Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1.C1OCCOCCOCCOCCOC1.[Cl:28][C:29]1[CH:38]=[C:37](Cl)[C:36]2[C:31](=[C:32]([Cl:42])[C:33]([O:40][CH3:41])=[CH:34][CH:35]=2)[N:30]=1>CN(C=O)C.O>[Cl:28][C:29]1[CH:38]=[C:37]([O:10][CH2:9][C:8]2[CH:11]=[CH:12][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[C:36]2[C:31](=[C:32]([Cl:42])[C:33]([O:40][CH3:41])=[CH:34][CH:35]=2)[N:30]=1
Reactant: COc1ccc2c(Cl)cc(Cl)nc2c1Cl
Reactant: COc1ccc(CO)cc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc(Cl)nc3c(Cl)c(OC)ccc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
NaH (60% in oil) (670 mg, 1.2 eq.) was added portionwise to a stirred solution of p-methoxybenzylalcohol (2.31 g, 1.2 eq.) and 15-crown-5 (3.32 mL, 1.2 eq.) in anhydrous DMF (10 mL). The mixture was stirred at room temperature for 30 min. Compound 220d (3.66 g, 1 eq.) in anhydrous DMF (25 mL) was then added and the reaction mixture was stirred at room temperature for 16 hrs. The reaction mixture was then poured into water (300 mL), extracted with EtOAC, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel (petroleum ether/DCM, 50/50) to give compound 221d as a yellow solid in 38% yield. 1H NMR (CDCl3, 376 MHz) δ (ppm) 3.86 (s, 3H), 4.05 (s, 3H). 5.20 (s, 2H), 6.77 (s, 1H), 6.98 (d, J=8.53 Hz, 2H), 7.23 (d, J=9.41, 1H), 7.42 (d, J=8.53 Hz, 2H), 8.08 (d, J=9.41 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:44])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C1(C)C=CC=CC=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:44])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)COc1cc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N2CCN(C(=O)OCC)CC2)nn1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1cc(C(=O)N[C@@H](CCC(=O)O)C(=O)N2CCN(C(=O)OCC)CC2)nn1-c1ccccc1

Procedure:
To a solution of 73 mg of 4-{(S)-4-tert-Butoxycarbonyl-2-[(5-ethoxycarbonylmethoxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 1 ml of DCM, 0.2 ml of TFA was added at RT. After 4 h 20 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[N:7][CH:6]=1)[NH2:4].[F:11][C:12]1[C:20]([F:21])=[C:19]([F:22])[CH:18]=[CH:17][C:13]=1[C:14](Cl)=O.N>>[N:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:4]=[C:14]([C:13]3[CH:17]=[CH:18][C:19]([F:22])=[C:20]([F:21])[C:12]=3[F:11])[O:1][N:2]=2)=[CH:6][N:7]=1
Reactant: O=C(Cl)c1ccc(F)c(F)c1F
Reactant: NC(=NO)c1ccnnc1
Agent: N
Product: Fc1ccc(-c2nc(-c3ccnnc3)no2)c(F)c1F

Procedure:
The titled compound was prepared according to the procedure of Method D using the product of Example 83D and 2,3,4-trifluorobenzoyl chloride (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.40-7.50 (m, J=9.3, 9.3, 7.0, 2.2 Hz, 1H), 8.10-8.20 (m, 1H), 8.39 (dd, J=5.4, 2.4 Hz, 1H), 9.46 (dd, J=5.3, 1.2 Hz, 1H), 9.87 (dd, J=2.2, 1.2 Hz, 1H) ppm; MS (DCI/NH3) m/z=279 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([NH:16][C:17]([C:19]4[N:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]5=[N:21][CH:20]=4)=[O:18])[CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:28][CH3:29])=[N:8]2)=[N:2]1.Br[CH2:31][CH:32]1[CH2:36][O:35][C:34]([CH3:38])([CH3:37])[O:33]1.O.[OH-].[Cs+]>CN(C)C=O>[CH3:37][C:34]1([CH3:38])[O:33][CH:32]([CH2:31][N:2]2[C:3]([CH2:6][N:7]3[C:15]4[C:10](=[C:11]([NH:16][C:17]([C:19]5[N:23]6[CH:24]=[CH:25][CH:26]=[CH:27][C:22]6=[N:21][CH:20]=5)=[O:18])[CH:12]=[CH:13][CH:14]=4)[C:9]([CH2:28][CH3:29])=[N:8]3)=[CH:4][CH:5]=[N:1]2)[CH2:36][O:35]1
Reactant: CCc1nn(Cc2cc[nH]n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reactant: CC1(C)OCC(CBr)O1
Agent: [Cs+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nn(Cc2ccnn2CC2COC(C)(C)O2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N-(1-((1H-pyrazol-3-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (40 mg, 0.104 mmol) in N,N-dimethylformamide (0.5 mL) was added 4-(bromomethyl)-2,2-dimethyl-1,3-dioxolane (20.2 mg, 0.104 mmol) and cesium hydroxide hydrate (17.4 mg, 0.104 mmol). The mixture was stirred for 16 hours at ambient temperature, filtered, washing with methanol and ethyl acetate, and concentrated under a stream of nitrogen. The resulting material was purified using preparative thin layer chromatography on silica, eluting with 10% methanol in dichloromethane. The isolated product (22.5 mg) was a 7:3 mixture of two regioisomers, N-(1-((1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-5-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide and N-(1-((1-(2,3-dihydroxypropyl)-1H-pyrazol-3-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide. This material was continued to the next step as a mixture.
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:19]=[CH:18][C:8]([CH:9]=[N:10]S(C(C)(C)C)(=O)=O)=[CH:7][C:6]=1[F:20].C1C[O:24][CH2:23][CH2:22]1>>[Br:4][C:5]1[CH:19]=[CH:18][C:8]([CH:9]([NH:10][C:23](=[O:24])[CH3:22])[CH3:1])=[CH:7][C:6]=1[F:20]
Reactant: CC(C)(C)S(=O)(=O)N=Cc1ccc(Br)c(F)c1
Reactant: C[Mg]Br
Reactant: C1CCOC1
Product: CC(=O)NC(C)c1ccc(Br)c(F)c1
Reaction time: 2 h

Procedure:
Under inert gas atmosphere 37.2 mL (112 mmol) of a 3N solution of methyl magnesium bromide in THF are added dropwise to 17.1 g (55.8 mmol) 2-methyl-propane-2-sulfonic acid 4-bromo-3-fluoro-benzylideneamide (IX.1) in 170 mL THF at −78° C. The cooling bath is removed and stirring is continued for 2 h. After that time, the mixture is poured into sat. NH4Cl-solution (300 mL) and extracted with EtOAc.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8]2[CH:17]=[CH:16][N:15]=[C:14]3[C:9]=2[C:10]2[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=2[C:12](=[O:18])[NH:13]3)[N:4]([CH2:23][C:24](NC2C=CC=CC=2)=[O:25])[N:3]=1.[F:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][C:40]=1[F:41])[NH2:37]>>[F:33][C:34]1[CH:35]=[C:36]([NH:37][C:24](=[O:25])[CH2:23][N:4]2[C:5]([NH:7][C:8]3[CH:17]=[CH:16][N:15]=[C:14]4[C:9]=3[C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[C:12](=[O:18])[NH:13]4)=[CH:6][C:2]([CH3:1])=[N:3]2)[CH:38]=[CH:39][C:40]=1[F:41]
Reactant: Cc1cc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)n(CC(=O)Nc2ccccc2)n1
Reactant: Nc1ccc(F)c(F)c1
Product: Cc1cc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)n(CC(=O)Nc2ccc(F)c(F)c2)n1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 300 using the carboxylic acid intermediate from example 308 and 3,4-di-fluoroaniline to provide 309. LC-MS (M+H=461, obsd.=461).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:35])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])=[C:18]([CH2:33][OH:34])[CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:38][C@H:39]1[CH2:44][CH2:43][CH2:42][CH2:41][N:40]1[C:45]1[N:49]2[CH:50]=[C:51]([O:54][C@H:55]3[C:64]4[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=4)[C@@H:58]([NH2:65])[CH2:57][CH2:56]3)[CH:52]=[CH:53][C:48]2=[N:47][N:46]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:65][C@@H:58]2[C:59]3[C:64](=[CH:63][CH:62]=[CH:61][CH:60]=3)[C@H:55]([O:54][C:51]3[CH:52]=[CH:53][C:48]4[N:49]([C:45]([N:40]5[CH2:41][CH2:42][CH2:43][CH2:44][C@@H:39]5[CH3:38])=[N:46][N:47]=4)[CH:50]=3)[CH2:56][CH2:57]2)=[O:35])[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][Si:23]([CH:30]([CH3:32])[CH3:31])([CH:24]([CH3:26])[CH3:25])[CH:27]([CH3:29])[CH3:28])=[C:18]([CH2:33][OH:34])[CH:17]=2)[N:9]=1)([CH3:14])([CH3:15])[CH3:13]
Reactant: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1CO)(C(C)C)C(C)C
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)cc1CO)(C(C)C)C(C)C
Yield: 57.3 %

Procedure:
A solution of Intermediate 61d (173 mg, 0.29 mmol), Intermediate B (100 mg, 0.27 mmol) and DIPEA (58 μL, 0.33 mmol) in 1,4-dioxane (2.9 mL) was stirred at 70° C. for 42 h. The mixture was evaporated in vacuo and the residue was partitioned between DCM and water. The aqueous layer was then extracted with DCM (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-5% MeOH in DCM, to give the title compound as a cream colored glass (127 mg, 58%). LCMS (Method 3): Rt 4.97 min, m/z 821 [MH+].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.[CH3:22][N:23]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][NH:39][CH3:40])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].[CH2:41]=O>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:40][N:39]([CH3:41])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][N:23]([CH3:22])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[C:19]([OH:21])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1
Reactant: O=C1/C(=C/c2c[nH]c3ccccc23)Oc2cc(O)ccc21
Reactant: C=O
Reactant: CNCCCCCCCCN(C)C(=O)OC(C)(C)C
Solvent: CCO
Product: CN(CCCCCCCCN(C)C(=O)OC(C)(C)C)Cc1c(O)ccc2c1O/C(=C\c1c[nH]c3ccccc13)C2=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
A solution of (Z)-2-[(1H-indol-3-yl)methylene]-6-hydroxybenzofuran-3(2H)-one (0.050 g, 0.18 mmol) obtained in Example A1, Step 1 in ethanol (3.0 mL) was added with tert-butyl methyl[8-(methylamino)octyl]carbamate (0.074 g, 0.27 mmol), and 37% aqueous formaldehyde (0.017 g, 0.22 mmol), and the mixture was stirred overnight at 70° C. in a sealed tube. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (90:10)) to obtain tert-butyl (Z)-8-[({2-[(1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)(methyl)amino]octyl(methyl)carbamate (0.045 g, 45%).
Reaction SMILES: [H-].[Na+].[C:3]12([C:13]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=3[OH:20])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[CH2:21]1COCC1>>[C:3]12([C:13]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=3[O:20][CH3:21])[CH2:4][CH:5]3[CH2:11][CH:9]([CH2:8][CH:7]([CH2:6]3)[CH2:12]1)[CH2:10]2
Reactant: C1CCOC1
Reactant: Oc1cc(Br)ccc1C12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Product: COc1cc(Br)ccc1C12CC3CC(CC(C3)C1)C2

Procedure:
1.6 g (53 mmol) of sodium hydride (80% in oil) and 50 ml of THF are introduced into a round-bottomed flask and a solution of 15 g (49 mmol) of the phenol obtained above in (a), dissolved in 100 ml of DMF, is added dropwise. The mixture is stirred until gaseous evolution has ceased and 3.1 ml (49 mmol) of methyl iodide are then introduced. The mixture is stirred at room temperature for four hours, the reaction medium is poured into water and the organic phase is separated after settling has taken place, then dried over magnesium sulphate and evaporated. The residue obtained is ground in the minimum amount of hexane and filtered off. 12.6 g (80%) of 2-(1-adamantyl)-5-bromoanisole, melting point 159°-160° C., are collected.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[C:11](Cl)=[N:12][C:13]([Cl:16])=[CH:14][CH:15]=1)=O.CCN(C(C)C)C(C)C.[NH2:27][NH2:28]>C(O)C.C1COCC1>[Cl:16][C:13]1[N:12]=[C:11]2[NH:27][N:28]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:10]2=[CH:15][CH:14]=1
Reactant: NN
Reactant: O=C(c1ccccc1Cl)c1ccc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCO
Product: Clc1ccc2c(-c3ccccc3Cl)n[nH]c2n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 42.7 %

Procedure:
(2-Chloro-phenyl)-(2,6-dichloro-pyridin-3-yl)-methanone (3.0 g, 10.47 mmol) was dissolved in 25 mL of ethanol/THF (4:1) and cooled in an ice bath. Hunig's base (N,N-diisopropylethylamine, 1.8 mL, 10.47 mmol) was added to the reaction mixture, followed by dropwise addition of 0.36 mL (11.52 mmol) of hydrazine. The reaction mixture was stirred at 0° C. for five minutes, then heated to 70° C. for 1.5 hours. Volatiles were removed under reduced pressure, and the residue was taken up in 150 mL of EtOAc, 10 mL of THF and 10 mL of MeOH. To this mixture was added 20 mL of saturated ammonium chloride and 110 mL of water. The organic phase was collected, and the aqueous phase was wahsed with an additional 100 mL of EtOAc. The combined organic layers wer washed with brine, dried (MgSO4), and solvent was removed to to yield 1.18 g of 6-chloro-3-(2-chloro-phenyl)-1H-pyrazolo[3,4-b]pyridine as a yellow solid. Mass Spec. M-H=262.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([S:18]([C:21]2[S:25][C:24]([C:26]#[N:27])=[CH:23][CH:22]=2)(=O)=[O:19])[CH2:13][CH2:12]3)=[CH:5][CH:4]=1.Cl.[NH2:31][OH:32].C(N(CC)CC)C.[OH2:40]>O1CCCC1.CO>[OH:32][NH:31][C:26]([C:24]1[S:25][C:21]([S:18]([N:14]2[C:15]3[C:11](=[CH:10][C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:28])([F:1])[F:29])=[CH:4][CH:5]=4)=[CH:17][CH:16]=3)[CH2:12][CH2:13]2)(=[O:19])=[O:40])=[CH:22][CH:23]=1)=[NH:27]
Reactant: O
Reactant: NO
Reactant: N#Cc1ccc(S(=O)(=O)N2CCc3cc(-c4ccc(C(F)(F)F)cc4)ccc32)s1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N=C(NO)c1ccc(S(=O)(=O)N2CCc3cc(-c4ccc(C(F)(F)F)cc4)ccc32)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
150 mg 5-[5-(4-Trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-thiophene-2-carbonitrile were dissolved in a mixture of 8 ml tetrahydrofuran and 8 ml methanol. 600 mg hydroxylamine hydrochloride were added followed by the addition of 1.20 ml triethylamine. The reaction mixture was stirred at room temperature for four hours. The mixture was poured on 100 ml water and extracted five times with portions of 50 ml ethylacetate. The combined organic extracts were washed with 100 ml brine, dried over MgSO4 and the solvent was evaporated in vacuo to obtain 163 mg N-Hydroxy-5-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-thiophene-2-carboxamidine. This material was used without further purification.
Reaction SMILES: [C:1]([S:8](F)(=[O:10])=[O:9])([C:4]([F:7])([F:6])[F:5])([F:3])[F:2].[CH3:12][NH2:13].S(=O)(=O)(O)O.[CH3:19][C:20]([O:23]C)(C)C>>[C:1]([S:8]([N:13]([CH2:19][CH2:20][OH:23])[CH3:12])(=[O:10])=[O:9])([C:4]([F:7])([F:6])[F:5])([F:3])[F:2].[C:1]([S:8]([NH:13][CH3:12])(=[O:10])=[O:9])([C:4]([F:7])([F:6])[F:5])([F:3])[F:2]
Reactant: CN
Reactant: COC(C)(C)C
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)F
Agent: O=S(=O)(O)O
Product: CN(CCO)S(=O)(=O)C(F)(F)C(F)(F)F
Product: CNS(=O)(=O)C(F)(F)C(F)(F)F

Procedure:
C2F5SO2N(CH3)CH2CH2OH was prepared from C2F5SO2F by reaction with monomethylamine in MTBE, followed by stripping of the solvent, acidification with 19% sulfuric acid, then water washing and distillation at 5.5 mm at a head temperature of 69° C. to give C2F5SO2N(CH3)H. The C2F5SO2N(CH3)H was then reacted with 3 equivalents of ethylene carbonate and 0.08 equivalents K2CO3 neat at 110° C. overnight. The product was isolated by successive washes with water, 3% sulfuric acid and water, followed by distillation at 0.5 mm at a head temperature of 98° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([S:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27](C)([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:31])=[CH:7][CH:6]=1)(=[O:4])=[O:3].CS(C1C=CC(N2C=CC(OC3CCN(C(OC(C)(C)C)=O)CC3)=CC2=O)=CC=1)(=O)=O>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([S:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][CH:27]([CH3:28])[CH3:29])=[O:25])[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:31])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(Sc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Agent: CC(C)(C)OC(=O)N1CCC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Product: CC(C)OC(=O)N1CCC(Sc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1

Procedure:
Example 39 was prepared according to procedures described in Example 3 substituting tert-butyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-ylthio)piperidine-1-carboxylate for tert-butyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate. 1H NMR (500 MHz, CDCl3) δ 8.09 (d, J=8.80 Hz, 2H), 7.62 (d, J=8.80 Hz, 2H), 7.22 (d, J=7.70 Hz, 1H), 6.66 (d, J=1.65 Hz, 1H), 6.27 (dd, J=7.42, 1.92 Hz, 1H), 4.88-5.00 (m, 1H), 4.04 (app brs, 2H), 3.47-3.58 (m, 1H), 3.12-3.17 (m, 2H), 3.11 (s, 3H), 2.08-2.16 (m, 2H), 1.61-1.73 (m, 2H), 1.26 (d, J=6.05 Hz, 6H). MS (ESI) 451 (M+H).
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:27][CH2:28][CH2:29][CH3:30])[N:23]([CH2:24][CH2:25][NH2:26])[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1>>[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:27][CH2:28][CH2:29][CH3:30])[N:23]([CH2:24][CH2:25][NH:26][C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:8])[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Reactant: O=C(Cl)C1CCCCC1
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)C1CCCCC1
Yield: 72.4 %

Procedure:
Using the general method of Example 92, cyclohexanecarbonyl chloride (94 μL, 0.7 mmol) was reacted with 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.2 g, 0.7 mmol) to provide 0.2 g of N1-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-1-cyclohexanecarboxamide as a white powder, m.p. 188-190° C. Analysis: Calculated for C22H30N6O: %C, 66.98; %H, 7.66; %N, 21.30. Found: %C, 66.72; %H, 7.57; %N, 21.48. HRMS (EI) calcd for C22H30N6O (M+) 394.2481 found 394.2475.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].[C:22]([O:28][CH2:29]Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].ClCCl>CC(C)=O.O>[C:22]([O:28][CH2:29][N:15]1[CH:14]=[CH:13][N:12]=[C:11]1[C@H:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1])[CH3:10])(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: Cc1cccc([C@H](C)c2ncc[nH]2)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O
Product: Cc1cccc([C@H](C)c2nccn2COC(=O)C(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of the compound of Example 58 (500 mg, 2.5 mmol) and caesium carbonate (1.79 g, 5.5 mmol) in anhydrous acetone (10 ml) was added chloromethyl pivalate (0.43 ml, 3.0 mmol). The reaction mixture was stirred at room temperature for 18 h. To the mixture was added dichloromethane (10 ml) and water (10 ml) and the two layers were separated. The aqueous phase was extracted with dichloromethane (2×10 ml) and the combined organic phases were dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: C(OC([NH:11][CH:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:22](=[O:40])[C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:39])[C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=3)=[CH:25][CH:24]=2)[CH2:13]1)=O)C1C=CC=CC=1.[H][H]>C(O)(=O)C>[NH2:11][CH:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:22](=[O:40])[C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:30](=[O:39])[C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=3)=[CH:27][CH:28]=2)[CH2:13]1
Reactant: O=C(NC1Cc2ccccc2N(C(=O)c2ccc(NC(=O)c3cc(Cl)cc(Cl)c3)cc2)C1)OCc1ccccc1
Reactant: [H][H]
Solvent: CC(=O)O
Product: NC1Cc2ccccc2N(C(=O)c2ccc(NC(=O)c3cc(Cl)cc(Cl)c3)cc2)C1
Yield: 63.3 %

Procedure:
To 3-benzyloxycarbonylamino-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (3.3 g) are added acetic acid (40 ml) and 10% Pd--C (0.4 g) and the reaction mixture is subjected to catalytic reduction at ordinary temperature under atmospheric pressure of hydrogen. One hour thereafter, the catalyst is removed by filtration and the filtrate is concentrated. The resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1), and recrystallized from ethanol to give 3-amino-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (1.6 g) as white powder, m.p. 207°-210° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH:13]([CH3:16])[CH2:14][OH:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>C1C=CC=CC=1>[F:1][C:2]([F:21])([F:22])[C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:18]=[CH:17][C:11]([O:12][CH:13]([CH3:16])[CH2:14][O:15][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(CO)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: c1ccccc1
Product: CC(COC(=O)c1ccccc1)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Yield: 75 %

Procedure:
1 g of β-[4-(4-Trifluoromethylphenoxy)phenoxy]propanol and 0.25 g of pyridine were dissolved in 10 ml of benzene, and 0.45 g of benzoyl chloride was added slowly to the solution while cooling. After completion of the addition, the mixture was allowed to react at a temperature of 20° C for 1 hour, and the reaction mixture was poured into an appropriate amount of water. The benzene layer was separated and, after drying, benzene was removed to obtain 1 g of the desired product (nD20 1.541) as an oily substance.