Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:49]([O:53][C:54]([N:56]1[CH:60]=[CH:59][CH:58]=[C:57]1[C:61]1[CH:66]=[CH:65][CH:64]=[C:63]([NH2:67])[CH:62]=1)=[O:55])([CH3:52])([CH3:51])[CH3:50]>CN(C=O)C>[C:49]([O:53][C:54]([N:56]1[CH:60]=[CH:59][CH:58]=[C:57]1[C:61]1[CH:66]=[CH:65][CH:64]=[C:63]([NH:67][C:22]([C:17]2[C:18](=[O:21])[O:19][C:20]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[OH:10])=[O:24])[CH:62]=1)=[O:55])([CH3:52])([CH3:50])[CH3:51]
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: CC(C)(C)OC(=O)n1cccc1-c1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1cccc1-c1cccc(NC(=O)c2cc3cccc(O)c3oc2=O)c1
Temperature: 25 °C
Yield: 65.3 %

Procedure:
DIEA (0.009 mL, 0.053 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.010 g, 0.048 mmol) and HATU (0.02 g, 0.053 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2-(3-Amino-phenyl)-pyrrole-1-carboxylic acid tert-butyl ester (0.013 g, 0.048 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.014 g of product in 62% yield: LCMS (ESI) m/z 447 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([CH3:14])[CH:7]=[C:8]([NH2:13])[CH:9]=2)[N:4]=1.F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([CH3:14])[CH:7]=[C:8]([NH:13][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-:24])=[O:23])[CH:9]=2)[N:4]=1
Reactant: COc1ccc2cc(N)cc(C)c2n1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc2cc(Nc3ccccc3[N+](=O)[O-])cc(C)c2n1

Procedure:
This compound, m.p. 185°, was prepared similarly to Preparation 20 using 2-methoxy-6-amino-8-methylquinoline, 1-fluoro-2-nitrobenzene, and sodium carbonate as starting materials. The product was characterised spectroscopically and used directly in Preparation 17 without further purification.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[O:31]1[CH2:36][CH2:35][CH:34]([CH2:37][CH:38]=[O:39])[CH2:33][CH2:32]1>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[CH:38]([OH:39])[CH2:37][CH:34]2[CH2:35][CH2:36][O:31][CH2:32][CH2:33]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCC1CCOCC1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(F)cnc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=S(=O)(c1ccccc1)n1c(C(O)CC2CCOCC2)cc2cc(F)cnc21
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
To a suspension of 1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridine (1.0 g, 3.62 mmol) in dry tetrahydrofuran (30 mL) at −78° C. was added a solution of n-butyllithium in n-hexane (1.6M, 2.72 mL, 4.35 mmol). The mixture was stirred at −78° C. for 5 min and then treated with (tetrahydro-pyran-4-yl)-acetaldehyde (0.7 g, 5.43 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and quenched with brine. The mixture was extracted with ethyl acetate (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 25% ethyl acetate/hexanes) afforded 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-ethanol (1.23 g, 84%): LC/MS m/e calcd for C20H21FN2O4S [M+H]+ 405.46, observed 405.2.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:5]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)[NH:4][N:3]=1.[H-].[Na+].[CH3:33]I.O>CN(C)C=O>[CH3:33][N:4]1[C:5]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[C:6]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[C:2]([CH3:1])=[N:3]1
Reactant: CI
Reactant: Cc1n[nH]c(-c2ccc(OCc3ccc4ccccc4n3)cc2)c1-c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(C)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)c1-c1ccncc1
Temperature: 25 °C

Procedure:
A solution of 2-((4-(3-methyl-4-(pyridin-4-yl)-1H-pyrazol-5-yl)phenoxy)methyl)quinoline (150 mg, 0.38 mmol) in anhydrous dimethylformamide (2 mL) was treated at 0° C. with sodium hydride dispersion (30 mg, 0.76 mmol of 60% NaH in oil) followed after 20 min with methyl iodide (54 mg, 0.38 mmol), and the stirred mixture was allowed to warm to RT overnight. Water was added and the mixture extracted with dichloromethane (3×20 mL). The organic layer was dried, concentrated, and the residue chromatographed on silica eluted with an ethyl acetate-hexane gradient containing 1% triethylamine, giving fractions containing two isomeric substances. The less polar isomer (18 mg) was thus obtained (methylation regiochemistry tentatively assigned by NMR). 1H NMR (CDCl3, 400 mHz) δ 8.41 (m, 2H), 8.21 (d, 1H, J=8.7 Hz), 8.07 (d, 1H, J=8.3 Hz), 7.84 (d, 1H, J=9.5 Hz), 7.74 (ddd, 1H), 7.67 (d, 1H, J=8.3 Hz), 7.55 (ddd, 1H), 7.12 (m, 2H), 7.05 (m, 2H), 7.0 (m, 2H), 5.40 (s, 2H), 3.71 (s, 3H), 2.37 (s, 3H). HPLC-MS 4.81 min, m/e 407 (MH+).
Reaction SMILES: [C@@H]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)O[C@H](CO)[C@@H](O)[C@H]1O.[I-].[Na+].[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][Cl:30])=[CH:27][CH:26]=1.[ClH:33]>CS(C)=O.CO>[ClH:30].[ClH:33].[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:12]2[C:13]3[C:14](=[O:15])[NH:16][C:17]([NH2:18])=[N:19][C:20]=3[N:10]=[CH:11]2)=[CH:27][CH:26]=1
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: COc1ccc(CCl)cc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: COc1ccc(Cn2cnc3nc(N)[nH]c(=O)c32)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 34.8 %

Procedure:
Guanosine (5.7 g; 20.0 mmol) was dissolved in 13.2 ml of dimethylsulfoxide. To this solution were added sodium iodide (0.6 g; 4 mmol) and 4-methoxybenzyl chloride (6.8 ml; 50.2 mmol), and the mixture was stirred at room temperature for 19 h. Conc. hydrochloric acid (10 ml) was added thereto, and stirred at 45° C. for 1 h. The mixture was cooled down to room temperature. Methanol (50 ml) was added thereto, and the mixture was stirred at room temperature for 3 h. The crystals precipitated were filtered, washed well with methanol (20 ml×3), and then dried at 50° C. under reduced pressure to obtain 2.5 g of 7-(4-methoxybenzyl)guanine dihydrochloride (34.8%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][NH:7][C:8]([C:10]([NH:12][CH2:13][C:14](=O)[CH3:15])=[O:11])=[O:9])=[O:5])[CH3:2].C(O)(C(F)(F)F)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(O)(=O)C>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:14]([CH3:15])=[CH:13][N:12]=[C:10]([OH:11])[C:8]1=[O:9])=[O:5])[CH3:2]
Reactant: CCOC(=O)CNC(=O)C(=O)NCC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cn1c(C)cnc(O)c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 3.43 g (14.9 mmol) of 7-2, 1.15 mL (14.9 mmol) of TFA and 2.104 mL (14.9 mmol) of trifluoroacetic anhydride in 60 mL of acetic acid was heated to 80° C. under a slow stream of Ar for 7 h. After HPLC analysis of the reaction progress, an additional 766 μL (9.9 mmol) of TFA and 1.4 mL (9.9 mmol) of trifluoroacetic anhydride were added and the reaction mixture was heated for an additional 24 h. After standing at rt for several hours, the solvents were removed at reduced pressure, and the residue digested in 7 mL of acetic acid at 60° C. for 10 min, then 35 mL of isopropyl acetate (iPAc) was added dropwise to the warm mixture. After the addition, the slurry was allowed to cool to rt, filtered, and washed with 1:5 HOAc-iPAc. The solid was air dried to give 7-3 as an almost colorless solid: 1H NMR (CDCl3) δ 10.92 (br s, 1H), 6.185 (s, 1H), 4.66 (s, 2H), 4.25 (q, 2H, 7.1 Hz), 2.08 (s, 3H), 1.30 (t, 3H, 7.1 H
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4]([C:6]1[CH:19]=[CH:18][C:9](C(Cl)C2C=CC=CC=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[I-].[Na+].C(N(C(C)C)CC)(C)C.C(N1C[C@@H](C)NC[C@@H]1C)C=C.C(N1C[C@H](C)NC[C@H]1C)C=C.C1(C)C=CC(C([C@@](C(O)=O)(O)[C@@](C(C2C=CC(C)=CC=2)=O)(O)C(O)=O)=O)=CC=1>C(#N)C>[CH2:20]([N:3]([CH2:1][CH3:2])[C:4](=[O:5])[C:6]1[CH:19]=[CH:18][CH:9]=[CH:8][CH:7]=1)[CH3:21]
Reactant: CCN(CC)C(=O)c1ccc(C(Cl)c2ccccc2)cc1
Agent: C=CCN1C[C@@H](C)NC[C@@H]1C
Agent: C=CCN1C[C@H](C)NC[C@H]1C
Agent: Cc1ccc(C(=O)[C@](O)(C(=O)O)[C@@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCN(CC)C(=O)c1ccccc1

Procedure:
The crude 4-(N,N-diethylcarbamoyl)benzhydryl chloride (125 mmol) was dissolved in acetonitrile (300 mL). Sodium iodide (18.64 g, 125 mmol), diisopropylethylamine (32.65 mL, 187 mmol), and (+)-(2S,5R)-1-allyl-2,5-dimethylpiperazine (19.23 g, 125 mmol, prepared by the method described in Example 1 for (−)-(2R,5S)-1-allyl-2,5-dimethylpiperazine, but using di-p-toluoyl-L-tartaric acid as the resolving agent) were added. The mixture was stirred at reflux, under nitrogen, for 3 hours. The acetonitrile was removed under reduced pressure, the reaction mixture was poured into ethyl acetate (500 mL) and potassium carbonate solution (150 mL of a 2M aqueous solution), and shaken. The organic phase was separated, washed with water and brine, dried over solid potassium carbonate, and concentrated in vacuo to give 55.35 g (100% crude yield) of 4-((αR and αS)-α-((2R,S5)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide as a 1:1 mixture of isomers, epimeric at the benzhydryl carbon.
Reaction SMILES: Br[C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:12]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)#[N:13].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.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>[C:12]([C:14]1[CH:19]=[C:18]([C:2]2[N:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH:17]=[CH:16][CH:15]=1)#[N:13]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: COC(=O)c1cccnc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: COC(=O)c1cccnc1-c1cccc(C#N)c1
Yield: 76.7 %

Procedure:
Methyl 2-bromonicotinate (2.0 g, 9.3 mmol) and 3-cyanophenylboronic acid (2.7 g, 18.4 mmol) were combined in 190 mL benzene. Sodium carbonate (19 mL of a 2 M aqueous solution), tetrabutylammonium bromide (152 mg, 0.5 mmol), and bis(triphenylphosphine)palladium(II) chloride (325 mg, 0.5 mmol) were added. The entire mixture was evacuated to remove dissolved gasses, then placed under argon. The reaction was refluxed for 14 hours, diluted with water and EtOAc, separated, dried over Na2SO4, filtered, and evaporated. The resulting yellow solid was chromatographed on silica gel (30% EtOAc/hexanes) to yield a light yellow solid (1.70 g, 77%). 1H NMR (CDCl3): δ8.81 (dd, 1H, J=4.8, J′=1.8), 8.23 (dd, 1H, J=8.0, J′=1.9), 7.85 (s, 1H), 7.73 (m, 2H), 7.55 (t, 1H, J=7.7), 7.43 (m, 1H), 3.76 (s, 3H).
Reaction SMILES: C([O-])=O.[Na+].Cl[C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([C:15]([F:18])([F:17])[F:16])=[CH:8][C:7]=1[N+:19]([O-])=O.C([O-])(=O)C.[Na+].NC1C(N)=C(C(F)(F)F)C=CC=1>C(O)(=O)C.[Pd]>[NH2:19][C:7]1[CH:8]=[C:9]([C:15]([F:16])([F:17])[F:18])[CH:10]=[C:11]([NH2:12])[CH:6]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: Nc1cccc(C(F)(F)F)c1N
Solvent: CC(=O)O
Product: Nc1cc(N)cc(C(F)(F)F)c1
Temperature: 40 °C
Yield: 45 %

Procedure:
Sodium formate (12.24 g) was added to a mixture of 4-chloro-3,5-dinitrobenzotrifluoride (5.41 g), sodium acetate (1.64 g) and 5% Pd/C (0.5 g) in glacial acetic acid (60 mL). The mixture was stirred and the resultant exotherm, which lasted about an hour, was controlled by cooling to maintain a reaction temperature of about 40° C. As the exotherm subsided, external heating was applied to maintain the temperature at about 40° C. Gas chromatographic analysis of the reaction mixture, at the end of one hour, indicated diaminobenzotrifluoride as the major component (35%) with no 4-chloro-3,5-dinitrobenzotrifluoride remaining. The maximum amount (about 45%) of 3,5-diaminobenzotrifluoride formed after 2 hours after which it was converted to other undesirable products.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][CH:26]=1)[O:7][C:8]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)([OH:3])=[O:2].CO.[C:29](OCC)(=O)C>C(Cl)Cl>[CH3:29][O:2][C:1]([C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][CH:26]=1)[O:7][C:8]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:3]
Reactant: CCOC(C)=O
Reactant: O=C(O)c1cccc(Oc2ncccc2OCCCc2ccncc2)c1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cccc(Oc2ncccc2OCCCc2ccncc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(3-Carboxyphenoxy)-3-[3-(pyridin-4-yl)propoxy]pyridine (0.20 g, 0.57 mmol) obtained in Example 52 is dissolved in methylene chloride (10 ml), and thereto are added 1-ethyl-3-(3′-dimethyl aminopropyl)carbodiimide.hydrochloride (0.13 g, 0.68 mmol) and methanol (0.10 ml), and the mixture is stirred at room temperature for 2 hours. To the reaction solution is added ethyl acetate (100 ml), and the mixture is washed with a saturated brine (30 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: chloroform/methanol) to give the title compound (0.17 g) as colorless oil.
Reaction SMILES: Cl.Cl.[CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])=[CH:16]3)[CH2:8][CH2:7]1)([CH3:5])[CH3:4].[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1>>[CH:30]1([C:33]([N:27]2[CH2:28][CH2:29][N:24]([C:22]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[CH:14][C:13]([O:12][CH:9]3[CH2:8][CH2:7][N:6]([CH:3]([CH3:5])[CH3:4])[CH2:11][CH2:10]3)=[CH:21][CH:20]=4)=[O:23])[CH2:25][CH2:26]2)=[O:34])[CH2:32][CH2:31]1
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCNCC4)cc3c2)CC1
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCN(C(=O)C5CC5)CC4)cc3c2)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone dihydrochloride and cyclopropanoyl chloride. Light-yellow solid. MS (m/z): 439.5 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH2:3][CH2:2]1.[CH3:20][C:21]1([CH3:27])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([N:24]3[CH2:25][CH2:26][C:21]([CH3:27])([CH3:20])[CH2:22][CH2:23]3)=[O:19])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH2:2][CH2:3]1
Reactant: CC1(C)CCNCC1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CCCO2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CCN(C(=O)c2ccc(C3CC3)c(OCC3CCCO3)n2)CC1

Procedure:
In analogy to the procedure described in Example 47 b), 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 4 b)) was reacted with 4,4-dimethyl-piperidine (4045-30-1) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=359.6 [MH+].
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][C@H:11]1[CH2:16][OH:17])=[O:9])([CH3:6])([CH3:5])[CH3:4].[N+](C1C=CC([O:27][C:28]([N:30]2[CH2:35][CH2:34][N:33]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[CH2:32][CH2:31]2)=O)=CC=1)([O-])=O.C([O-])(O)=O.[Na+]>C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][C@@H:11]1[CH2:16][O:17][C:28]([N:30]1[CH2:31][CH2:32][N:33]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)=[O:27])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccc(F)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1CO
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC[C@@H]1COC(=O)N1CCN(c2ccc(F)cc2)CC1
Temperature: -5 °C
Yield: 57.5 %

Procedure:
NaH (60% in oil, prewashed with hexane; 1.38 g, 34.5 mmol) was suspended in anhydrous THF (50 mL) under nitrogen, the reaction mixture cooled to −5° C. with stirring and a solution of (R)-3-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (2.50 g, 11.5 mmol) in THF (50 mL) was added dropwise. The reaction mixture was stirred for 30 min at 0 to 3° C. 4-(4-Fluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 6; 5.01 g, 14.5 mmol) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was cooled with an ice bath and a 10% aq NaHCO3 solution (11 mL) was added. The solvents were removed in vacuo and the residue was partitioned between EtOAc (350 mL) and 10% aq NaHCO3 solution (100 mL)/water (200 mL). The EtOAc layer was dried (MgSO4) and the solvent removed in vacuo. The residue was purified by column chromatography (normal phase silica, 70 g Isolute-Si column, gradient of EtOAc in hexane). The residue was dissolved in DCM and evaporated in vacuo and repeated once before drying in vacuo to give (3R)-3-[4-(4-fluorophenyl)-piperazine-1-carbonyloxymethyl]-morpholine-4-carboxylic acid tert-butyl ester (2.80 g) as a pale yellow gum.
Reaction SMILES: NN.[N:3]1([N:8]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH:7]=[CH:6][N:5]=[CH:4]1>C(O)C.[Ru]>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([N:8]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(N(c2ccc([N+](=O)[O-])cc2)n2ccnc2)cc1
Agent: [Ru]
Agent: NN
Solvent: CCO
Product: N#Cc1ccc(N(c2ccc(N)cc2)n2ccnc2)cc1
Yield: 48.1 %

Procedure:
Hydrazine (1.52 ml, 49.00 mmol) was added portionwise to a suspension of 4-[N-(1H-imidazol-1-yl)-N-(4-nitrophenyl)amino]benzonitrile (3.00 g, 9.80 mM) and ruthenium, 5 wt. % on carbon (0.30 g, 0.15 mM) in ethanol (35 ml) at reflux with stirring. When TLC showed complete reaction, the mixture was cooled and the catalyst was filtered. The solvent was concentrated under vacuum. The residue was poured into water and extracted with dichloromethane, dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product (2.50 g as solid). Crystallization from ethyl acetate with ethanol yielded the expected product (1.30 g, 50%, mp: 147° C.).
Reaction SMILES: [CH2:1]([C:6]1[S:7][C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH:18]C(=O)C(Cl)(Cl)Cl)[C:9]=2[N:25]=1)[CH2:2][CH2:3][CH2:4][CH3:5].N.ClCCl>CO>[CH2:1]([C:6]1[S:7][C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:18])[C:9]=2[N:25]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1nc2c(NC(=O)C(Cl)(Cl)Cl)nc3ccccc3c2s1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CCCCCc1nc2c(N)nc3ccccc3c2s1

Procedure:
Trichloroacetyl isocyanate (0.51 mL) was added to a solution of 2-pentylthiazolo[4,5-c]quinoline-5N-oxide (0.78 g) in dichloromethane (50 mL). The reaction mixture was stirred at ambient temperature for about 75 minutes and then concentrated under vacuum to provide crude N-(2-pentylthiazolo[4,5-c]quinolin-4-yl)trichloroacetamide. The amide was combined with a solution of ammonia in methanol (40 mL of 2M). Dichloromethane was added to bring all of the material into solution. When the reaction was completed as indicated by thin layer chromatography, the reaction mixture was concentrated under vacuum. The residue was mixed with dichloromethane and sodium bicarbonate. The organic layer was separated, washed with sodium bicarbonate then with water, dried over magnesium sulfate and then concentrated under vacuum to provide a white solid. This material was recrystallized from ethyl acetate to provide 2-pentylthiazolo[4,5-c]quinolin-4-amine as an off-white crystalline solid, m.p. 119-121° C. Analysis: Calculated for C15H17N3S: % C, 66.39; % H, 6.31; % N, 15.48; Found: % C, 66.21; % H, 6.35; % N, 15.39.
Reaction SMILES: Br[C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([C:11]2[S:15][C:14]([NH:16][C:17](=[O:26])[C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[F:25])=[N:13][C:12]=2[CH3:27])[CH:3]=1.[CH3:28][N:29](C=O)C>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:28]([C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([C:11]2[S:15][C:14]([NH:16][C:17](=[O:26])[C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[F:25])=[N:13][C:12]=2[CH3:27])[CH:3]=1)#[N:29]
Reactant: Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1cc(Br)c2c(c1)OCO2
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1cc(C#N)c2c(c1)OCO2
Temperature: 100 °C

Procedure:
A degassed mixture of Compound 56 (80 mg, 0.18 mmol), zinc cyanide (26 mg, 0.22 mmol) and tetrakis(triphenylphosphine)palladium (20.0 mg, 0.017 mmol) in DMF (2.0 mL) was heated to 100° C. overnight. The mixture was cooled to room temperature, diluted with ethyl acetate. The mixture was washed with a solution of saturated NaHCO3 then with brine, dried (Na2SO4), filtered and concentrated. The residue was purified on silica to provide Compound 58 (55 mg).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].C(N(CC)C(C)C)(C)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C>[CH:9]1([NH:8][C:5]2[N:6]=[N:7][C:2]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])=[CH:3][CH:4]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1ccc(NC2CCC2)nn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)C#Cc1ccc(NC2CCC2)nn1
Temperature: 80 °C
Reaction time: 16 h
Yield: 74.4 %

Procedure:
6-Bromo-N-cyclobutylpyridazin-3-amine (0.60 g, 2.63 mmol), trimethylsilylacetylene (TMSA) (1.29 g, 13.1 mmol), Pd(PPh3)4 (0.15 g), and CuI (0.04 mg) were placed in a vial with a rubber septum. After the mixture underwent 3 cycles of vacuum/filling with Ar2, DMF (3.0 mL) and N,N-diisopropylethylamine (DIPEA) (0.41 g, 3.2 mmol) were added. The mixture was then stirred at 80° C. for 16 hrs. The reaction mixture was concentrated and the resulting residue was purified by silica gel chromatography (eluent: 30% ethyl acetate in n-hexane, ethyl acetate was added 0.5% Et3N) to give an off-white solid (0.48 g, 74.5%). 1H NMR (300 MHz, CDCl3) δ: 7.26-7.29 (1H, d, J=9.0 Hz), 6.50-6.53 (1H, d, J=9.0 Hz), 5.55 (1H, s), 4.17-4.24 (1H, m), 2.40-2.46 (2H, m), 1.89-1.98 (2H, m), 1.77-1.85 (2H, m), 0.28 (9H, s).