Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]2[C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:33].O>C1COCC1>[CH3:33][N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]1[C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=1)=[O:9]
Reactant: O=C(Nc1ccccc1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of N-phenyl-1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (100 mg, 0.252 mmol, example 9 (step 3) in THF (1 mL) was added sodium hydride (12 mg, 0.505 mmol) slowly. The resulting mixture was stirred at RT for 15 min and iodomethane (16 μL, 0.252 mmol) was added. The mixture was stirred at RT for 16 h. Then, H2O (2 mL) was added and the mixture was extracted with EtOAc (2×2 mL). The combined organic extracted were dried over MgSO4 and concentrated. The residue was then dissolved in DMSO (1 mL) and the solution mixture was purified by preparative HPLC (10%-400% of MeCN (0.1% TFA)/H2O (0.1% TFA) to give the title compound as an off-white solid. MS (ESI, positive ion) m/z: 411 (M+H).
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]([OH:11])(C(F)F)[C:4]([F:7])([F:6])[F:5].ClC(Cl)(Cl)C(=O)C(Cl)Cl>>[F:5][C:4]([F:7])([F:6])[C:3](=[O:11])[CH:2]([F:12])[F:1]
Reactant: OC(C(F)F)(C(F)F)C(F)(F)F
Agent: O=C(C(Cl)Cl)C(Cl)(Cl)Cl
Product: O=C(C(F)F)C(F)(F)F

Procedure:
As another preparation example, 2-difluoromethyl-1,1,1,3,3-pentafluoro-2-propanol may be prepared by fluorinating commercially available 1,1,1,3,3-pentachloro-2-propanone to form 1,1,1,3,3-pentafluoro-2-propanone which may then be reacted with CF2 carbene to form 2-difluoromethyl-1,1,3,3,3-tetrafluoro-1-propene. The 2-difluoromethyl-1,1,3,3,3-tetrafluoro-1-propene may then be reacted with sulfuric acid and then water to form 2-difluoromethyl-1,1,1,3,3-pentafluoro-2-propanol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:21]C)[CH:5]=[C:6]([CH3:20])[C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:20][C:6]1[CH:5]=[C:4]([OH:21])[CH:3]=[C:2]([CH3:1])[C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:17]([CH3:18])[CH3:19])[CH:10]=1
Reactant: COc1cc(C)c(Cc2ccc(OC)c(C(C)C)c2)c(C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(O)cc(C)c1Cc1ccc(O)c(C(C)C)c1
Temperature: -78 °C
Reaction time: 10 h
Yield: 69 %

Procedure:
To 3,5-dimethyl-4-(3'-isopropyl-4'-methoxybenzyl) anisole (8) (1.3 g, 4.35 mmol) in 75 mL of methylene chloride at -78° C. was added 44 mL of boron tribromide 1.0M in methylene chloride). The reaction mixture was stirred for 30 min at -78° C. and for 10 hours at room temperature. The reaction mixture was washed with water (2×100 mL), dried (MgSO4), and evaporated to give crude product (1.5 g). Purification using flash column chromatography (silica gel, 80:20 hexane/ethylacetate) gave 3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl) phenol (9) (812 mg, 3.00 mmol, 69%); 1HNMR (CDCl3) δ 1.2 (d, 6H), 2.23 (s, 6H), 3.15 (heptet, 1H), 3.87 (s, 2H), 6.58 (m, 4H), 6.92 (s, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[C:7]([C:8]([OH:10])=O)[C:6]=1[C:17]([OH:19])=[O:18])(=[O:3])[CH3:2].C(Cl)(=O)C>C(OC(=O)C)(=O)C>[C:1]([NH:4][C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[C:7]2[C:8]([O:19][C:17](=[O:18])[C:6]=12)=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c([N+](=O)[O-])ccc(C(=O)O)c1C(=O)O
Solvent: CC(=O)Cl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1c([N+](=O)[O-])ccc2c1C(=O)OC2=O
Reaction time: 2 h
Yield: 58 %

Procedure:
3-Acetamido-4-nitrophthalic acid (0.538 g, 2.00 mmol) was dissolved in acetic anhydride (10 ml) at 80° C., and the solution was added with acetyl chloride (1 ml) and stirred for 2 hours. The solvent was evaporated, and a small amount of anhydrous dichloromethane was added to the residue, and precipitates were collected by filtration to obtain the title compound (0.29 g, 58%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[Cl:20][C:21]1[CH:37]=[CH:36][C:24]2[N:25]([CH:29]3[CH2:34][CH2:33][NH:32][CH:31]([CH3:35])[CH2:30]3)[C:26](=[O:28])[NH:27][C:23]=2[CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[Cl:20][C:21]1[CH:37]=[CH:36][C:24]2[N:25]([CH:29]3[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][CH:5]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)[C:6]4[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=4)[CH:31]([CH3:35])[CH2:30]3)[C:26](=[O:28])[NH:27][C:23]=2[CH:22]=1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Reactant: CC1CC(n2c(=O)[nH]c3cc(Cl)ccc32)CCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CC1CC(n2c(=O)[nH]c3cc(Cl)ccc32)CCN1CCCC(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
A mixture of 7 parts of 1-chloro-4,4-bis(4-fluorophenyl)-butane, 5.5 parts of 5-chloro-1,3-dihydro-1-(2-methyl-4-piperidinyl)-2H-benzimidazol-2-one, 6.4 parts of sodium carbonate, 0.2 parts of potassium iodide and 160 parts of 4-methyl-2-pentanone is stirred and refluxed for 36 hours. After cooling, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The oily residue is converted into the hydrochloride salt in 2-propanol and 2,2'-oxybispropane. The salt is filtered off. The free base is liberated in the conventional manner and extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silicagel, using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is crystallized from 2-propanol, yielding 5-chloro-1-{1-[4,4-bis(4-fluorophenyl)butyl]- 2-methyl-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 171.1° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10]1[N:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22]C(=O)OCC4C=CC=CC=4)=[CH:18][CH:17]=3)=[N:14][CH:15]=1)[CH2:2]2>C(O)C.[Pd]>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH:3]([O:9][C:10]1[N:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)=[N:14][CH:15]=1)[CH2:2]2
Reactant: O=C(Nc1ccc(-c2cnc(OC3CN4CCC3CC4)cn2)cc1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(-c2cnc(OC3CN4CCC3CC4)cn2)cc1
Yield: 85.4 %

Procedure:
The product of Example 13A (0.68 g, 1.58 mmol) in ethanol (20 mL) was treated with Pd/C (Aldrich, 10% wt., 70 mg) under H2 at ambient temperature for 4 hours. The mixture was filtered through a short column of diatomaceous earth and the filtrate was concentrated to give the title product as a solid (400 mg, yield, 86%). 1H NMR (MeOH-d4, 300 MHz) δ 1.47-1.62 (m, 1H), 1.64-1.90 (m, 2H), 1.97-2.12 (m, 1H), 2.19-2.27 (m, 1H), 2.73-3.03 (m, 5H), 3.34-3.44 (m, 1H), 5.07-5.14 (m, 1H), 6.78 (dt, J=8.8, 2.7 Hz, 2H), 7.68 (dt, J=8.5, 2.7 Hz, 2H), 8.17 (d, J=1.4 Hz, 1H), 8.45 (d, J=1.4 Hz, 1H) ppm. MS (DCl/NH3) m/z 297 (M+H)+.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][CH:44]([CH2:75][N:76]1[CH2:81][CH2:80][S:79][CH2:78][CH2:77]1)[CH2:45][NH:46][C:47]([C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][C:54]([O:58][CH2:59][CH2:60][CH2:61][O:62][CH3:63])=[CH:53][C:52]=2[N:64]([CH3:74])[S:65]([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][N:69]=1)(=[O:67])=[O:66])=O)C1C=CC=CC=1.C1(SC)C=CC=CC=1.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:63][O:62][CH2:61][CH2:60][CH2:59][O:58][C:54]1[CH:55]=[C:56]2[C:51](=[C:52]([N:64]([CH3:74])[S:65]([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][N:69]=3)(=[O:67])=[O:66])[CH:53]=1)[NH:50][C:49]([C:47]1[S:43][CH:44]([CH2:75][N:76]3[CH2:81][CH2:80][S:79][CH2:78][CH2:77]3)[CH2:45][N:46]=1)=[CH:57]2
Reactant: COCCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(CN3CCSCC3)SCc3ccccc3)cc2c1
Agent: O=C([O-])O
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CSc1ccccc1
Solvent: CC#N
Product: COCCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CN4CCSCC4)S3)cc2c1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 34.4 %

Procedure:
To a mixture of triphenylphosphine oxide (610 mg) and acetonitrile (10 mL) was added trifluoromethanesulfonic anhydride (310 mg) at 2° C., and the mixture was stirred at 0-5° C. for 30 min. A solution of N-[2-(benzylthio)-3-thiomorpholinopropyl]-5-(3-methoxypropoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxamide (380 mg) and thioanisole (140 mg) in acetonitrile (10 mL) was added dropwise to the reaction mixture at 0-5° C., and the mixture was stirred at 0-5° C. for 30 min. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was extracted with concentrated hydrochloric acid (10 mL×3), and the hydrochloric acid layers were combined, and washed with ethyl acetate. The aqueous layer was basified with potassium carbonate, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to basic silica gel column chromatography, and eluted with hexane-ethyl acetate (9:1-1:2, volume ratio) to give the title compound (110 mg, yield 34%) as a colorless oil.
Reaction SMILES: [S:1]([CH:13]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]([NH2:20])[CH2:14]1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[C:21](OC(=O)C)(=[O:23])[CH3:22].O>CO>[S:1]([CH:13]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]([NH:20][C:21](=[O:23])[CH3:22])[CH2:14]1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: CC(=O)OC(C)=O
Reactant: NC1CCCCC(S[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)C1
Solvent: O
Solvent: CO
Product: CC(=O)NC1CCCCC(S[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)C1

Procedure:
In one example, the primary amine group of compound B5 can optionally be acylated by contacting B5 with an excess of acetic anhydride in methanol containing a trace of water. Generally, this reaction is conducted at about 25° C. to about 30° C. for about 2 to about 24 hours to provide for 3-acetamidocycloheptyl 1-thio-β-galactopyranoside, C5.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([OH:6])=[O:5])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1
Reactant: O=C(O)c1ccccc1I
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(Nc2ccccc2C(=O)O)c([N+](=O)[O-])c1
Temperature: 200 °C

Procedure:
2-iodobenzoic acid (5 g, 20.16 mmol), 4-methyl-2-nitroaniline (6.12 g, 40.32 mmol), potassium carbonate (2.8 g, 20.3 mmol) and Cul (0.2 g) were thoroughly mixed and heated to 200° C. for 1 hour. After cooling the solid reaction mixture was partitioned between ethyl acetate and aqueous sodium hydroxide (1M). The product precipitated from the aqueous phase on acidification with hydrochloric acid (4M). Yield 3.69 g, mp 209°-213° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]2[CH3:14])=[CH:4][C:3]=1[O:15][CH3:16].[NH:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:24]([CH2:31][C:32](O)=[O:33])[N:23]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:32](=[O:33])[CH2:31][N:24]3[C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:30]4[C:22]([C:18]4[NH:17][CH:21]=[CH:20][N:19]=4)=[N:23]3)[CH2:10][C@@H:9]2[CH3:14])=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1cc(N2CCNC[C@@H]2C)ccc1Cl
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4cccnc43)C[C@@H]2C)ccc1Cl

Procedure:
The title compound was prepared following protocol A. (S)-1-(4-Chloro-3-methoxyphenyl)-2-methylpiperazine and [3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]acetic acid were used as the coupling components. The crude product was purified by silica gel chromatography (1% to 7% MeOH in CH2Cl2) to provide 1-[(S)-4-(4-chloro-3-methoxyphenyl)-3-methylpiperazin-1-yl]-2-[3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]ethanone as a tan solid: 1H NMR (CDCl3, 400 MHz) δ 8.77 (d, 0.6H), 8.66 (d, 0.3H), 8.57-8.54 (m, 1H), 7.30-7.19 (m, 4H), 6.48-6.40 (m, 2H), 5.54-5.36 (m, 2H), 4.25 (br. d, 0.6H), 4.00 (br. d, 0.6H), 3.88 (s, 1.3H), 3.86 (s, 1.7H), 3.82-3.48 (m, 3.2H), 3.36-3.29 (m, 0.6H), 3.17-3.13 (m, 2H), 1.51-1.43 (m, 3H); LC/MS m/z (M+H)+ 466.4.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([NH:36][S:37]([C:40]3[CH:45]=[CH:44][C:43](I)=[CH:42][CH:41]=3)(=[O:39])=[O:38])[CH2:26][O:27][C:28]3[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=3)[C:31]#[N:32])=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:47]([O:51][CH2:52][CH3:53])(=[O:50])[CH:48]=[CH2:49].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CCCC)CCCC)CCC>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([NH:36][S:37]([C:40]3[CH:45]=[CH:44][C:43](/[CH:49]=[CH:48]/[C:47]([O:51][CH2:52][CH3:53])=[O:50])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[CH2:26][O:27][C:28]3[CH:35]=[CH:34][CH:33]=[C:30]([C:31]#[N:32])[CH:29]=3)=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(OC[C@H](Cc2ccc(OC3CCN(C(=O)OCc4ccccc4)CC3)cc2)NS(=O)(=O)c2ccc(I)cc2)c1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)/C=C/c1ccc(S(=O)(=O)N[C@H](COc2cccc(C#N)c2)Cc2ccc(OC3CCN(C(=O)OCc4ccccc4)CC3)cc2)cc1

Procedure:
738 mg (1.00 mmol)) of 3-[(2S)-3-[4-[1-(benzyloxycarbonyl)-4-piperidyloxy]phenyl]-2-(4-iodobenzenesulfonylamino)propoxy]benzonitrile was dissolved in 5 ml of acetonitrile. 0.22 ml (2.0 mmol) of ethyl acrylate, 11 mg (0.05 mmol) of palladium acetate, 91 mg (0.3 mmol) of tris-o-tolylphosphine and 0.48 ml (2.0 mmol) of tributylamine were added to the solution, and they were heated under reflux for 15 hours. After the same isolation process as that of step 1 in Example 1 with dichloromethane as the extractant, the crude product was obtained, which was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH:12](Br)([CH3:14])[CH3:13].P([O-])([O-])([O-])=O>CN(C=O)C>[CH:12]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)([CH3:14])[CH3:13]
Reactant: OCc1ccc(O)cc1
Reactant: CC(C)Br
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(CO)cc1
Reaction time: 18 h
Yield: 69.6 %

Procedure:
4-Hydroxybenzylalcohol (1 g) in DMF (10 ml) under nitrogen at 0° C. was treated portionwise with sodium hydride (355 mg). The resulting solution was stirred for 0.5 h before isopropyl bromide (0.99 g) was added, and the solution was stirred for a further 18 h. Phosphate buffer (pH=6.5) was then added and the solution was extracted with EtOAc. The combined organic layers were then washed with water, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography (Biotage, 90 g) eluting with 40-60° C. petroleum ether-EtOAc (4:1) to give the title compound (931 mg). LCMS RT=2.51 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1C(OC(C)(C)C)=O.Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cccc(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1cccc(OC[C@@H]2CCCN2)c1
Reaction time: 2 h

Procedure:
tert-Butyl (2S)-2-[(3-chlorophenoxy)methyl]pyrrolidine-1-carboxylate (Preparation 89, 1.50 g, 4.81 mmol) was stirred with 4 M of hydrogen chloride in 1,4-dioxane (10 mL). After 2 h, the reaction mixture was concentrated in vacuo (TLC analysis showed only baseline material in 3:1 hexanes-ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.[N:16]1([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:20][CH2:19][CH2:18][CH2:17]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]([N:26]1[CH2:25][CH2:24][N:23]([CH2:22][CH2:21][N:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:28][CH2:27]1)=[O:15]
Reactant: C1CCN(CCN2CCNCC2)C1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1C(=O)N1CCN(CCN2CCCC2)CC1
Temperature: 25 °C

Procedure:
5-Methyl-3-phenylisooxazole-4-carboxylic acid (40 mg, 0.197 mmol), 1-(2-(1-Pyrrolidinyl)-ethyl)-piperazine (39.4 mg, 0.215 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (86.2 mg, 0.268 mmol) and diisopropylethylamine (25.4 mg, 0.197 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C21H28N4O2: 368.2212, found 368.2217.
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]([CH3:9])[CH:5]1[CH2:8][NH:7][CH2:6]1.Cl.[Cl:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]([N:18]2[C:22](=[O:23])[C:21]([N:24]3[CH:28]=[CH:27][N:26]=[N:25]3)=[CH:20][NH:19]2)[CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[ClH:11].[ClH:1].[CH3:3][N:4]([CH3:9])[CH:5]1[CH2:8][N:7]([C:12]2[N:17]=[CH:16][N:15]=[C:14]([N:18]3[C:22](=[O:23])[C:21]([N:24]4[CH:28]=[CH:27][N:26]=[N:25]4)=[CH:20][NH:19]3)[CH:13]=2)[CH2:6]1
Reactant: O=c1c(-n2ccnn2)c[nH]n1-c1cc(Cl)ncn1
Reactant: CN(C)C1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C1CN(c2cc(-n3[nH]cc(-n4ccnn4)c3=O)ncn2)C1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
271 mg (1.5 mmol) of N,N-dimethylazetidine-3-amine dihydrochloride, 400 mg (1.5 mmol) of the compound from Example 12A and 847 mg (6.1 mmol) of potassium carbonate are suspended in 8 ml of N,N-dimethylformamide and stirred at 100° C. for 16 h. The reaction mixture is concentrated under reduced pressure and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% strength trifluoroacetic acid). Further purification is carried out by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% strength formic acid). 2 ml of 1 N hydrochloric acid is added to the product-containing fractions, and the mixture is stirred at RT for 1 h. The solid is filtered off and dried under high vacuum. Yield: 62 mg (17% of theory)
Reaction SMILES: Cl[C:2]1[N:13]=[C:12]([NH:14][CH:15]2[CH2:20][CH2:19][CH:18]([N:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]2)[C:11]2[C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[S:5][C:4]=2[N:3]=1.CO.[NH3:26]>>[CH3:22][N:21]([CH3:23])[CH:18]1[CH2:19][CH2:20][CH:15]([NH:14][C:12]2[C:11]3[C:10]4[CH2:9][CH2:8][CH2:7][C:6]=4[S:5][C:4]=3[N:3]=[C:2]([NH2:26])[N:13]=2)[CH2:16][CH2:17]1
Reactant: CN(C)C1CCC(Nc2nc(Cl)nc3sc4c(c23)CCC4)CC1
Reactant: N
Solvent: CO
Product: CN(C)C1CCC(Nc2nc(N)nc3sc4c(c23)CCC4)CC1
Temperature: 140 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
A 20-mL sealed tube containing a solution of 4-N-[10-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]-1-N,1-N-dimethylcyclohexane-1,4-diamine (80 mg, 0.23 mmol, 1.00 equiv) in 10 mL of saturated methanol-NH3 solution. The resulting solution was stirred overnight at 140° C. in an oil bath and concentrated under vacuum. The crude product (80 mg) was purified by Prep-HPLC with the following conditions (SHIMADZU): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% NH4HCO3 and CH3CN (6.0% CH3CN up to 50.0% in 12 min); UV detection at 254 nm. This resulted 12-N-[4-(dimethylamino)cyclohexyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraene-10,12-diamine (13 mg, 17%) was obtained as a brown solid. MS (ES, m/z) 332 [M+H]+; 1H NMR (300 MHz, CDCl3): δ 4.61 (s, 3H), 3.87-3.97 (m, 1H), 2.80-2.83 (m, 4H), 2.35-2.45 (m, 2H), 2.24 (s, 6H), 2.01-2.18 (m, 3H), 1.86 (s, 3H), 1.29-1.41 (dd, 2H), 1.14-1.18 (t, 3H).
Reaction SMILES: [I-].[Na+].[CH3:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][N:18]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[N+:35]([O-:37])=[O:36])(=[O:28])=[O:27])[CH2:19][CH2:20]OS(C)(=O)=O)=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]1=[O:38].[N:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][O:46][CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH:40]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[CH3:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:19][CH2:20][N:50]3[CH2:51][CH2:52][CH:47]([O:46][CH2:45][C:41]4[CH:40]=[N:39][CH:44]=[CH:43][CH:42]=4)[CH2:48][CH2:49]3)[S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[N+:35]([O-:37])=[O:36])(=[O:27])=[O:28])=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]1=[O:38]
Reactant: Cn1c(=O)ccc2cc(OCCCN(CCOS(C)(=O)=O)S(=O)(=O)c3ccccc3[N+](=O)[O-])ccc21
Reactant: c1cncc(COC2CCNCC2)c1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cn1c(=O)ccc2cc(OCCCN(CCN3CCC(OCc4cccnc4)CC3)S(=O)(=O)c3ccccc3[N+](=O)[O-])ccc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
Sodium iodide (2.93 g) was added to a acetonitrile solution (20 ml) of methanesulfonic acid 2-[[3-(1-methyl-2-oxo-1,2-dihydro-quinolin-6-yloxy)propyl]-(2-nitro-benzenesulfonyl)amino]-ethyl ester (4.37 g), and stirred at 60° C. for 1 hours. The reaction mixture was cooled to room temperature. 4-(pyridin-3-ylmethoxy)piperidine (1.87 g) and N-ethyl diisopropylamine (4.23 ml) were then added to the reaction mixture and stirred at 60° C. for 5 hours. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. Water was added to the residue, and extraction with dichloromethane was performed. The organic layer was washed with water, and a saturated sodium chloride aqueous solution, in this order. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=1:0→10:1). The purified product was concentrated under reduced pressure to give the title compound (3.48 g) as a yellow solid.