (260 mg, 2 mmol) in DMF (5 mL) and the mixture was vigorously stirred at room temp. for 16 h, then addition of 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (692 mg, 2 mmol), triethylamine (0.82 mL, 6 mmol), PdCl2(PPH3)2 (41 mg, 3 mol %), PPh3 (31 mg, 6 mol %) were stirred for 10 minutes at 23° C. while being purged with Argon, then CuI (3 mg, 1 mol %) was added. Stirring was continued for 16 h at 90° C. Purification by SiO2 column chromatography (heptane/EtOAc 3:1), trituration with ether, filtration and dried to give the product as an orange solid (120 mg, 10%). MS (ISN) 613.8 [(M−H)−]; mp 230-232° C.
Reaction SMILES: [CH2:1]([OH:5])[CH:2]([OH:4])[CH3:3].[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].CCN(C(C)C)C(C)C>C(Cl)Cl.CCOCC>[Si:10]([O:5][CH2:1][CH:2]([OH:4])[CH3:3])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(O)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: CC(O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of propylene glycol (1.0 g, 13 mmol) in DCM (60.0 mL) was added tert-butyldimethylchlorosilane (2.0 g, 13 mmol) followed by DIPEA (3.2 mL, 18 mmol). The reaction mixture was stirred at ambient temperature for 18 hours. The solution was diluted with ether, washed with saturated aqueous NaHCO3, brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:9][CH2:8][CH2:7][O:6]C1=O)[CH3:2].[C:10](=[O:13])([O-])[O-:11].[K+].[K+].[CH3:16]O>S(=O)(=O)(O)O>[CH2:1]([CH:3]([CH2:9][CH2:8][CH2:7][OH:6])[C:10]([O:11][CH3:16])=[O:13])[CH3:2]
Reactant: CO
Reactant: O=C([O-])[O-]
Reactant: CCC1CCCOC1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCC(CCCO)C(=O)OC
Reaction time: 0.33 h
Yield: 86 %

Procedure:
A solution of 30.0 g (0.234 mmol) of 2-ethylvalerolactone in 150 mL of dry methanol and 0.5 mL of conc. sulfuric acid was stored under argon for 17 h at 20° C. Then 10.0 g of potassium carbonate was added and the mixture stirred for 20 min. After filtration, and concentration at 40° C. under vacuum, the residue was dissolved in 100 mL of ether. The solution was washed with 200 mL of satd. sodium carbonate, 100 mL of satd. brine, dried over MgSO4, filtered, concentrated and the residue distilled to give 32.1 g (86%) of methyl 2-ethyl-5-hydroxyvalerate, bp 58°-60° C. (0.5 mm Hg).
Reaction SMILES: [Cl:1][C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.[I:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.CCOC(C)=O.O>[Cl:1][C:2]1[N:11]([CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[I:15])[C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1
Reactant: ClCc1ccccc1I
Reactant: Cn1c(=O)c2[nH]c(Cl)nc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2I)n(C)c1=O
Temperature: 25 °C
Reaction time: 168 h

Procedure:
8-Chlorotheophylline (8.5 g, 39.6 mmol) was dissolved in 400 ml of DMF and 2-iodobenzyl chloride (10.0 g, 39.6 mmol), potassium carbonate (5.47 g, 39.6 mmol), and potassium iodide (10 mg, 0.06 mmol) were added. The mixture was stirred at room temperature for 7 days. Water (2500 ml) and EtOAc (800 ml) were added and the layers were separated. The aqueous layer was extracted with 2×500 ml of EtOAc, and the combined organic layer was washed with 500 ml of water, 500 ml of brine, dried over sodium sulphate, and filtered. The solvent was evaporated and the crude product was crystallized from diethyl ether and petrol, to give compound (5A) as white crystals. The mother liquor was evaporated and resuspended in diethyl ether and petrol, to give a second crop of compound (5A).