Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:15]([C:17]4[C:25]5[C:20](=[CH:21][C:22]([C:26]6[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=6)=[CH:23][CH:24]=5)[N:19]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[CH:18]=4)=[O:16])=[C:10]3[CH2:9][S:8]2)[CH:2]=1.[OH-].[Li+].Cl>C1COCC1.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:15]([C:17]4[C:25]5[C:20](=[CH:21][C:22]([C:26]6[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=6)=[CH:23][CH:24]=5)[N:19]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH:18]=4)=[O:16])=[C:10]3[CH2:9][S:8]2)[CH:2]=1
Reactant: CCOC(=O)CCn1cc(C(=O)c2ccn3c2CSC3c2cccnc2)c2ccc(-c3ccc(F)cc3)cc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCn1cc(C(=O)c2ccn3c2CSC3c2cccnc2)c2ccc(-c3ccc(F)cc3)cc21

Procedure:
A mixture of 3-(pyridin-3-yl)-7-[1-(2-carboethoxyethyl)-6-(4-fluorophenyl)indol-3-ylcarbonyl]-1H,3H--pyrrolo[1,2-c]thiazole (90 mg, 0.17 mmol), and lithium hydroxide (11 mg), where stirred in 33% aqueous THF (15 mL) for 45 min. The reaction mixture was diluted with H2O and taken to pH 4 with 1M aqueous HCl. The reaction mixture was extracted three times with ethyl acetate. The combined organic layers where dried over MgSO4, filtered,and concentrated in vacuo. 3-(Pyridin-3-yl)-7-[1-(2-carboxyethyl)-6-(4-fluorophenyl)indol-3-ylcarbonyl]-1H,3H-pyrrolo[1,2-c]thiazole (63 mg), was crystallized from ethyl acetate, hexanes. 1H NMR (CDCl3, 300MHz) δ2.95 (t, 2H, J=6, 7 Hz), 4.5-4.65 (m, 4H), 6.14 (d, 1H, J=3 Hz), 6.45 (s, 1H), 6.73 (d, 1H, J=3 Hz), 7.15 (t, 2H, J=9, 11Hz), 7.38-7.43 (m, 1H), 7.52 (d, 2H, J=8 Hz), 7.6-7.7 (m, 3H), 8.05 (s, 1H), 8.46 (d, 1H, J=9 Hz), 8.57 (bs, 2H), MS (DCI/NH3) m/e 512 (M+H)+. Anal calcd for C29H22N3O3SF; C, 68.09; H, 4.33; N, 8.21. Found: C, 67.78; H, 3.90; N, 8.06.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[C:7]([S:10][C:11]1[C:20]([Cl:21])=[CH:19][C:18]2[CH2:17][CH:16]([NH:22][CH2:23][CH3:24])[CH2:15][CH2:14][C:13]=2[CH:12]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)=[O:28]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[C:7]([S:10][C:11]1[C:20]([Cl:21])=[CH:19][C:18]2[CH2:17][CH:16]([N:22]([CH2:23][CH3:24])[C:27]([O:29][C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)=[O:28])[CH2:15][CH2:14][C:13]=2[CH:12]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCNC1CCc2cc(SC(C)(C)C(=O)OC(C)(C)C)c(Cl)cc2C1
Reactant: Cc1ccc(OC(=O)Cl)cc1
Solvent: ClCCl
Product: CCN(C(=O)Oc1ccc(C)cc1)C1CCc2cc(SC(C)(C)C(=O)OC(C)(C)C)c(Cl)cc2C1
Temperature: 25 °C
Reaction time: 144 h
Yield: 29 %

Procedure:
To a mixture of 2-(3-chloro-6-ethylamino-5,6,7,8-tetrahydro-naphthalen-2-ylsulfanyl)-2-methyl-propionic acid tert-butyl ester and borane complex (80 mg; 201 μmol), dissolved in CH2Cl2 (2 mL), at 0° C. is added p-tolyl chloroformate (35 μL; 241 μmol). The reaction was slowly warmed to RT and allowed to stir at RT for 6 days. The solvent was removed under reduced pressure and the crude residue was purified by flash chromatography (SiO2) eluting with a hexanes-EtOAc gradient to afford 30 mg (29%) of 2-[3-chloro-6-(ethyl-p-tolyloxycarbonyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-ylsulfanyl]-2-methyl-propionic acid tert-butyl ester as a clear oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:18])[N:15]=[C:16]([CH3:17])[C:3]=12.[F-:19].[K+]>CN(C=O)C>[F:19][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:18])[N:15]=[C:16]([CH3:17])[C:3]=12
Reactant: [F-]
Reactant: Cc1nn(C)c2nnc(-c3ccccc3)c(Cl)c12
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn(C)c2nnc(-c3ccccc3)c(F)c12
Temperature: 120 °C
Reaction time: 16 h
Yield: 29.1 %

Procedure:
A suspension of 4-chloro-1,3-dimethyl-5-phenyl-pyrazolo[3,4-c]pyridazine (44 mg, 0.17 mmol), potassium fluoride (50 mg, 0.85 mmol) in dry DMF (1 mL) was stirred at 120° C. for 16 h. The reaction mixture was purified by preparative HPLC to provide Compound 24 (12 mg).
Reaction SMILES: COC1C=C(C(Cl)=O)C=CC=1OC.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][N:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.[CH3:36][O:37][C:38]1[CH:39]=[C:40]([C:46]([N:48]=[C:49]=[S:50])=[O:47])[CH:41]=[CH:42][C:43]=1[O:44][CH3:45]>C1(C)C=CC=CC=1.C(O)C>[CH3:36][O:37][C:38]1[CH:39]=[C:40]([C:46]([N:48]=[C:49]=[S:50])=[O:47])[CH:41]=[CH:42][C:43]=1[O:44][CH3:45].[CH3:36][O:37][C:38]1[CH:39]=[C:40]([CH:41]=[CH:42][C:43]=1[O:44][CH3:45])[C:46]([NH:48][C:49]([NH:33][C:32]1[CH:34]=[CH:35][C:29]([O:28][C:19]2[C:18]3[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=3)[N:22]=[CH:21][N:20]=2)=[CH:30][CH:31]=1)=[S:50])=[O:47]
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: COc1ccc(C(=O)Cl)cc1OC
Agent: COc1ccc(C(=O)N=C=S)cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ncnc4cc(OC)c(OC)cc34)cc2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
3,4-Dimethoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3,4-dimethoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3,4-dimethoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (57 mg, yield 65%).
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[C:4]([NH:6][CH3:7])=[O:5].[C:21](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O.[OH-].[Na+]>C1(C)C=CC=CC=1.CC(C)=O>[CH3:21][O:1]/[N:2]=[C:3](\[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)/C(=N/O)c1ccccc1Oc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: COS(=O)(=O)OC
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CNC(=O)/C(=N/OC)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 9 h
Yield: 94.4 %

Procedure:
To E-2-hydroxyimino-N-methyl-2-(2-phenoxyphenyl)acetamide (10.00 g, 0.037 mole) were added acetone (200 ml), potassium carbonate (15.34 g, 0.111 moles) and dimethylsulfate (9.33 g, 0.074 moles) and the mixture was stirred at room temperature for 9 hours. After completion of the reaction, the reaction mixture was filtered, washed with acetone and concentrated under reduced pressure. The oil thus obtained was dissolved in toluene (50 ml) and to this was added an aqueous 1N sodium hydroxide solution (50 ml), followed by stirring at room temperature for 30 minutes. The mixture was extracted with toluene, washed with water and concentrated, and then the resulting residue was recrystallized (methanol/water) to obtain E-2-methoxyimino-N-methyl-2-(2-phenoxyphenyl)acetamide (9.93 g, yield: 94.4%) as colorless crystals (melting point: 81.5°-83° C.).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:5][CH2:4]1.C(Cl)Cl.[F:22][C:23]1([F:35])[O:27][C:26]2[CH:28]=[CH:29][C:30]([C:32](Cl)=[O:33])=[CH:31][C:25]=2[O:24]1.C([O-])(O)=O.[Na+]>CCOC(C)=O.C1COCC1>[F:35][C:23]1([F:22])[O:27][C:26]2[CH:28]=[CH:29][C:30]([C:32]([NH:1][CH2:2][CH:3]3[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:5][CH2:4]3)=[O:33])=[CH:31][C:25]=2[O:24]1
Reactant: O=C(Cl)c1ccc2c(c1)OC(F)(F)O2
Reactant: CC(C)(C)OC(=O)NCCN1CCC(CN)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCN1CCC(CNC(=O)c2ccc3c(c2)OC(F)(F)O3)CC1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 2-(4-(aminomethyl)piperidin-1-yl)ethylcarbamate (50 mg, 0.19 mmol) and TEA (135 μL, 0.972 mmol) in a mixture of 1:1 CH2Cl2:THF (2.5 mL) was treated with 2,2-difluorobenzo[d][1,3]dioxole-5-carbonyl chloride (51 mg, 0.23 mmol). The resulting solution was stirred overnight, then transferred to a test tube containing saturated aqueous NaHCO3 (4 mL) and EtOAc (4 mL). The biphasic mixture was mixed vigorously and allowed to separate for 15 minutes. After separation, the mixture was cooled to −20° C. until the aqueous layer was frozen. The organic layer was then poured off and the solvent was removed under reduced pressure at 50° C. The resulting residue was purified by HiTOPs.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C@@H:12]1[N:17]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:16][C@@H:15]2[O:29]C(C)(C)[O:31][C@H:14]2[C@@H:13]1[OH:34])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1.CO>[CH2:1]([O:8][NH:9][C:10]([C@H:12]1[C@@H:13]([OH:34])[C@H:14]([OH:31])[C@@H:15]([OH:29])[CH2:16][N:17]1[S:18]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)(=[O:20])=[O:19])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N2C[C@@H]3OC(C)(C)O[C@H]3[C@H](O)[C@@H]2C(=O)NOCc2ccccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)N2C[C@H](O)[C@@H](O)[C@H](O)[C@@H]2C(=O)NOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 95.8 %

Procedure:
The above compound (5-2) (100 mg) was dissolved in a solvent mixture of 1,4-dioxane/methanol (5–15 mL) and a cation exchange resin (Muromac, 2.5 g) was added, and then the mixture was stirred at room temperature for 14 hours. The insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel medium pressure column chromatography (chloroform:methanol=20:1→10:1) to obtain the titled compound (88 mg).
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH2:5]([Mg]Br)[CH3:6].C(OCC)C.[CH3:14][C@H:15]1[C:19](=[O:20])[CH2:18][CH2:17][N:16]1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>>[CH2:15]([C@:19]1([OH:20])[CH2:18][CH2:17][N:16]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[C@H:5]1[CH3:6])[CH3:14]
Reactant: C[C@H]1C(=O)CCN1C(=O)OCc1ccccc1
Reactant: CC[Mg]Br
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CCOCC
Product: CC[C@]1(O)CCN(C(=O)OCc2ccccc2)[C@H]1C

Procedure:
By an operation in the same manner as in Reference Example 3 and using cerium chloride (7.94 g), 3 mol/L ethylmagnesium bromide-diethyl ether solution (9.46 mL) and benzyl (2S)-2-methyl-3-oxopyrrolidine-1-carboxylate (3.0 g), the title compound was obtained as pale-yellow oil (yield: 1.96 g, yield: 58%).
Reaction SMILES: [CH2:1]([C:4]1[N:8]2[C:9](=[S:13])[NH:10][N:11]=[CH:12][C:7]2=[CH:6][N:5]=1)[CH2:2][CH3:3].[Na].[CH3:15]I>CO>[CH2:1]([C:4]1[N:8]2[C:9]([S:13][CH3:15])=[N:10][N:11]=[CH:12][C:7]2=[CH:6][N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ncc2cn[nH]c(=S)n12
Reactant: CI
Agent: [Na]
Solvent: CO
Product: CCCc1ncc2cnnc(SC)n12

Procedure:
A 3.98 gm. portion of 6-n-propyl-imidazo[1,5-d]-as-triazine-4(3H)-thione is added to a solution of 0.46 gm. of sodium in 15 ml. of methanol under nitrogen. A 1.56 ml. portion of methyl iodide is added. The reaction procedes as described in Example 30 giving the desired product, m.p. 132°-134° C.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.C(OCC1N(C[C:25]2([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)C2C3C=CC=CC=3N=CC=2N=1)C.C(N(CC)CC)C>ClCCl>[CH:1]1([C:4]([N:28]2[CH2:29][CH2:30][CH:25]([OH:31])[CH2:26][CH2:27]2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CC1)N1CCC(O)CC1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere cyclopropanecarbonyl chloride (0.84 mL, 9.25 mmol) was added dropwise to a chilled mixture of 4-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidin-4-ol (3.00 g, 8.81 mmol), triethylamine (1.47 mL, 10.6 mmol) and dichloromethane (90 mL). The reaction mixture was allowed to warm to ambient temperature. After 2 hours the reaction mixture was washed with water. The organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel eluting with 90/10 dichloromethane/methanol) to provide 3.16 g of 4-[2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-1-(cyclopropylcarbonyl)piperidin-4-ol as a light orange frothy solid.
Reaction SMILES: [C:1]([CH:4]=[N:5][C:6]1[C:7](=[CH:11][CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:8]([OH:10])=[O:9])([OH:3])=[O:2].OS(O)(=O)=O>C(O)C1C=CC=CC=1>[C:1]([CH:4]=[N:5][C:6]1[C:7](=[CH:11][CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:8]([OH:10])=[O:9])([O:3][CH2:8][C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:6]=1)=[O:2]
Reactant: O=C(O)C=Nc1cc(Cl)ccc1C(=O)O
Agent: O=S(=O)(O)O
Solvent: OCc1ccccc1
Product: O=C(C=Nc1cc(Cl)ccc1C(=O)O)OCc1ccccc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
10 g (43.6 mmol) of N-carboxymethylene-4-chloro-anthranilic acid are dissolved in 40 ml of benzyl alcohol, 444 mg (4.3 mmol) of H2SO4 are added and the mixture is stirred at 110° C. for 2 hours. It is cooled to room temperature and the product which has precipitated out is filtered off with suction, washed with benzyl alcohol and dried. 7.3 g (22.9 mmol; 53% of pale yellow crystalline N-carbobenzoxymethylene-4-chloro-anthranilic acid are obtained.
Reaction SMILES: [CH:1]([C:3]1[C:8](I)=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]=[C:13]([C:15]#[N:16])[C:12]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:20][CH:19]=2)=[N:11]1)=[O:2].[C:32]([C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[C:42](=[O:46])[NH:41][N:40]=[CH:39]2)([CH3:35])([CH3:34])[CH3:33].C(=O)(O)[O-].[Na+]>CS(C)=O>[C:32]([C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[C:42](=[O:46])[N:41]([C:8]1[C:3]([CH:1]=[O:2])=[C:4]([N:10]3[CH:14]=[C:13]([C:15]#[N:16])[C:12]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[O:25])=[CH:20][CH:19]=4)=[N:11]3)[CH:5]=[CH:6][CH:7]=1)[N:40]=[CH:39]2)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)c1ccc2c(=O)[nH]ncc2c1
Reactant: N#Cc1cn(-c2cccc(I)c2C=O)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-n4cc(C#N)c(Nc5ccc(C(=O)N6CCOCC6)cc5)n4)c3C=O)ncc2c1
Reaction time: 1 h
Yield: 41.9 %

Procedure:
1-(2-Formyl-3-iodophenyl)-3-(4-(morpholine-4-carbonyl)phenylamino)-1H-pyrazole-4-carbonitrile (71 mg, 0.135 mmol), 6-tert-butylphthalazin-1(2H)-one (27.2 mg, 0.135 mmol), cuprous iodide (25.6 mg, 0.135 mmol) and sodium bicarbonate (22.6 mg, 0.269 mmol) were combined in 2 mL of DMSO. The mixture was thoroughly degassed with argon and then stirred in an oil bath preheated to 100° C. After 1 hr, the mixture was extracted with dichloromethane and water. The organic layer was dried over sodium sulfate and filtered. Solvents were evaporated and the residue was purified by flash column chromatography (12 g silica gel, 0% to 5% methanol in dichloromethane) to give 1-(3-(6-tert-butyl-1-oxophthalazin-2(1H)-yl)-2-formylphenyl)-3-[4-(morpholine-4-carbonyl)phenylamino]-1H-pyrazole-4-carbonitrile as a pale pink solid (34 mg, 42% yield). LC/MS clacd for C34H31N7O4 (m/e) 601.24, obsd 602.1 (M+H, ES+); 1H NMR (400 MHz, CDCl3) δ ppm 1.45 (s, 9H), 3.68 (br. m., 8H), 6.68 (br. s., 1H), 7.39 (d, J=8.6 Hz, 2H), 7.46 (d, J=8.6 Hz, 2H), 7.57 (dd, J=8.0, 1.1 Hz, 1H), 7.65-7.74 (m, 1H), 7.74-7.81 (m, 2H), 7.93 (dd, J=8.6, 1.8 Hz, 1H), 8.17 (s, 1H), 8.40 (d, J=8.6 Hz, 1H), 8.47 (br. s., 1H), 9.90 (br. s., 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:11]([NH:14][CH:15]2[CH2:17][CH2:16]2)(=[O:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.ClC1C=C(C=CC=1S(NC1CC1)(=O)=O)C(O)=O.Cl.Cl.[CH3:37][C:38]1[N:42]([CH:43]2[CH2:49][CH:48]3[N:50]([CH2:51][CH2:52][C:53]4([C:59]5[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=5)[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]4)[CH:45]([CH2:46][CH2:47]3)[CH2:44]2)[C:41]2[CH:65]=[CH:66][CH:67]=[CH:68][C:40]=2[N:39]=1.CC1N(C2CC3N(CCC4(C5C=CC=CC=5)CCN(C(C5C=CC=CC=5S(NC(=O)OC(C)(C)C)(=O)=O)=O)CC4)C(CC3)C2)C2C=CC=CC=2N=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:11]([NH:14][CH:15]2[CH2:17][CH2:16]2)(=[O:13])=[O:12])=[C:6]([C:7]([N:56]2[CH2:55][CH2:54][C:53]([CH2:52][CH2:51][N:50]3[CH:45]4[CH2:46][CH2:47][CH:48]3[CH2:49][CH:43]([N:42]3[C:41]5[CH:65]=[CH:66][CH:67]=[CH:68][C:40]=5[N:39]=[C:38]3[CH3:37])[CH2:44]4)([C:59]3[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=3)[CH2:58][CH2:57]2)=[O:9])[CH:10]=1
Reactant: O=C(O)c1cc(Cl)ccc1S(=O)(=O)NC1CC1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Agent: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: O=C(O)c1ccc(S(=O)(=O)NC2CC2)c(Cl)c1
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2cc(Cl)ccc2S(=O)(=O)NC2CC2)CC1
Yield: 11 %

Procedure:
The title compound was prepared from a mixture of 5-chloro-2-[(cyclopropyl amino)sulfonyl]benzoic acid and 3-chloro-4-[(cyclo propylamino)sulfonyl]benzoic acid 2c and endo 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride II following the general procedure for tert-butyl {2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenyl piperidin-1-yl)carbonyl]phenyl}sulfonylcarbamate 1c. The desired regioisomer was purified by column chromatography on silica gel eluting with 10% methanol in ethyl acetate to afford 4-chloro-N-cyclopropyl-2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzene sulfonamide 3 as a white solid (15 mg, 11% yield). 1H NMR (400 MHz, CDCl3) δ 8.18 (d, 1H, J=8.1 Hz), 7.65 (m, 1H), 7.54 (m, 1H), 7.41-7.12 (m, 9H), 5.48 (s, 1H), 4.60 (m, 1H), 4.20 (m, 1H), 3.45-3.23 (m, 6H), 2.56 (s, 3H), 2.40-2.33 (m, 3H), 2.20-2.17 (m, 1H), 1.97-1.58 (m, 10H), 0.70-0.56 (m, 4H). ES-LCMS m/z 688.35 (M+2H). Analytical HPLC (Method Y) Rt 3.34 (89.34%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:33])=[C:19]([NH:23][S:24]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:35]>>[ClH:1].[NH2:35][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:33])=[C:19]([NH:23][S:24]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cn1cc(S(=O)(=O)Nc2cccc(-c3nc(C(C)(C)C)sc3-c3ccnc(Cl)n3)c2F)cn1
Reactant: [NH4+]
Agent: [OH-]
Product: Cl
Product: Cn1cc(S(=O)(=O)Nc2cccc(-c3nc(C(C)(C)C)sc3-c3ccnc(N)n3)c2F)cn1

Procedure:
Following a procedure analogous to the procedure described in Example 282 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1-methyl-1H-pyrazole-4-sulfonamide (750 mg, 1.47 mmol) and ammonium hydroxide (12 ml), the title compound was obtained as a white solid (183 mg, 23%). 1HNMR (DMSO-d6): δ ppm 10.13 (s, 1H), 8.23 (s, 1H), 8.11 (br s, 1.5H), 7.68 (s, 1.5H), 7.46-7.49 (dd, J1=7.6 Hz, J2=0.8 Hz, 1H), 7.35 (br s, 1H), 7.27-7.31 (t, J=8.0 Hz, 1H), 6.06 (br s, 2H), 3.82 (s, 3H), 1.42 (s, 9H); MS: 488 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]=[N+:7]=[N-:8])=[N+:2]=[N-:3].[CH2:9]([Mg]Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH4+]>C1COCC1>[CH2:9]([NH:3][N:2]=[N:1][CH2:4][CH2:5][N:6]=[N:7][NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [N-]=[N+]=NCCN=[N+]=[N-]
Reactant: Cl[Mg]Cc1ccccc1
Agent: [NH4+]
Solvent: C1CCOC1
Product: c1ccc(CNN=NCCN=NNCc2ccccc2)cc1
Temperature: -60 °C

Procedure:
A solution of 1.12 g (10 mmoles) of 1,2-diazidoethane in 20 ml. of THF was cooled to -60° C. This solution was treated with 15 ml of 2.0M benzylmagnesium chloride in THF (30 mmoles) dropwise with stirring. The reaction mixture was allowed to come to room temperature slowly, and was then cooled again to -60° C., and 10 ml. of ammonium buffer (see preparation above) was added and the reaction was allowed to come to room temperature. The reaction mixture was mixed with 100 ml. of diethylether and the organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was removed on a rotary evaporator. The pink residual oil was subjected to high vacuum overnight, which produced a pale yellow solid. This material was crystallized from ether/pentane (1:1) to produce 1.71 g of colorless powdery solid m.p. 73°-75° C. Spectroscopy (nmr and mass) were consistent with the structure.
Reaction SMILES: [CH2:1]([CH:9]([C:14]([CH3:16])=O)[C:10]([O:12]C)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:17][C:18]1[NH:22][N:21]=[C:20]([NH2:23])[CH:19]=1>C(O)CCC>[OH:12][C:10]1[N:21]2[N:22]=[C:18]([CH3:17])[CH:19]=[C:20]2[N:23]=[C:14]([CH3:16])[C:9]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC(C(C)=O)C(=O)OC
Reactant: Cc1cc(N)n[nH]1
Solvent: CCCCO
Product: CCCCCCCCc1c(C)nc2cc(C)nn2c1O
Yield: 79.2 %

Procedure:
200 g of methyl 2-n-octylacetoacetate and 94 g of 3(5)-amino-5(3)-methylpyrazole in 400 ml of n-butanol are refluxed for 5 hours. The mixture is cooled, and the product is filtered off under suction, washed with cold methanol and dried under reduced pressure at 60° C. to give 191 g of 7-hydroxy-2,5-dimethyl-6-n-octylpyrazolo[1,5-a]pyrimidine of melting point 199° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[C@@H:5]([CH3:21])[CH2:4][N:3]1C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>>[CH3:21][C@H:5]1[CH2:4][NH:3][C@H:2]([CH3:1])[CH2:7][N:6]1[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=2)[N:13]=1
Reactant: C[C@@H]1CN(c2ccc3nnc(C(F)(F)F)n3n2)[C@@H](C)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(c2ccc3nnc(C(F)(F)F)n3n2)[C@@H](C)CN1
Reaction time: 0.25 h
Yield: 78.1 %

Procedure:
(2R,5S)-tert-Butyl 2,5-dimethyl-4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazine-1-carboxylate (6.01 g, 15 mmol) was added in portions to stirred TFA (25 mL) over 5 minutes. There was a moderate exotherm and the reaction mixture was allowed to stir for a further 15 minutes. The bulk of the TFA was evaporated and the residue was basified with 1M aqueous K2CO3. It was extracted thoroughly with DCM (4×200 mL) and the combined organic phase was dried over MgSO4 and evaporated to give an oil which rapidly crystallised. The solid was collected by filtration and dried under vacuum to give 6-[(2S,5R)-2,5-dimethylpiperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (3.52 g, 78%) as a white crystalline solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:11]([Br:12])=[CH:10][N:9]=[C:8]([NH:13][C:14]2[CH:15]=[C:16]([NH:20][C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[CH:17]=[CH:18][CH:19]=2)[N:7]=1.CCN(C(C)C)C(C)C.[C:37]1([N:43]=[C:44]=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCOCC1>[Br:12][C:11]1[C:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:44]([NH:43][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:45])=[N:7][C:8]([NH:13][C:14]2[CH:15]=[C:16]([NH:20][C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[CH:17]=[CH:18][CH:19]=2)=[N:9][CH:10]=1
Reactant: O=C=Nc1ccccc1
Reactant: NCCCNc1nc(Nc2cccc(NC(=O)N3CCCC3)c2)ncc1Br
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCCNc1nc(Nc2cccc(NC(=O)N3CCCC3)c2)ncc1Br)Nc1ccccc1
Reaction time: 8 h
Yield: 61.4 %

Procedure:
To a suspension of N-(3-((4-((3-aminopropyl)amino)-5-bromo-2-pyrimidinyl)amino)phenyl)-1-pyrrolidinecarboxamide (100 mg, 0.2 mmol) and DIEA (0.14 mL, 0.8 mmol) in 1,4-dioxane (5 mL) was added phenyl isocyanate (35 mg, 0.3 mmol). The resulting solution was stirred overnight and concentrated. The crude residue was directly purified by prep HPLC using acetonitrile/water to give the title compound (68 mg).