Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[N+]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)([O-])=O.[CH2:19]([OH:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[C:21]1([CH2:20][CH2:19][O:27][C:10]2[CH:11]=[C:12]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:14][CH:15]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Reactant: OCCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: O=[N+]([O-])c1cccc(OCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 168 h
Yield: 219.9 %

Procedure:
Potassium t-butoxide (11.2 g; 0.1 mol) is added under a nitrogen atmosphere to a stirred mixture of m-dinitrobenzene (16.8 g; 0.1 mol), phenethyl alcohol (12.2 g; 0.1 mol) and hexamethylphosphoramide (HMPA; 200 ml). Almost instantly a dark red color develops and then slowly fades in the course of the reaction and turns black. The reaction mixture is stirred for 7 days at room temperature. It is then drowned in water, and extracted twice with methylene chloride (500 ml). The methylene chloride solution is washed with water (3X), saturated brine (1X), dried over magnesium sulfate and evaporated to yield 53.5 g of a dark oil. Additional solvent (HMPA) and some m-dinitrobenzene is removed from the oil by heating same at about 90° C. under 0.5 mm vacuum. The residual oil (~25 g) is chromatographed on 1 kg silica gel with 3:1 hexane:methylene chloride. Collected fractions, containing the same material by thin layer chromatography, are combined and evaporated to afford 7.4 g (30%) of product, a light yellow oil. On standing, the oil crystallizes, mp. 46.5°-49° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].Cl[C:9]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.CO.N>ClCCl>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:9]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: NCCCCCN
Reactant: COc1cc(Cl)nc2ccccc12
Agent: N
Solvent: ClCCl
Solvent: CO
Product: COc1cc(NCCCCCN)nc2ccccc12

Procedure:
The title compound was prepared by an analogous procedure to that described in example 1a from 1,5-diaminopentane (5 g, 49 mmol) and 2-chloro-4-methoxyquinoline (0.93 g, 4.8 mmol) to yield, after chromatography over silica gel eluting with an increasing concentration of 9:1 methanol/ammonia in dichloromethane, a cream coloured solid (30%). δH (CDCl3) 1.0-1.8 (8H, envelop), 2.72 (2H, t), 3.4-3.5 (2H, m), 3.97 (3H, s), 4.6-4.79 (1H, m), 5.94 (1H, m), 7.18 (1H, t), 7.51 (1H, t), 7.60 (1H, d), 7.96 (1H, d). MS (ES+) 260 (90%) MH+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:21])([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][C:10](OCC)=[O:11])=[CH:4][CH:3]=1.[CH3:22][NH2:23]>O.C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:21])([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][C:10]([NH:23][CH3:22])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(O)(c1ccc(Br)cc1)c1cccnc1
Reactant: CN
Solvent: CCO
Solvent: O
Product: CNC(=O)CC(O)(c1ccc(Br)cc1)c1cccnc1
Yield: 79 %

Procedure:
19.4 g (0.05 mole) of ethyl 3-(4-bromophenyl)-3-hydroxy-3-(3-pyridyl)-propanoate, 200 ml of 40% solution of methylamine in water and 30 ml of absolute ethanol was stirred for 24 hours at room temperature. The precipitate was filtered off and recrystallized from isopropyl alcohol, which gave 13.2 g (79%) of the amide. M.p. 188°-191° C. The formula C15H15BrN2O2 was verified through elemental analysis. (The elemental analyses throughout this application were carried out for all elements of the compounds prepared, and are within ± 0.4 percent of the theoretical values if not otherwise stated.) ##STR28##
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH3:13])[CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=O)=[CH:31][CH:30]=1>O1CCCC1>[F:27][C:28]([F:38])([F:39])[C:29]1[CH:30]=[CH:31][C:32]([C:33]2[O:5][C:4](=[O:6])[C:3]3[CH:7]=[C:8]([C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)([CH3:13])[CH3:12])[CH:9]=[CH:10][C:2]=3[N:1]=2)=[CH:36][CH:37]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(c1ccccc1)c1ccc(N)c(C(=O)O)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(c1ccccc1)c1ccc2nc(-c3ccc(C(F)(F)F)cc3)oc(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.1 %

Procedure:
To a solution of 2-amino-5-α-cumylbenzoic acid (13.5 g, 0.53 mol, prepared in Example 20) and triethylamine (7.8 g, 0.56 mol) in tetrahydrofuran (200 mL) is added dropwise at room temperature a solution of 4-trifluoromethylbenzoyl chloride (11 g, 0.53 mol). The resulting suspension is stirred at room temperature overnight, then filtered and concentrated to a solid that is then suspended in acetic anhydride and heated to 115° C. for three hours. The resulting solution is cooled and concentrated to an oil. The oil is taken up in ethanol (100 mL) and allowed to stand. The resulting solid formed is coiled and dried to give 15.4 g of the title compound melting at 104–105° C. The structure of the compound is confirmed by 1Hnmr (CDCl3) 500 MHz: δ 1.78 (s, 6H); 7.23 (t, 1H); 7.23 (d, 2H); 7.31 (t, 2H); 7.60 (d, 1H); 7.64 (dd, 1H); 7.78 (d, 2H); 8.26 (d, 1H). 19Fnmr (fluorinated species at −69.57 ppm).
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:20])[N:7]3[C:21]([CH3:24])=[N:22][N:23]=[C:6]3[N:5]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:4]=2[N:3]=1.[CH3:30][S:31]C.[Na].C(COC)OC>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:20])[N:7]4[C:21]([CH3:24])=[N:22][N:23]=[C:6]4[N:5]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:4]=3[N:3]=[C:2]2[S:31][CH3:30])=[CH:13][CH:14]=1
Reactant: CCCCCn1c2nc(Br)n(Cc3ccc(OC)cc3)c2c(=O)n2c(C)nnc12
Reactant: CSC
Agent: [Na]
Solvent: COCCOC
Product: CCCCCn1c2nc(SC)n(Cc3ccc(OC)cc3)c2c(=O)n2c(C)nnc12
Yield: 78.1 %

Procedure:
A mixture of 7-bromo-6-(4-methoxybenzyl)-3-methyl-9-pentyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (271 mg, 0.6 mmol) and sodium methyl sulfide (45.5 mg, 0.65 mmol) in dimethoxyethane (13.4 ml, 129 mmol) was refluxed for 2 h. The reaction was quenched with water. The solid formed was filtered and dried to yield the desired product (200 mg, 79.5%). LCMS calculated for C21H27N6O2S (M+H): 427.2; found 427.2.
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:30][CH3:31])=[C:24]([C:27](=[O:29])[NH2:28])[CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:12][C:11]=2[C:32]([F:35])([F:34])[F:33])C=CC=CC=1.[CH3:37][NH2:38]>>[C:27]([C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:30][CH3:31])[N:20]=[CH:19][CH:18]=[C:17]2[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:8]([NH:38][CH3:37])=[O:7])=[C:11]([C:32]([F:34])([F:33])[F:35])[CH:12]=1)(=[O:29])[NH2:28]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)c(C(F)(F)F)c3)c2cc1C(N)=O
Reactant: CN
Product: CNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(N)=O)cc23)cc1C(F)(F)F
Reaction time: 0.17 h

Procedure:
After adding [4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-trifluoromethylphenyl]carbamic acid phenyl ester (25 mg) to methylamine 2N tetrahydrofuran solution (1.00 ml), the mixture was stirred for 10 minutes. The precipitated crystals were filtered out and washed with tetrahydrofuran to obtain the title compound (10 mg).
Reaction SMILES: [C:1]1([N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]1([NH:28][NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[C:22]1([NH:28][N:29]=[CH:12][C:11]2[CH:14]=[CH:15][C:8]([N:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:9][CH:10]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NNc1ccccc1
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: C(=NNc1ccccc1)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 87 %

Procedure:
A mixture of 4-(diphenylamino)benzaldehyde (10 g, 0.037 mol) and 300 ml of methanol was added to 500 ml 3-neck round bottom flask equipped with a reflux condenser and a mechanical stirrer. The mixture was mildly heated by a heating mantle until all solid entered into solution. Then a solution of N-phenylhydrazine (5.94 g, 0.055 mol, from Aldrich, Milwauke, Wis.) in 50 ml of methanol was added. The reaction mixture was refluxed for 0.5 hour and then cooled to room temperature. The yellow precipitated product was filtered off, washed with a large amount of methanol, and dried to yield 11.7 g (86.7%) of 4-(diphenylamino)benzaldehyde N-phenylhydrazone. The melting point was found to be 168–169° C. The 1H-NMR spectrum (100 MHz) of the product in CDCl3 was characterized by the following chemical shifts (δ, ppm): 6.55–7.64 (m, 21H, Ar, ═CH, —NH). The IR spectrum of the product was characterized by the following absorption frequencies (KBr, cm−1): ν(N—H) 3294, ν(arene C—H) 3026, ν(C═C in Ar) 1595; 1489, ν(C—N) 1282; 1257, γ(Ar) 750; 731. The mass spectrum of the product was characterized by the following mass peaks (m/z): 364 (100%, M+1), 314, 223, 159.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[O:13]=[C:14]1[CH2:17][CH:16]([C:18]([OH:20])=O)[CH2:15]1.[CH3:21][NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH2:23]([N:22]([CH3:21])[C:18]([CH:16]1[CH2:15][C:14](=[O:13])[CH2:17]1)=[O:20])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CNCc1ccccc1
Reactant: O=C1CC(C(=O)O)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)C(=O)C1CC(=O)C1
Yield: 64.2 %

Procedure:
CDI (40 g, 0.25 mol) was added to a solution of 3-oxo-cyclobutanecarboxylic acid (23 g, 0.2 mol) in THF (100 ml) at 0° C. under stirring, the mixture was stirred at RT for 1 h. N-methylbenzylamine (32 ml, 0.25 mol) was added to the mixture and the mixture was stirred at RT for 3 h and evaporated. The residue was purified by chromatography (silica gel, 63-100 μm, 500 g, CHCl3/MeOH 100:0→95:5). The title compound (27.9 g, 64%) was obtained as a colorless oil. 1H NMR data (DMSO-d6): 7.20 (m, 5H, Ph); 4.62 s, 4.55 s (2H, CH2); 3.46-3.62 (m, 1H); 3.28 (m, 4H,); 2.85 s, 2.94 s (3H, NCH3).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C([N:12]([CH2:15][CH3:16])[CH2:13]C)C.N1CCC1>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:12]2[CH2:13][CH2:16][CH2:15]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCN(CC)CC
Agent: C1CNC1
Solvent: C1CCOC1
Product: Brc1ccc(CN2CCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
A solution of 4-bromobenzyl bromide (1.00 g, 4.0 mmol) and triethylamine (0.84 ml, 6.0 mmol) in THF (20 mL) was stirred at ambient temperature for 10 minutes. Azetidine (0.54 ml, 8.0 mmol) was then added and a white precipitate resulted. The slurry was stirred at ambient temperature for 18 h then evaporated in vacuo. The resultant residue was partitioned between DCM and saturated aqueous sodium hydrogen carbonate, the organic phase was separated, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (0.76 g, 3.40 mmol) as a colourless oil. 1H NMR (CDCl3, 400 MHz): 7.42 (d, J=8.3 Hz, 2H), 7.15 (d, J=8.2 Hz, 2H), 3.50 (s, 2H), 3.19 (t, J=7.0 Hz, 4H), 2.08 (p, J=7.0 Hz, 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[CH3:12][S-:13].[Na+]>C1COCC1.C(=O)(O)[O-].[Na+]>[Cl:11][C:4]1[C:5]2[CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=[C:2]([S:13][CH3:12])[N:3]=1
Reactant: C[S-]
Reactant: Clc1nc(Cl)c2c(n1)CCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nc(Cl)c2c(n1)CCC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.3 %

Procedure:
A mixture of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.250 g, 1.32 mmol) and sodium thiomethoxide (0.093 g, 1.32 mmol) in THF (10 mL) was stirred at rt for 6 h. After this time, the mixture was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.210 g, 84%) as an off-white solid. MW=200.69. 1H NMR (DMSO-d6, 300 MHz) δ 2.90 (t, J=7.6 Hz, 2H), 2.71 (t, J=7.6 Hz, 2H), 2.56 (s, 3H), 2.10 (quin, J=7.6 Hz, 2H); APCI MS m/z 201 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].C(OCC)(OCC)[O:14][CH2:15][CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C(Cl)Cl.C(O)CO>[CH3:1][C:2]1([C:4]2[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=2)[O:14][CH2:15][CH2:16][O:3]1
Reactant: CCOC(OCC)OCC
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: OCCO
Product: CC1(c2ccc([N+](=O)[O-])cc2)OCCO1
Temperature: 25 °C

Procedure:
P-Nitroacetophenone (1.65 g, 10 m mol), ethylene glycol (5 ml, 89 m mol), triethyl orthoformate (2.96 g, 20 m mol), and p-toluenesulfonic acid (0.086 g, 0.5 m mol) were combined in methylene chloride (4 ml). The solution was heated with an oil bath (50°-70° C., 6 hrs), cooled to room temperature, and poured into excess 10% sodium hydroxide solution. The phases were separated and the aqueous phase was extracted twice with methylene chloride. The combined organic phase was washed three times with water and dried with anhydrous sodium sulphate. Evaporation of the solvent left a light yellow product (1.78 g) with mp. 69°-71° C., [lit. 73°-75° C., see J. Pharm. Sci. 57, 784 (1968)].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])[N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1>>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([O:16][CH3:17])=[C:9]([C:4]2[N:3]=[C:2]([NH:25][C:22]3[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=3)[CH:7]=[C:6]([NH2:8])[CH:5]=2)[CH:14]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COc1ccc(Cl)cc1-c1cc(N)cc(Cl)n1
Product: COc1ccc(Cl)cc1-c1cc(N)cc(Nc2ccc(Cl)cc2)n1
Yield: 22 %

Procedure:
Following the method described in Example 3, 2-chloro-6-(5-chloro-2-methoxy-phenyl)-pyridin-4-yl-amine and 4-chloro-phenylamine, provided the title compound (22% yield). 1H NMR (acetone-d6) δ 3.90 (s, 3H, CH3), 5.39 (s, 2H, NH2), 6.90 (d, 1H, J=1.7 Hz, Ar), 7.12 (d, 1H, J=8.8 Hz, Ar), 7.24 (d, 2H, J=8.9 Hz, Ar), 7.34 (dd, 1H, J=8.8 Hz, J=2.8 Hz, Ar), 7.73 (d, 2H, J=8.9 Hz, Ar), 7.91 (d, 1H, J=2.8 Hz, Ar), 8.09 (s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[CH:22]=[N:21][CH:20]=[CH:19][N:18]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Reactant: Clc1cnccn1
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cnccn1

Procedure:
The title compound, MS: m/e=295.3 (M+H+), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 2-chloropyrazine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11](OCC)=[O:12])=[N:9][N:8]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:5]2=[N:6][CH:7]=1.[NH3:24]>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([NH2:24])=[O:12])=[N:9][N:8]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=O)c1nn(Cc2ccccc2F)c2ncc(F)cc12
Reactant: N
Solvent: CO
Product: NC(=O)c1nn(Cc2ccccc2F)c2ncc(F)cc12

Procedure:
1.00 g (3.152 mmol) of the compound obtained in example 25A was stirred in 10 ml of a 7N solution of ammonia in methanol at RT for three days. This was followed by concentration under reduced pressure. This gave 908 mg (99% of theory) of the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[I:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[I:10][C:11]1[CH:16]=[CH:15][C:14]([O:1][CH:2]2[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)=[CH:13][CH:12]=1
Reactant: OC1CN2CCC1CC2
Reactant: Ic1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Ic1ccc(OC2CN3CCC2CC3)cc1
Temperature: 110 °C

Procedure:
3-Hydroxy quinuclidine (Aldrich, 2.54 g, 20 mmol) in toluene (anhydrous, Aldrich, 50 mL) was treated with 1,4-diiodobenzene (Aldrich, 7.9 g, 24 mmol), Cul (Strem Chemicals, 0.38 g, 2 mmol), 1,10-phenanthroline (Aldrich, 0.72 g, 4 mmol), and Cs2CO3 (Aldrich, 8.15 g, 25 mmol), heated at 110° C. for 40 hours. The reaction mixture was allowed to cool to room temperature, diluted with chloroform (100 mL), and washed with water (2×10 mL). The organic phase was concentrated and the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.20) as oil (3.7 g, yield, 56%). 1H NMR (MeOH-d4, 300 MHz) δ 1.40–1.56 (m, 1H), 1.64–1.80 (m, 2H), 1.90–2.08 (m, 1H), 2.10–2.21 (m, 1H), 2.60–3.00 (m, 5H), 3.34–3.40 (m, 1H), 4.46 (m, 1H), 6.73 (d, J=8.8 Hz, 2H), 7.56 (d, J=8.8, Hz, 2H), ppm. MS (DCl/NH3) m/z 330 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[F:48][C:49]([F:60])([F:59])[C:50]1[CH:51]=[C:52](B(O)O)[CH:53]=[CH:54][CH:55]=1.[O:61]1[CH2:66][CH2:65][CH:64]=[CH:63][C:62]1=[O:67]>O1CCOCC1>[F:48][C:49]([F:60])([F:59])[C:50]1[CH:51]=[C:52]([CH:64]2[CH2:65][CH2:66][O:61][C:62](=[O:67])[CH2:63]2)[CH:53]=[CH:54][CH:55]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=C1C=CCCO1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Solvent: O
Product: O=C1CC(c2cccc(C(F)(F)F)c2)CCO1
Reaction time: 0.5 h

Procedure:
(Acetylacetonato)bis(ethylene)rhodium (I) (180 mg) was dissolved in 1,4-dioxane (144 mL). Racemic BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthalene) (867 mg) was added at room temperature, followed by stirring for 30 minutes. Subsequently, water (14.4 mL) and 3-(trifluoromethyl)phenylboronic acid (5.29 g) were added, followed by stirring for 10 minutes. Then, 5,6-dihydro-2H-pyran-2-one (2 mL) was added and the mixture was reacted at 100° C. for 12 hours. The reaction solution was partitioned with ethyl acetate and water. Then, the organic layer was washed with a saturated sodium bicarbonate solution and dried over magnesium sulfate. Concentration under reduced pressure gave an oil. The oil was purified by silica gel column chromatography (mobile phase:ethyl acetate/heptane=0 to 60%) to obtain the title compound (2.5 g).
Reaction SMILES: Cl.[F:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([C:15](=[NH:17])[NH2:16])=[N:7]1.C([N:24](CC)CC)C.O.NN>C(O)C>[F:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([C:15](=[NH:16])[NH:17][NH2:24])=[N:7]1
Reactant: CCN(CC)CC
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: N=C(NN)c1nn(Cc2ccccc2F)c2ncccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50.000 g (163.535 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide hydrochloride were dissolved in 700 ml of ethanol, and 66.192 g (654.141 mmol) of triethylamine and 10.233 g (163.535 mmol) of hydrazine hydrate (80% strength solution in water) were added at 0° C. The mixture was stirred at RT overnight and then concentrated on a rotary evaporator. The residue was taken up in ethyl acetate and the solution was washed three times with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate and concentrated on a rotary evaporator. The residue was stirred with diethyl ether, filtered off with suction and dried under high vacuum. 46.49 g (46% of theory, 68% pure) of the title compound were obtained.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:41])=[N:14][C:15]2[N:16]([N:33]=[C:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:35]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([OH:32])[CH3:31])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[C:47]([Si:51](Cl)([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([CH3:50])([CH3:49])[CH3:48].O>CN(C=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:41])=[N:14][C:15]2[N:16]([N:33]=[C:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:35]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([O:32][Si:51]([C:47]([CH3:50])([CH3:49])[CH3:48])([C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH3:31])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N3CCC(C)(OCCCC[C@@H](C)O)CC3)n2n1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N3CCC(C)(OCCCC[C@@H](C)O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CC3)n2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.5 %

Procedure:
To a solution of ethyl 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4-(((R)-5-hydroxyhexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (800 mg, 1.387 mmol) in DMF (10 mL) at 0° C. was added imidazole (142 mg, 2.081 mmol) followed by tert-butylchlorodiphenylsilane (0.533 mL, 2.081 mmol) and the resulting mixture was stirred at room temp for 16 h. Water (20 mL) was then added and the mixture was extracted with ether (2×25 mL). Ether layer was then washed with brine (25 mL), dried (Na2SO4), filtered and concentrated. The residue was purified via Biotage (0-10% EtOAc/hexane) to afford ethyl 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (1 g, 1.227 mmol, 88% yield) as viscous liquid. 1H NMR (400 MHz, CDCl3) δ 7.69 (dd, J=8.0, 1.5 Hz, 4H), 7.47-7.28 (m, 6H), 7.01 (s, 1H), 5.82 (br. s., 1H), 4.50-4.38 (m, 2H), 4.31-4.07 (m, 2H), 3.94-3.77 (m, 1H), 3.41-3.24 (m, 3H), 2.61 (s, 3H), 1.88 (br. s., 2H), 1.67 (br. s., 1H), 1.54 (br. s., 1H), 1.51-1.39 (m, 5H), 1.30 (s, 3H), 1.26-1.23 (m, 6H), 1.22 (s, 9H), 1.08 (s, 3H), 1.06 (s, 9H). 4 missing piperidine hydrogens. LCMS (M+H)=816.4.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.C[NH2+]C.[Cl:30][C:31]1[CH:32]=[C:33]([CH:41]=[CH:42][C:43]=1[Cl:44])[CH2:34][N:35]1[CH2:38][CH:37]([CH2:39][NH2:40])[CH2:36]1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10](=[O:12])[NH:40][CH2:39][CH:37]1[CH2:38][N:35]([CH2:34][C:33]2[CH:41]=[CH:42][C:43]([Cl:44])=[C:31]([Cl:30])[CH:32]=2)[CH2:36]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)C1
Agent: C[NH2+]C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)NCC1CN(Cc2ccc(Cl)c(Cl)c2)C1
Reaction time: 0.08 h

Procedure:
A solution of tert-Butoxycarbonylamino-acetic acid (1.88 g, 10.7 mmol) in dichloromethane (15 ml) is treated with triethylamine (1.5 ml, 10.7 mmol) and [Dimethylamino-[1,2,3]-triazolo-[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluoro phosphate (4.06 g, 10.7 mmol) and stirred for 5 minutes. To the reaction mixture is added a solution of C-[1-(3,4-Dichloro-benzyl)-azetidin-3-yl]-methylamine (2.64 g, 10.7 mmol) in dichloromethane (15 ml) with stirring for a further 3 hours. The reaction mixture is partitioned between dichloromethane and saturated sodium bicarbonate solution, the organic phase is washed with brine, dried over magnesium sulphate and evaporated. The crude product is purified by chromatography over flash silica eluting with 7% methanol in dichloromethane to afford the title compound.