Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:16][OH:17].[N+]([O-])(O)=O>O>[CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH:16]=[O:17]
Reactant: Cc1[nH]c(-c2ccc([N+](=O)[O-])cc2)nc1CO
Solvent: O=[N+]([O-])O
Solvent: O
Product: Cc1[nH]c(-c2ccc([N+](=O)[O-])cc2)nc1C=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
A mixture of 5-methyl-2-(p-nitrophenyl)-4-imidazolemethanol (2.9 gm., 0.012 mole) and 70% nitric acid (20 ml.) is stirred at 50° C. for 3 hours, followed by dilution with water and neutralization with base. The precipitated yellow solid is collected by filtration to yield 2.4 gm. (0.011 mole) of title product, dec. >270° C.
Reaction SMILES: [N:1]12CCCN=C1CCCC[CH2:2]2.[Br:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[N+:15]([O-])[CH:14]=1.C([Si](C)(C)C)#N>C1COCC1>[Br:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:2]#[N:1])=[N:15][CH:14]=1
Reactant: [O-][n+]1cc(Br)c2ccccc2c1
Reactant: C1CCC2=NCCCN2CC1
Agent: C[Si](C)(C)C#N
Solvent: C1CCOC1
Product: N#Cc1ncc(Br)c2ccccc12
Yield: 81.5 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (1.67 mL, 11.2 mmol) was added to a mixture of compound 470A (1.12 g, 5.00 mmol) and cyanotrimethylsilane (0.75 mL, 5.5 mmol) in 35 mL of THF. The resulting homogeneous mixture was refluxed for 20 min. After concentrating in vacuo, the residue was purified by flash chromatography on a 5×15 cm silica gel column, eluting with 3:1 hexane:ethyl acetate to give 0.95 g (82%) of compound 470B as a white powder. 1H NMR (400 MHz, CDCl3): δ 8.85 (s, 1H), 8.36 (d, 1H, J=8.5 Hz), 8.28 (d, 1H, J=8.5 Hz), 7.96 (t, 1H, J=8.5 Hz), 7.89 (t, 1H, J=8.5 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:17][CH2:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])[C:5]2[N:6]([C:8]([C:12]([O:14]CC)=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.[OH-].[Li+].Cl>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([O:17][CH2:18][C:19]2[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=2[F:25])[C:5]2[N:6]([C:8]([C:12]([OH:14])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(Br)cn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2c(OCc3c(F)cccc3F)cc(Br)cn2c1C(=O)O
Temperature: 40 °C
Reaction time: 6 h

Procedure:
1.5 g of ethyl 6-bromo-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate (Example 18A; 3.5 mmol, 1 equivalent) were dissolved in 72 ml of THF/methanol 5:1, 17.6 ml of 1N aqueous lithium hydroxide solution (17.6 mmol, 5 equivalents) were added and the mixture was warmed to 40° C. and stirred at this temperature for 6 h. Using 6 N aqueous hydrochloric acid, the mixture was then adjusted to pH 4 and concentrated under reduced pressure. Water was added to the solid formed and the solid was triturated, filtered off, washed with water and dried under reduced pressure. This gave 1.24 g of the title compound (88% of theory).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[C:16]([C:37]3[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=3)=[C:17]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[N:18]([Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH:19]=2)([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].CO>[F:36][C:33]1[CH:34]=[CH:35][C:30]([C:17]2[N:18]([Si:20]([CH:24]([CH3:26])[CH3:25])([CH:27]([CH3:29])[CH3:28])[CH:21]([CH3:22])[CH3:23])[CH:19]=[C:15]([C:11]3([OH:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:16]=2[C:37]2[CH:38]=[CH:39][N:40]=[CH:41][CH:42]=2)=[CH:31][CH:32]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C2(O)CCN(Cc3ccccc3)CC2)c(-c2ccncc2)c1-c1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C2(O)CCNCC2)c(-c2ccncc2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.8 %

Procedure:
0.58 g of 10% palladium on carbon were added to a solution of 0.58 g (1.00 mmol) of 4-(1-benzyl-4-hydroxypiperidin-4-yl)-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1-triisopropylsilyl-1H-pyrrole [prepared as described in step 9(i) above] in 15 ml of methanol. The resulting mixture was stirred under a hydrogen atmosphere at room temperature for 5 hours. At the end of this time, the reaction mixture was filtered and the filtrate was concentrated by evaporation under reduced pressure to give 483 mg (yield 98%) of the title compound as a white amorphous solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH2:11])=[C:9]([Br:12])[CH:8]=[C:7]([Cl:13])[N:6]=1)=[O:4]>CO.[OH-].[Na+]>[NH2:11][C:10]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]([Cl:13])=[CH:8][C:9]=1[Br:12]
Reactant: COC(=O)c1nc(Cl)cc(Br)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1c(Br)cc(Cl)nc1C(=O)O
Temperature: 50 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
3-Amino-4-bromo-6-chloro-pyridine-2-carboxylic acid methyl ester (169 mg) was suspended in methanol (3 mL) and 2N sodium hydroxide solution (2 mL). The suspension was stirred at 50° C. for 3 hours. The precipitate was filtered off and washed carefully with diethyl ether. The precipitate was dissolved in a mixture of 2N hydrochloric acid and ethyl acetate and the layers were separated. The aqueous layer was 2× extracted with ethyl acetate, washed with brine, dried over MgSO4 and concentrated in vacuum to afford 138 mg of the title compound of the formula
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([N:20](C)[C:21](=O)C(F)(F)F)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO.O>[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([NH:20][CH3:21])[CH2:16][CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN(C(=O)C(F)(F)F)C1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CNC1CCN(Cc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 128.3 %

Procedure:
Potassium carbonate (662 mg, 4.79 mmol) was added to a solution of N-(1-benzyl-4-piperidinyl)-2,2,2-trifluoro-N-methylacetamide (720 mg, 2.40 mmol) in a mixture of methanol (14 ml) and water (2 ml) at room temperature and stirred at 50° C. for 1.5 hours. After the reaction solution was concentrated, a saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove the solvent, whereby 1-benzyl-N-methylpiperidin-4-amine (629 mg, 100%) was obtained.
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][CH:6]1[O:11][CH:10](Br)[CH:9]([O:13][C:14]([CH3:16])=[O:15])[CH:8]([O:17][C:18]([CH3:20])=[O:19])[CH:7]1[O:21][C:22]([CH3:24])=[O:23])=[O:3].[CH3:25][S:26](=[S:29])([O-:28])=[O:27].[Na+]>C1(C)C=CC=CC=1>[CH3:25][S:26](=[S:29])([O:28][C@@H:10]1[O:11][C@H:6]([CH2:5][O:4][C:2](=[O:3])[CH3:1])[C@H:7]([O:21][C:22](=[O:23])[CH3:24])[C@H:8]([O:17][C:18](=[O:19])[CH3:20])[C@H:9]1[O:13][C:14](=[O:15])[CH3:16])=[O:27]
Reactant: CS(=O)([O-])=S
Reactant: CC(=O)OCC1OC(Br)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)OC[C@H]1O[C@@H](OS(C)(=O)=S)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 66.4 %

Procedure:
Acetobromogalactose 1 (1.1 g, 2.68 mmol) and sodium methanethiosulfonate (0.45 g, 3.35 mmol) in toluene (50 mL) were concentrated in vacuo to approximately 30 mL to remove any water as the azeotrope. The mixture was made up to 50 mL with more toluene and again concentrated to 30 mL. A catalytic amount of tetrabutylammonium iodide was added and the mixture heated at reflux for 75 minutes. After cooling, Celite (to stop the formation of a salt cake on top of the column) was added and the whole mixture loaded directly on to a flash silica column. Elution with 40% ethyl acetate in petroleum ether and recrystallization from petroleum ether/ethyl acetate gave the title compound (787 mg, 67%) as colorless prisms; mp 118-119° C. (petroleum ether/ethyl acetate); [α]23D=+8.5 (c 1.0, CHCl3); IR (KBr) 1753 (C═O), 1325, 1138 (S—SO2) cm−1;1H NMR (400 MHz, CDCl3) δ 1.99 (s, 3H, Ac), 2.50 (s, 3H, Ac), 2.08 (s, 3H, Ac), 2.17 (s, 3H, Ac), 3.43 (s, 3H, CH3SO2—), 4.05 (ddd, J 7.4, 4.2, 0.9 Hz, 1 H), 4.08 (dd, J 18.3, 7.5 Hz, 1H), 4.20 (dd, J 10.8, 4.3 Hz, 1H), 5.13 (dtd, J 10.7, 7.6, 3.4 Hz, 1H), 5.26 (s, 1H), 5.27 (dd, J 14.8, 10.3 Hz, 1H), 5.48 (dd, J 3.4, 0.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 20.5, 20.6, 20.6, 20.6 (4×CH3CO), 52.7 (CH3SO2—), 61.8 (C-6), 65.8, 67.0, 71.3, 75.3, 87.0 (1J1CH 165 Hz, C-1), 169.7, 169.7, 170.0, 170.2 (4×C═O); HRMS m/z (ES): found 460.0951; C15H26NO11S2 requires 460.0947.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]([OH:10])=[O:9].[CH2:11](O)[CH3:12].C(N(C(C)C)CC)(C)C>S(Cl)(Cl)=O>[CH2:11]([O:9][C:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:10])[CH3:12]
Reactant: CCO
Reactant: O=C(O)c1cnccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cnccc1Cl
Temperature: 80 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
A suspension of 4-chloro-pyridine-3-carboxylic acid (5.0 g, 31.7 mmol) in thionyl chloride (100 ml) is heated at 80° C. for 1.5 h. The reaction mixture is cooled to RT and excess thionyl chloride is distilled off. The crude product is azeotropped with toluene (3×30 ml) to afford a solid, which is added in portions to a mixture of ethanol (40 ml) and diisopropylethylamine (25 ml) at 0° C. The resulting reaction mixture is stirred at RT for 4 h. After completion of the reaction, the mixture is evaporated to dryness; the residue is diluted with water (20 ml) and extracted with EtOAc (3×25 ml). The combined organic layers are washed with water (30 ml), brine (30 ml), dried over anhydrous sodium sulfate and evaporated to get 4-chloro-pyridine-3-carboxylic acid ethyl ester (4.50 g, 24.3 mmol, 77%), which is used in the next step without further purification.
Reaction SMILES: Br[CH:2]1[CH2:19][C@@:18]([C:21](=[O:27])[CH2:22][O:23][C:24](=[O:26])[CH3:25])([OH:20])[CH2:17][C:16]2[C:15]([OH:28])=[C:14]3[C:5]([C:6](=[O:30])[C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=4[C:13]3=[O:29])=[C:4]([OH:31])[C:3]1=2.[CH2:32]([CH2:34][NH2:35])[OH:33]>>[OH:33][CH2:32][CH2:34][NH:35][C@H:2]1[CH2:19][C@@:18]([C:21](=[O:27])[CH2:22][O:23][C:24](=[O:26])[CH3:25])([OH:20])[CH2:17][C:16]2[C:15]([OH:28])=[C:14]3[C:5]([C:6](=[O:30])[C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=4[C:13]3=[O:29])=[C:4]([OH:31])[C:3]1=2
Reactant: NCCO
Reactant: CC(=O)OCC(=O)[C@]1(O)Cc2c(O)c3c(c(O)c2C(Br)C1)C(=O)c1ccccc1C3=O
Product: CC(=O)OCC(=O)[C@]1(O)Cc2c(O)c3c(c(O)c2[C@@H](NCCO)C1)C(=O)c1ccccc1C3=O

Procedure:
In the same manner as in Example 4-(1), 7-bromo-9(S)-acetoxyacetyl-6,9,11-trihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione (200 mg) obtained in Reference Example 4 was treated with ethanolamine (30 mg) and the reaction product was post-treated to give dark reddish brown crystals of 7(S)-β-hydroxyethylamino-9(S)-acetoxyacetyl-6,9,11-trihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione. M.P., 100°-103° C. [α]D20 =+166.2° (c=0.1, CHCl3).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+:12]([O-])=O)[CH:8]=[CH:7][CH:6]=2.[CH3:15][NH:16][CH3:17]>>[CH3:15][N:16]([CH3:17])[C:2]1[N:3]=[CH:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([NH2:12])[C:10]=2[CH:11]=1
Reactant: CNC
Reactant: O=[N+]([O-])c1cccc2cnc(Cl)cc12
Product: CN(C)c1cc2c(N)cccc2cn1
Temperature: 100 °C
Yield: 59 %

Procedure:
3-Chloro-5-nitroisoquinoline (Description 108, 160 mg, 0.767 mmol) was dissolved in 33% ethanolic dimethylamine (6 ml) and the mixture then heated in a sealed tube at 100° C. for 2.5 h. After cooling to room temperature the solvent and excess dimethylamine was evaporated and the residue reduced according to the procedure of Description 45 to give the title compound (85 mg, 59%).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][N:7]1[C:11]([CH3:13])([CH3:12])[C:10](=[O:14])[NH:9][C:8]1=[O:15]>C(Cl)Cl>[Cl:3][CH2:6][N:7]1[C:11]([CH3:13])([CH3:12])[C:10](=[O:14])[NH:9][C:8]1=[O:15]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)C(=O)NC(=O)N1CO
Solvent: ClCCl
Product: CC1(C)C(=O)NC(=O)N1CCl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.69 ml Thionyl chloride was added to a solution of 500 mg 1-Hydroxymethyl-5,5-dimethyl-imidazolidine-2,4-dione in 5 ml DCM at 0° C. for 30 minutes, then left to stir at 25° C. for 16 hours. The mixture was evaporated to dryness and used crude in the synthesis of example 23.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.[C:11]1(C)C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>CO>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1
Reactant: Cc1ccccc1
Reactant: O=C(O)C1CCC(O)CC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H](O)CC1
Reaction time: 16 h

Procedure:
1 g of 4-hydroxycyclohexanecarboxylic acid (6.94 mmol, 1 eq.) is placed in 50 mL of a 4/1 mixture of toluene and methanol. 5.55 mL of trimethylsilyldiazomethane (11.10 mmol, 1.6 eq.) are added dropwise to the reaction medium with stirring. After 16 hours, the solvents are evaporated off to give 1.3 g of methyl trans-4-hydroxycyclohexanecarboxylate.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[CH:10]=[N:9][C:8]=12)(O)=[O:2].Cl.[C:28]([C:30]1([NH2:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)#[N:29].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CN(C)C=O.C(N(CC)CC)C.O>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:11]1[CH:10]=[N:9][C:8]2[N:7]([N:6]=[CH:5][C:4]=2[C:1](=[O:2])[NH:36][C:30]2([C:28]#[N:29])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1
Reactant: N#CC1(N)CCCCC1
Reactant: O=C(O)c1cnn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CC1(NC(=O)c2cnn3c(-c4ccc(Cl)cc4)c(-c4ccccc4Cl)cnc23)CCCCC1
Reaction time: 0.25 h
Yield: 21.1 %

Procedure:
To a solution of 3-carboxy-6-(2-chlorophenyl)-7-(4-chlorophenyl)pyrazolo-[1,5-a]pyrimidine (compound obtained in Reference Example 1-(4); 58 mg) and 1-cyanocyclohexylamine hydrochloride (25 mg) in chloroform (1.0 mL containing amylene) were added a 0.5 M solution of 1-hydroxybenzotriazole monohydrate in chloroform (0.45 mL containing amylene), a 0.5 M solution of 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride in N,N-dimethylformamide (0.45 mL) and triethylamine (63 μL), and the mixture was stirred at room temperature overnight. To the reaction mixture were added an aqueous saturated sodium hydrogencarbonate solution (2 mL), water (2 mL) and chloroform (4 mL), and the mixture was vigorously stirred for 15 minutes. The organic layer was separated, and the aqueous layer was extracted with chloroform (3 mL). The combined organic layer was washed successively with an aqueous saturated sodium hydrogencarbonate solution (3 mL) and brine (3 mL) and concentrated in vacuo. The resultant crude product was purified by liquid chromatograph-mass spectrometer (LCMS, column; XTerra MS C18, solvent; 10 mM ammonium carbonate/methanol 40/60 to 10/90) and lyophilized to give 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-(1-cyanocyclohexyl)carbamoyl]pyrazolo[1,5-a]pyrimidine (15.6 mg; yield: 21%) as a powder.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]3[C:22]([CH:23]=2)=[N:21][N:20]([CH3:24])[CH:19]=3)=[O:13])[CH:5]=[CH:4][N:3]=1.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[N:40]1([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44][S:43][CH2:42][CH2:41]1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:24][N:20]1[CH:19]=[C:18]2[C:22]([CH:23]=[C:15]([NH:14][C:12]([C:11]3[CH:25]=[CH:26][CH:27]=[CH:28][C:10]=3[NH:9][CH2:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:48][C:46]([N:40]4[CH2:45][CH2:44][S:43][CH2:42][CH2:41]4)=[O:47])[CH:7]=3)=[O:13])[CH:16]=[CH:17]2)=[N:21]1
Reactant: NC(=O)N1CCSCC1
Reactant: Cn1cc2ccc(NC(=O)c3ccccc3NCc3ccnc(Br)c3)cc2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Cn1cc2ccc(NC(=O)c3ccccc3NCc3ccnc(NC(=O)N4CCSCC4)c3)cc2n1
Temperature: 110 °C
Yield: 65 %

Procedure:
2-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-benzamide (500 mg, 1.15 mmol) was suspended in dioxane (14 mL) and treated consecutively with DMF (5 mL), Pd2dba3 (23 mg, 0.023 mmol), Xantphos (42 mg, 0.07 mmol), cesium carbonate (454 mg, 1.38 mmol) and thiomorpholine-4-carboxylic acid amide (511 mg, 3.5 mmol). The reaction mixture was placed under a nitrogen atmosphere and heated for 4 hours at 110° C. (bath temperature). On cooling the reaction was partitioned between EtOAc and water. The organic phase was washed with brine, dried, filtered and concentrated in vacuo. The residue was purified by chromatography on Isolute® Flash silica gel (Separtis) (Gradient elution: 100% CH2Cl2 to CH2Cl2/EtOH 10:1) to give thiomorpholine-4-carboxylic acid (4-{[2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide (375 mg, 65%) as a solid; 1H-NMR (300 MHz, d6-DMSO) 10.14 (1H, s), 9.20 (1H, s), 8.25 (1H, s), 8.15 (1H, d), 8.11 (1H, s), 7.95 (1H, t), 7.80 (1H, s), 7.72 (1H, d), 7.63 (1H, d), 7.23-7.33 (2H, m), 6.95 (1H, d), 6.67 (1H, t), 6.54 (1H, d), 4.44 (2H, d), 4.13 (3H, s), 3.70-3.73 (4H, m), 2.55-2.58 (4H, m); m/z (ES+) 502 [M+H]+.
Reaction SMILES: O1CCCC1.[C:6]1([S:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[N:21][OH:22])=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:24]([C:26]1[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[C:6]1([S:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]4[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[CH:30][CH:31]=4)[O:22][N:21]=3)=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: ON=C(Cl)Cc1ccc(Sc2ccccc2)nc1
Reactant: C#Cc1ccc(N)nc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1ccc(-c2cc(Cc3ccc(Sc4ccccc4)nc3)no2)c(N)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
To a tetrahydrofuran (4 mL) solution of the (6-phenylsulfanyl-pyridin-3-yl)acetohydroximoyl chloride (100 mg, 0.359 mmol) described in Manufacturing Example 97-1-4 and 3-ethynyl-pyridin-2,6-diamine (15 mg, 0.13 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (55 μL, 0.40 mmol), which was stirred under nitrogen atmosphere for 1 hour at 50° C. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain the title compound (25 mg, 58%).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH:9]=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:11][S:12](Cl)(=[O:14])=[O:13].N1C=CC=CC=1>C(Cl)Cl>[S:12]([O:10][CH2:9][C:3]1([CH:2]=[O:1])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)([CH3:11])(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: O=CC1(CO)CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(C=O)CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
To a cold (0° C. mixture of alcohol 54 (75 g, 0.54 mole) and 65.29 g (0.57 mole) of methanesulfonyl chloride in 80 ml of methylene chloride was added a solution of pyridine (47.96 g, 0.57 mole) in 40 ml of methylene chloride. The reaction mixture was stirred at room temperature for 18 h then quenched with water, acidified with conc. HCl and extracted with methylene chloride. The organic layer was washed with water, brine, and dried over sodium sulfate and concentrated under vacuum to give 91.63 g (77.8%) of thick oil. Proton NMR and mass spectra were consistent with the product.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4](S(Cl)(=O)=O)=[CH:3][CH:2]=1.[OH:12][CH:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21]CC)=[O:20])[CH2:15][CH2:14]1>N1C=CC=CC=1>[O:12]([CH:13]1[CH2:14][CH2:15][CH:16]([C:19]([OH:21])=[O:20])[CH2:17][CH2:18]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: O=C(O)C1CCC(Oc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.63 g of p-toluenesulfonyl chloride was added to a solution of 0.522 g of ethyl 4-hydroxycyclohexanecarboxylate in 5.0 ml of pyridine. The reaction was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo. The resulting solid was taken up in water and ethyl acetate, and the organic phase was washed three times with 2N hydrochloric acid and once with saturated NaCl solution. The organic phase was dried over sodium sulfate and concentrated in vacuo. The resulting product was employed without further purification in the next step. The resulting product (0.55 g) was dissolved in 11.2 ml of DMF, and 0.159 g of phenol and 0.549 g of cesium carbonate were added. The solution was then heated at 80° C. for 6 hours. After cooling, the mixture was concentrated in vacuo and purified by column chromatography on silica gel (eluent: ethyl acetate/n-heptane 1:1). The desired product was obtained. Molecular weight 248.32 (C15H20O3), MS: 249 (M+H+).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][N:12]=[C:11]([S:20][CH3:21])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C(CC)CNC1C(C(OC)=O)=CN=C(SC)N=1)C>>[CH2:1]([NH:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[C:11]([S:20][CH3:21])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc(SC)nc1NCc1ccccc1
Agent: CCC(CC)CNc1nc(SC)ncc1C(=O)OC
Product: CSc1ncc(C(=O)O)c(NCc2ccccc2)n1

Procedure:
The title compound was prepared according to the procedure of Example 108B substituting the product of Example 150A for the product of Example 108A. (0.185 g, 78%).
Reaction SMILES: [C:1]([N:10]([CH2:12][C:13]1[S:14][CH:15]=[C:16]([CH2:18][S:19][CH2:20][CH2:21][NH2:22])[N:17]=1)[CH3:11])(OC1C=CC=CC=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].Cl>O1CCCC1.C(O)C.C(OCC)C.O>[CH3:11][N:10]([CH2:12][C:13]1[S:14][CH:15]=[C:16]([CH2:18][S:19][CH2:20][CH2:21][NH2:22])[N:17]=1)[CH3:1]
Reactant: CN(Cc1nc(CSCCN)cs1)C(=O)Oc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CN(C)Cc1nc(CSCCN)cs1
Reaction time: 3 h
Yield: 64.2 %

Procedure:
To a solution of 2-{[2-(N-Carbophenoxy-N-methylamino)methyl-4-thiazolyl]methylthio}ethylamine (0.50 g; 1.48 mmoles) [prepared in Step D] in 10 ml of dry tetrahydrofuran under a nitrogen atmosphere was added lithium aluminum hydride (0.17 g; 4.48 mmoles) and the mixture was heated at reflux temperature for 0.5 hour. An additional 10 ml of tetrahydrofuran was added and heating was continued for 3 hours. The reaction mixture was treated with 0.17 ml of H2O, 0.17 ml of 15% aqueous NaOH and 0.51 ml of H2O, and filtered through Celite and dried. The filtrate was filtered and evaporated under reduced pressure to give an oil which was dissolved in absolute ethanol, diluted with diethyl ether and acidified with dry HCl. The hydroscopic hydrochloride salt of the title compound was collected and partitioned between aqueous 2.5 N NaOH and methylene chloride. The organic phase was washed with water, dried and filtered. The filtrate was evaporated under reduced pressure to give the free base of the title compound as an oil (0.22 g; 0.95 mmole) which was combined with anhydrous oxalic acid (0.24 g; 1.90 mmole) in 30 ml of hot acetonitrile. The mixture was evaporated from hot absolute ethanol to yield the title compound the bis-oxalate, mp 168°-171°.