Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:23]=[CH:22][C:9]([CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])=[CH:8][CH:7]=1.[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])=[CH:22][CH:23]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(C#CCCO)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(CCCCO)cc1
Yield: 92.8 %

Procedure:
To a solution of 2-[4-(4-hydroxy-but-1-ynyl)-benzyl]-isoindole-1,3-dione (2.0 g, 6.55 mmol) in ethanol/ethyl acetate (3:1, 163 mL) was added palladium on carbon (10 wt. %, 1.04 g). The reaction stirred at room temperature overnight under 50 psi of hydrogen. The reaction was monitored by 1H NMR to see conversion to product. Upon completion, the reaction mixture was filtered through diatomaceous earth (Celite®), washed with ethyl acetate, and concentrated to obtain the product as a yellow oil (1.88 g, 93% yield). 1H NMR (600 MHz, CDCl3): δ 7.81 (2H, m), 7.67 (m, 2H), 7.33 (d, 2H, J=8.1 Hz), 7.10 (d, 2H, J=8.1 Hz), 4.79 (s, 2H), 3.69 (q, 3H, J=7.0 Hz), 3.60 (t, 2H, J=6.5 Hz), 2.58 (t, 2H, J=7.4 Hz), 1.64 (m, 2H), 1.55 (m, 2H); 13C NMR (150 MHz, CDCl3): 168.3, 142.2, 134.1, 134.0, 132.3, 128.8, 128.8, 123.5, 62.9, 41.5, 35.4, 32.4, 27.6.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[CH3:7].[CH2:8]([O:10][C:11](=[O:32])[N:12]([C:21]1[CH:26]=[C:25](Br)[N:24]=[C:23]([NH2:28])[C:22]=1[N+:29]([O-:31])=[O:30])[CH2:13][C:14]1[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=1)[CH3:9]>>[CH2:8]([O:10][C:11](=[O:32])[N:12]([C:21]1[CH:26]=[C:25]([C:4]2[O:5][C:6]([CH3:7])=[C:2]([CH3:1])[N:3]=2)[N:24]=[C:23]([NH2:28])[C:22]=1[N+:29]([O-:31])=[O:30])[CH2:13][C:14]1[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=1)[CH3:9]
Reactant: Cc1ncoc1C
Reactant: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Product: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(-c2nc(C)c(C)o2)nc(N)c1[N+](=O)[O-]

Procedure:
The title compound was prepared following the example in preparation 70, using 4,5-dimethyl-oxazole (47 mg) and (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(6-methyl-pyridin-3-ylmethyl)-carbamic acid ethyl ester (100 mg), giving the product (75 mg) as a yellow gum.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10]C)=O)[C:5]([O:12][CH3:13])=[N:4][C:3]=1[NH:14][CH2:15][CH3:16].[NH2:17][CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH2:24][CH3:25]>CO>[CH2:24]([N:20]1[CH2:21][CH2:22][CH2:23][CH:19]1[CH2:18][NH:17][C:8]([C:6]1[C:5]([O:12][CH3:13])=[N:4][C:3]([NH:14][CH2:15][CH3:16])=[C:2]([Cl:1])[N:7]=1)=[O:10])[CH3:25]
Reactant: CCNc1nc(OC)c(C(=O)OC)nc1Cl
Reactant: CCN1CCCC1CN
Solvent: CO
Product: CCNc1nc(OC)c(C(=O)NCC2CCCN2CC)nc1Cl

Procedure:
In 20 ml. of methanol were dissolved 2.0 g. of methyl 6-chloro-5-ethylamino-3-methoxypyrazine-2-carboxylate and 2.0 g. of 2-aminomethyl-1-ethylpyrrolidine and the solution was refluxed for 24 hours. After cooling, the solvent was distilled off under reduced pressure from the reaction mixture to provide an oily residue. The residue was dissolved in 30 ml. of a dilute aqueous hydrochloric acid solution and the solution was washed three times each time with 10 ml. of chloroform. (The chloroform washings was washed with water, dried, and then the solvent was distilled off under reduced pressure, whereby 1.05 g. of methyl 6-chloro-5-ethylamino-3-methoxypyrazine-2-carboxylate used as the starting material was recovered.). The aqueous layer was basified with a 3 N aqueous sodium hydroxide solution and the oily material formed was extracted with 30 ml. of chloroform. The extract was washed with water, dried, the solvent was distilled off under reduced pressure, and the oily residue formed was allowed to stand, whereby the oily residue was crystallized. After recrystallizing the crystals from toluene, 0.88 g. of N-(1-ethylpyrrolidin-2-ylmethyl)-6-chloro-5-ethylamino-3-methoxypyrazine-2-carboxamide melting at 167°-169° C. was obtained.
Reaction SMILES: [CH2:1]([C:3]1[N:16](CC2C=CC3NC4C=CC=CC=4CCC=3C=2)[C:6]2=[N:7][C:8]([CH3:15])=[CH:9][C:10]([C:11](F)(F)F)=[C:5]2[N:4]=1)[CH3:2].C(C1NC2=NC(C)=CC(C(F)(F)F)=C2N=1)C>>[CH2:1]([C:3]1[NH:16][C:6]2=[N:7][C:8]([CH3:15])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C(F)(F)F)cc(C)nc2n1Cc1ccc2c(c1)CCc1ccccc1N2
Agent: CCc1nc2c(C(F)(F)F)cc(C)nc2[nH]1
Product: CCc1nc2c(C)cc(C)nc2[nH]1

Procedure:
[step 1] 2-(2-Ethyl-5-methyl-7-trifluoromethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-dihydro-5H-dibenzo[b,f]azepine (153 mg, 50%) was obtained in the same manner as in step 1 of Example 1, using 2-ethyl-5-methyl-7-trifluoromethyl-3H-imidazo[4,5-b]pyridine (160 mg, 0.700 mmol), obtained in Reference Example 3, instead of 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14]O)[N:9]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Se:32]C#N)([O-:25])=[O:24].C(P(CCCC)CCCC)CCC>C1COCC1.N1C=CC=CC=1.CC(OC)(C)C>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][Se:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N+:23]([O-:25])=[O:24])[N:9]1[C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: N#C[Se]c1ccccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(CCO)N1C(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)[C@@H]1CCC(CC[Se]c2ccccc2[N+](=O)[O-])N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A solution of 4.18 g of alcohol 184 (13.3 mmol) in 50 ml of anhydrous THF and 17 ml of anhydrous pyridine was added with 3.31 g of ortho-nitrophenyl selenocyanate (14.6 mmol, 1.1 eq.). Slow dropwise addition of 4.30 ml of tri-n-butylphosphine (17.3 mmol, 1.3 eq.) with cooling in an ice bath resulted in a dark-red solution. After stirring for 30 min at RT, the batch was diluted with 200 ml of MTBE and filtered over a small amount of silica gel. Concentrating the filtrate afforded a brownish-yellow residue that was purified using silica gel column chromatography (EE/CH 1:4), thereby isolating 6.06 g of the selenyl ether 47 (12.1 mmol, 92%) as an intensely yellow colored oil.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14](O)=[O:15])[N:10]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[N:9]=[CH:8]2.[O:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([NH:36][CH:33]1[CH2:34][CH2:35][O:30][CH2:31][CH2:32]1)=[O:15])[N:10]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[N:9]=[CH:8]2
Reactant: NC1CCOCC1
Reactant: O=C(O)c1cc2c(cnn2C2CCCCO2)cc1Oc1ccc([N+](=O)[O-])cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NC1CCOCC1)c1cc2c(cnn2C2CCCCO2)cc1Oc1ccc([N+](=O)[O-])cc1F
Yield: 80.9 %

Procedure:
The solution of 5-(2-fluoro-4-nitrophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-carboxylic acid (0.5 g, 1.25 mmol), tetrahydropyran-4-ylamine (0.13 g, 1.25 mmol), EDCI (0.24 g, 1.25 mmol), HOBT (0.17 g, 1.25 mmol), N-methylmorpholine (0.5 mL) in DMF (5 mL) is stirred at RT overnight. Then the reaction mixture is partitioned with saturated aqueous NH4Cl (20 mL) and EtOAc (50 mL). The organic phase is separated, dried over MgSO4, and concentrated. The residue is purified by silica gel column chromatography eluting with PE:EtOAc (1:1) to provide the product (0.49 g, 81.2% yield). MS (m/z): 485.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[N:12]3[N:29]=[CH:30][C:31]([CH:32]=[C:33]4[C:37](=[O:38])[NH:36][C:35](=[O:39])[NH:34]4)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:12]3[N:29]=[CH:30][C:31]([CH:32]=[C:33]4[NH:34][C:35](=[O:39])[NH:36][C:37]4=[O:38])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Nc3cccc(Cl)c3)nc3c(C=C4NC(=O)NC4=O)cnn23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC(=O)C(=Cc2cnn3c(NC4CCNCC4)cc(Nc4cccc(Cl)c4)nc23)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl 4-(5-(3-chlorophenylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-7-ylamino)piperidine-1-carboxylate (640 mg, 1.2 mmol) was dissolved in 10 mL of TFA/DCM (1:1) and stirred at room temperature for 1 hour then quenched by addition to ice cold 6N NaOH. The mixture was diluted with water then the aqueous layer was decanted. The organic layer was diluted with hexanes and filtered. The product, 5-((5-(3-chlorophenylamino)-7-(piperidin-4-ylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione, was collected as a solid in quantitative yield. LCMS (M+1=453)
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[N:4]([CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-])=O>CO.Cl[Cu]>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[N:4]([CH3:14])[C:5]1[C:6]([NH2:11])=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CN(c1ccccc1Cl)c1ccccc1[N+](=O)[O-]
Agent: Cl[Cu]
Solvent: CO
Product: CN(c1ccccc1N)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 100 %

Procedure:
Compound 2 (0.121 g, 0.46 mmol) was stirred at room temperature in MeOH (4.6 mL). To this, CuCl (0.137 g, 1.38 mmol) was added and mixture stirred at room temperature for 5-10 min. KBH4 (0.174 g, 3.22 mmol) was added in portions. The reaction was stirred at room temperature until the solution became clear. The reaction was quenched with deionized H2O and extracted 3 times with 15 mL of a 90:10 mixture of ethyl acetate:dichloromethane. The organic layers were combined and dried over Na2SO4. The solvent was removed to give a brownish-black solid (107 mg, 100% yield). 1H NMR (300 MHz, CDCl3) δ 7.32 (1H, dd, J=7.8, 1.4 Hz), 7.25 (1H, dd, J=7.3, 1.7 Hz), 7.22 (1H, dd, J=7.1, 1.7 Hz), 7.16, (1H, dd, J=8.0, 1.6 Hz), 7.00-6.95 (2H, m), 6.76 (1H, ddd, J=9.3, 7.7, 1.4 Hz), 6.67 (1H, ddd, J=8.9, 7.6, 1.5 Hz); 13C (75 MHz, CDCl3) δ 147.6 (q), 142.2 (q), 136.9 (q), 130.7 (t), 130.68 (q), 127.4 (t), 125.5 (t), 123.6 (t), 121.9 (t), 118.6 (t), 115.8 (t), 41.1.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:13]=[O:14])=[CH:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[Cl:32][C:33]1[N:37]([CH3:38])[N:36]=[C:35]([CH3:39])[C:34]=1[S:40](Cl)(=[O:42])=[O:41]>>[Cl:32][C:33]1[N:37]([CH3:38])[N:36]=[C:35]([CH3:39])[C:34]=1[S:40]([N:5]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:2]([CH3:1])[C:3]([CH:13]=[O:14])=[CH:4]1)(=[O:41])=[O:42]
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Reactant: Cc1c(C=O)c[nH]c1-c1ccccc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)n1cc(C=O)c(C)c1-c1ccccc1

Procedure:
By a reaction under similar conditions as in Reference Example 65 and using 4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg), sodium hydride (60% in oil, 60 mg), 15-crown-5 (0.30 mL) and (5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl chloride (298 mg), the title compound was obtained as an oil (yield 379 mg, about 100%).
Reaction SMILES: [C:1]1([NH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][S:14](O)(=[O:16])=[O:15]>>[CH2:11]([O:10][C:8](=[O:9])[NH:7][C:1]1[CH:6]=[CH:5][C:4]([S:14]([Cl:13])(=[O:16])=[O:15])=[CH:3][CH:2]=1)[CH3:12]
Reactant: CCOC(=O)Nc1ccccc1
Reactant: O=S(=O)(O)Cl
Product: CCOC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Temperature: 60 °C

Procedure:
To a stirred solution of chlorosulfonic acid (20 ml) at 0° C., was added N-phenylurethane (9.90 g) at such a rate that the temperature did not exceed 20° C. The reaction was then heated at 60° C. for 3 hours, cooled to ambient temperature and poured carefully onto ice. The resultant precipitate was collected by filtration and dried in vacuo to give (4-chlorosulfonyl-phenyl)-carbamic acid ethyl ester (14.50 g) as an off-white solid. LC-MS (METHOD B): RT=3.11 minutes, 284.23 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(N(CC)CC)C>[N+:14]([C:11]1[CH:10]=[CH:9][C:8]([CH2:7][N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH2:1][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=1)([O-:16])=[O:15]
Reactant: Cc1nccn1Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1nccn1Cc1ccc([N+](=O)[O-])cc1

Procedure:
24.8 g of 2-methyl-1-(4-nitrobenzyl)imidazole was reacted with 22 ml of ethyl chloroformate in the presence of 32 ml of triethylamine to obtain 13.9 g of ethyl 1-(4-nitrobenzyl)imidazol-2-ylacetate.
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[NH:16][C:15]=2[CH2:24][CH2:25][NH:26][C:27](=[O:29])[CH3:28])=[CH:7][CH:6]=1)C.Br[CH:32]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CC(C)([O-])C.[OH-].[K+].Cl>C(#N)C.O>[C:27]([NH:26][CH2:25][CH2:24][C:15]1[N:16]([CH:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:17]2[C:22]([C:14]=1[CH2:13][CH2:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([C:4]([OH:3])=[O:30])=[CH:10][CH:9]=1)=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)(=[O:29])[CH3:28]
Reactant: CCOC(=O)c1ccc(CCCc2c(CCNC(C)=O)[nH]c3ccc(Cl)cc23)cc1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)NCCc1c(CCCc2ccc(C(=O)O)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Temperature: 3 °C
Reaction time: 7 h
Yield: 53.7 %

Procedure:
To a suspension of the 4-{3-[2-(2-Acetylamino-ethyl)-5-chloro-1H-indol-3-yl]-propyl}-benzoic acid ethyl ester (250.0 g, 0.585 mol, WAY-185133) and bromodiphenylmethane (203.0 g, 0.82 mol) in acetonitrile (10.0 L) at 3° C. was added potasssium tert.butoxide (92.0 g, 0.82 mol). The reaction mixture was stirred for 7 hours at 3° C. Water (125 ml) was added to the reaction mixture and then 7.5 L of solvent was distilled off. To the concentrated reaction mixture, potassium hydroxide (82.1 g, 1.46 mol) was added followed by 2 hours of reflux. To the cooled reaction mixture at 35° C., dil. HCl was added to bring pH to 4-5. The reaction mixture suspension was then cooled to 3° C. It was then filtered, washed with water (250 mL×2). The wet cake was slurried in ethyl acetate (750 ml) at reflux for 2 h. The suspension was cooled to ambient temperature, filtered and washed with ethyl acetate (85 mL×2). Drying the product in vacuo at 50° C. provided 177.5 g (yield 54%, HPLC 93%, SLI 1.4%) of 4-{3-[2-(2-Acetylamino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-propyl}-benzoic acid (WAY-185008). Mass spectrum (electrospray, m/e): M+H 565. 1H NMR (DMSO−d6): δ12.30 (br.s, 1H), 8.06 (m,1H), 7.86 (m, 2H), 7.45 (d, 1H, J=3 Hz), 7.34 (m, 6H), 7.21 (s, 1H), 7.12 (m, 4H), 6.77 (dd, 1H, J=9 Hz& 3 Hz), 6.45 (d,1H, J=9 Hz), 3.28 (m, 2H), 2.87 (m, 2H), 2.72 (m, 4H), 1.90 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[CH:13]=[CH:12][C:11]=2[F:19])[CH:3]=1.CN1C(=O)[CH2:24][CH2:23][CH2:22]1.C([Mg]Cl)(C)C>C1COCC1.CCOCC>[CH2:17]([O:16][C:14]1[CH:13]=[CH:12][C:11]([F:19])=[C:10]([C:4]2[CH:3]=[C:2]([CH:23]([CH3:24])[CH3:22])[N:7]=[C:6]([C:8]#[N:9])[CH:5]=2)[CH:15]=1)[CH3:18]
Reactant: CCOc1ccc(F)c(-c2cc(Cl)nc(C#N)c2)c1
Reactant: CN1CCCC1=O
Agent: CC(C)[Mg]Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOc1ccc(F)c(-c2cc(C#N)nc(C(C)C)c2)c1
Temperature: 0 °C

Procedure:
A mixture of 6-chloro-4-(5-ethoxy-2-fluoro-phenyl)pyridine-2-carbonitrile (which may be prepared as described in Description 113) (1.5 g, 5.42 mmol) NMP (2.61 mL, 27.07 mmol) and Fe(acac)3 (95.73 mg, 0.2700 mmol) in THF (27.106 mL) was stirred at 0° C. and treated with 2M isopropyl magnesium chloride in THF (7.59 mmol) and the mixture was stirred at 0° C. for 30 mins. The mixture was diluted with ether (200 ml) and quenched with brine. The product was extracted into ether (3x) and the extracts were dried (Na2SO4) and evaporated. The product was purified by flash chromatography (0-100% DCM in isohexane) to give 4-(5-ethoxy-2-fluoro-phenyl)-6-isopropyl-pyridine-2-carbonitrile (D114) as a white solid;
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[NH:10][N:11]=[CH:12][N:13]=2)[CH:3]=1.Cl[CH2:15][C:16](Cl)=[O:17].[OH-].[Na+].Cl>O1CCOCC1.N1C=CC=CC=1.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:16](=[O:17])[CH2:15][N:10]3[C:9](=[N:13][CH:12]=[N:11]3)[C:4]=2[CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(Br)cc1-c1ncn[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C1Cn2ncnc2-c2cc(Br)ccc2N1
Temperature: 11 °C
Reaction time: 1.25 h
Yield: 45.7 %

Procedure:
A solution of 4-bromo-2-(2H-[1,2,4]triazol-3-yl)-phenylamine (25.0 g, 105 mmol) in dioxane (870 mL) and pyridine (10.0 mL) was cooled to 12° C. A solution of chloroacetyl chloride (9.56 mL, 121 mmol) in diethylether (34.7 mL) was added dropwise over a period of 8 min. The mixture was stirred at 10-12° C. for 75 min and treated within 5 min with aq NaOH (2 N, 126 mL, 251 mmol). The mixture was stirred for 17.5 h at ambient temperature. The pH thereby dropped to about pH=9 and it was adjusted to pH=8 with HCl (3 N, 6 mL). After evaporation the residue was stirred at 15° C. for 30 min in water (650 mL) and ethyl acetate (22 mL). The crystals were filtered off, washed with cold water and dried in vacuo. Trituration in ethyl acetate (100 mL) afforded the title compound (13.4 g, 46%) as a light yellow solid. MS: m/e =279.0/281.0 [M+H+].
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:19][CH:18]=1)=[C:11](OS(C(F)(F)F)(=O)=O)[CH:10]=[CH:9]2)(=[O:4])=[O:3].[F:41][C:42]1[CH:51]=[CH:50][C:45]2B(O)[O:47][CH2:48][C:44]=2[CH:43]=1>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>[F:41][C:42]1[CH:51]=[CH:50][C:45]([C:11]2[C:12]([C:16](=[O:32])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]4)=[CH:19][CH:18]=3)=[C:13]3[C:8](=[CH:9][CH:10]=2)[CH:7]=[C:6]([O:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:15]=[CH:14]3)=[C:44]([CH2:48][OH:47])[CH:43]=1
Reactant: CS(=O)(=O)Oc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: OB1OCc2cc(F)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CS(=O)(=O)Oc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(F)cc3CO)ccc2c1
Reaction time: 8 h
Yield: 72.9 %

Procedure:
Charge a 100 mL round bottom flask with trifluoro-methanesulfonic acid 6-methanesulfonyloxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (2.3 g, 3.8 mmol), 5-fluoro-3H-benzo[c][1,2]oxaborol-1-ol (1.16 g, 7.6 mmol) and Pd(PPh3)4 (220 mg, 0.19 mmol) and purge with nitrogen. Add degassed DME (36 mL) and 2M Na2CO3 (4 mL) to the flask and plunge into a 75° C. oil bath and stir overnight. Pour the reaction into saturated aqueous sodium bicarbonate and extract with methylene chloride. Wash the organic layer with water and dry with sodium sulfate. Filter and concentrate to an amber foam. Purify the crude material on silica gel (1% to 6% methanol in methylene chloride) to yield 1.6 g (73%) of the title compound as a tan foam. 1H NMR (CDCl3) δ7.98 (d, J=8.4 Hz, 1H), 7.90 (d, J=2.5 Hz, 1H), 7.60 (bs, 3H), 7.43 (d, J=8.4 Hz, 1H), 7.35 (d, J=8.6 Hz, 1H), 7.23 (bs, 11), 6.90-6.70 (m, 4H), 4.40-4.25 (m, 2H), 4.12 (m, 2H), 3.23 (s, 3H), 2.76 (t, J=5.4 Hz, 2H), 2.49 (bs, 4H), 1.59 (m, 5H), 1.45 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH3:17])[CH2:13][CH:14]=1.Cl>CO.[Pt]=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]1
Reactant: CCCN1CC=C(c2cccc(Cl)c2Cl)CC1
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: CCCN1CCC(c2cccc(Cl)c2Cl)CC1
Reaction time: 1 h
Yield: 99.3 %

Procedure:
A mixture of 4-(2,3-dichlorophenyl)-1-propyl-1,2,3,6-tetrahydropyridine (0.4 g, 1.48 mmol), platinum oxide (0.05 g) and hydrochloric acid (0.1 ml, conc) in methanol (30 ml) was hydrogenated at 50 psi for 1 h under hydrogen gas. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated and evaporated to dryness to give 0.4 g of the title compound as the hydrochloric acid salt (87%). Recrystallization from ethanol/diethyl ether: M.p. 265-267° C. MS m/z (relative intensity, 70 eV) 271 (M+, 4), 243 (66), 242 (bp), 164 (9) 115 (17).
Reaction SMILES: [N+]([O-])([O-])=O.[K+].[CH2:6]([C:9]1[S:10][C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13]([NH2:21])[C:12]=2[N:22]=1)[CH2:7][CH3:8].[OH-].[NH4+:24]>S(=O)(=O)(O)O>[CH2:6]([C:9]1[S:10][C:11]2[C:20]3[CH:19]=[C:18]([NH2:24])[CH:17]=[CH:16][C:15]=3[N:14]=[C:13]([NH2:21])[C:12]=2[N:22]=1)[CH2:7][CH3:8]
Reactant: [NH4+]
Reactant: CCCc1nc2c(N)nc3ccccc3c2s1
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Product: CCCc1nc2c(N)nc3ccc(N)cc3c2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium nitrate (0.46 g, 4.52 mmol) was added to a solution of 2-propylthiazolo[4,5-c]quinolin-4-amine (1 g, 4.11 mmol, Example 12) in sulfuric acid (10 mL). The reaction mixture was stirred at ambient temperature for 30 minutes, then poured onto ice, neutralized (pH=7) with ammonium hydroxide (150 mL) and then extracted with dichloromethane. The extract was washed with sodium bicarbonate, dried over magnesium sulfate and then concentrated under vacuum to provide 1 g of a yellow solid. This material was recrystallized from isopropanol/water to provide 0.84 g of 8-nitro-2-propylthiazolo[4,5-c]quinoline as a yellow solid, m.p. 228-230° C. Analysis: Calculated for C13H12N4O2S: % C, 54.15; % H, 4.20; % N, 19.43; Found: % C, 54.22; % H, 4.05; % N, 19.04.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][N:7]1[C:15]([OH:16])=[N:14][C:13]2[C:8]1=[N:9][C:10]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[N:11][C:12]=2[NH2:17].P(Br)(Br)[Br:27]>C1COCC1>[Br:27][CH2:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][N:7]1[C:15]([OH:16])=[N:14][C:13]2[C:8]1=[N:9][C:10]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[N:11][C:12]=2[NH2:17]
Reactant: BrP(Br)Br
Reactant: COCCOc1nc(N)c2nc(O)n(Cc3cccc(CO)c3)c2n1
Solvent: C1CCOC1
Product: COCCOc1nc(N)c2nc(O)n(Cc3cccc(CBr)c3)c2n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of Compound (8) (51.4 mg, 0.148 mmol) in THF (2 mL) was added phosphorus tribromide (0.2 mL). The reaction mixture was allowed to stir at room temperature for 5 minutes then quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were dried over NaSO3 and evaporated to give Compound (9) as a white solid. The crude mixture was used in the next step without further purification. The identity of the product was verified by LCMS. LCMS: m/z for C16H19N5O4++H observed 346.1 at 1.69 minutes of a 3.5 minute run, gradient 5-95% CH3CN in H2O. LCMS: m/z for C16H18BrN5O3++H observed 408.0 and 410.1 at 2.03 minutes of a 3.5 minute run, gradient 5-95% CH3CN in H2O (C18 column).