Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([N:13]=[C:14]=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=1[NH:26][C:27](=[O:48])[CH2:28][N:29]1[CH2:34][CH2:33][N:32]([C@@H:35]2[CH2:40][CH2:39][NH:38][C@@H:37]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:36]2)[CH2:31][CH2:30]1>C(Cl)Cl>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:38]2[CH2:39][CH2:40][C@@H:35]([N:32]3[CH2:33][CH2:34][N:29]([CH2:28][C:27]([NH:26][C:20]4[C:21]([CH3:25])=[CH:22][CH:23]=[CH:24][C:19]=4[CH3:18])=[O:48])[CH2:30][CH2:31]3)[CH2:36][C@@H:37]2[CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN([C@@H]2CCN[C@@H](Cc3ccccc3)C2)CC1
Solvent: ClCCl
Product: Cc1cccc(C)c1NC(=O)CN1CCN([C@@H]2CCN(C(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](Cc3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
3,5-di(trifluoromethyl)-1-isocyanatobenzene (0.0025 mol) in DCM (10 ml) was added to a mixture of (±)-trans-N-(2,6-dimethylphenyl)-4-[2-(phenylmethyl)-4-piperidinyl]-1-piperazineacetamide (0.0025 mol) in DCM (15 ml). The mixture was stirred at RT overnight. The precipitate was filtered off and dried, yielding 0.66 g (40%) of (±)-trans-4-[1-[[[3,5-bis(trifluoromethyl)phenyl]amino]carbonyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide (compound 143).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:23])(C)(C)C.CC1(C)O[C:30]([C:32]2[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=2)[C:35]#[N:36])=[CH:29][C:28](=[O:40])O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]#[C:14][C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:30]([C:32]4[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=4)[C:35]#[N:36])[CH2:29][C:28](=[O:40])[NH:23][C:9]=3[CH:10]=2)=[CH:21][CH:20]=1
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(Cl)cc2)cc1N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccc(C#Cc4ccc(Cl)cc4)cc3NC(=O)C2)c1
Yield: 47 %

Procedure:
Prepared from [2-amino-4-(4-chloro-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester (Example G13) (187 mg, 0.5 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) (184 mg, 0.6 mmol) according to the general procedure K. The obtained material (234 mg) was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow powder (93 mg).
Reaction SMILES: S(=O)(=O)(O)O.[Na].[CH2:7]([N:9]([CH2:16][CH2:17]O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:8].[N-:19]=[N+:20]=[N-:21].[Na+]>>[CH2:7]([N:9]([CH2:16][CH2:17][N:19]=[N+:20]=[N-:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:8]
Reactant: CCN(CCO)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [Na]
Product: CCN(CCN=[N+]=[N-])c1ccccc1

Procedure:
The coupling component of Example 25 was prepared by reaction of the sulphuric acid semi-ester (or its sodium salt) of N-ethyl-N-β-hydroxyethyl-aniline with sodium azide to form N-ethyl-N-β-azido-ethylaniline in a two-phase aqueous organic solvent system, for example in water/chlorobenzene, and reaction of the azido compound thus obtained with acetylene.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[N:23]1[C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=[CH:25][C:24]=1[C:32]([OH:34])=[O:33].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:29]([C:28]3[N:23]=[C:24]([C:32]([OH:34])=[O:33])[CH:25]=[CH:26][CH:27]=3)=[O:30])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: O=C(O)c1cccc(C(=O)O)n1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)n1

Procedure:
In a third alternate process for preparing the above named compound, 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (0.1 mmol) and 2,6-pyridinedicarboxylic acid (0.1 mmol) was dissolved in DCM (3 mL), and HOBt was added (1.0 eq, 14.0 mg) along with EDC (1.0 eq, 19.0 mg). The resultant solution was stirred overnight. The solution was purified by preparative HPLC (Gilson) to yield 6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid. This compound was dissolved in 3 mL of DCM along with 1,1-dimethylethyl (2S)-4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (41.3 mg, 0.1 mmol), followed by the addition of HOBt (1.0 eq, 14.0 mg) and EDC (1.0 eq, 19.0 mg). The resultant solution was stirred overnight and product was purified by preparative HPLC (Gilson) to give 1,1-dimethylethyl (2S)-4-[(5′-{[({6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinyl}carbonyl)amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate. This compound was then dissolved in 2 mL of dioxane:MeOH (3:1). Three drops of HCl (concentrated) were added to the resultant solution and it was heated at 60° C. for 1 h. The solution was applied to the amine column, rinsed with 10 mL of dioxane:MeOH (3:1) to afford 2.2 mg (2.9%) of the above named product. LC-MS m/z 749 (M+H)+, 1.32 min (ret time).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[C:7]([C:9](=[O:23])/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20](O)=[O:21])=[CH:14][CH:13]=2)[CH:8]=1.C1C=CC2[N:39]([OH:40])N=NC=2C=1.C(Cl)CCl.NOC1CCCCO1>C(Cl)Cl>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[C:7]([C:9](=[O:23])/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([NH:39][OH:40])=[O:21])=[CH:14][CH:13]=2)[CH:8]=1
Reactant: CN1CCN(c2ccc(Cl)cc2C(=O)/C=C/c2ccc(/C=C/C(=O)O)cc2)CC1
Reactant: On1nnc2ccccc21
Agent: Cl
Agent: NOC1CCCCO1
Solvent: ClCCCl
Solvent: ClCCl
Product: CN1CCN(c2ccc(Cl)cc2C(=O)/C=C/c2ccc(/C=C/C(=O)NO)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.1 %

Procedure:
A mixture of (E)-3-(4-{(E)-3-[5-chloro-2-(4-methyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid hydrochloride (250 mg, 0.56 mmol), HOBT (139 mg, 1.03 mmol), EDC (196 mg, 1.03 mmol), TEA (0.568 ml, 4.08 mmol) and NH2OTHP (89 mg, 0.765 mmol) in DCM (5 ml) was stirred overnight at room temperature. The solvent was evaporated and the residue was partitioned between water and AcOEt. The phases were separated and the aqueous layer was brought to basic conditions with NH4OH and extracted with DCM. The collected organic extract were dried over Na2SO4 and evaporated in vacuo. The crude mixture was purified by silica gel chromatography (eluent: DCM/MeOH/NH4OH 97:3:0.1) and the resulting product was dissolved in DCM and treated with HCl/Et2O for 2.5 h. The precipitate was filtered and triturated with isopropanol and di-isopropylether to give 61 mg of (E)-3-(4-{(E)-3-[5-chloro-2-(4-methyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-N-hydroxy-acrylamide hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[CH3:18][O:19][C:20](=[O:33])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[CH3:18][O:19][C:20](=[O:33])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](=[O:30])(=[O:31])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:25][CH:24]=1
Reactant: COC(=O)CCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ncccc1C(=O)c1cc(Cl)ccc1N
Product: COC(=O)CCc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2cccnc2C)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2 amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone and 3-(4-Chlorosulfonyl-phenyl)-propionic acid methyl ester and purified by HPLC. 1H-NMR (CDCl3) δ 10.75 (br s, 1H, NH), 8.64 (dm, 1H, J=4.8 Hz), 7.79 (dd, 1H, J=9.2 Hz, J=1.1 Hz), 7.75 (d, 2H, J=7.3 Hz), 7.49 (dm, 1H,J=9.2 Hz), 7.1-7.3 (m, 5H), 3.65 (s, 3H), 2.97(t, 2H, J=7.6 Hz), 2.61 (t, 2H, J=7.6 Hz), 2.35 (s, 3H). MS: m/z 473 (M+1).
Reaction SMILES: [CH3:1][C:2]1[S:18][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]([NH2:17])=O)=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:19].P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH3:1][C:2]1[S:18][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]#[N:17])=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:19]
Reactant: Cc1sc2nc3ccc(C(N)=O)cn3c(=O)c2c1C
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1sc2nc3ccc(C#N)cn3c(=O)c2c1C
Yield: 94.2 %

Procedure:
From 1.0 g (0.0037 mol) of 2,3-dimethyl-4-oxo-4H-pyrido[1,2-a]-thieno[2,3-d]pyrimidine-7-carboxamide (Example 26), 50 ml of phosphorus oxychloride and 50 ml of chloroform and refluxing on a steam bath for eighteen hours, following the procedure of Example 27, there is obtained 0.89 g of 2,3-dimethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile; mp 306°-307° C. after recrystallization from glacial acetic acid.
Reaction SMILES: [C:1]([OH:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].I[CH2:13][C:14]([OH:16])=[O:15]>C(O)C.O>[C:1]([S:8][CH2:13][C:14]([OH:16])=[O:15])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(=S)c1ccccc1
Reactant: O=C(O)CI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CSC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 97.8 %

Procedure:
To a purged stirring solution at 0° C. of (5.74 g, 41.6 mmoles) thiobenzoic acid in (100 mL) ethanol was added (27.8 mL, 3N, 83.2 mmoles) potassium hydroxide followed by (7.70 g, 41.6 mmoles) iodoacetic acid in (30 mL) ethanol. The solution stirred for 10 hours at room temperature under argon. The ethanol was rotavapped and the orange solid product was dissolved in (40 mL) water. The solution was acidified to pH 2.0 where an orange precipitate formed. This was filtered, washed with water, and dried in vacuo to give (7.98 g, 99% yield) benzoylmercaptoacetic acid.
Reaction SMILES: [Cl:1]/[C:2](/[CH3:9])=[CH:3]\[CH2:4][CH2:5][C:6]([OH:8])=[O:7].[N+](=[CH2:12])=[N-]>CCOCC>[CH3:12][O:7][C:6](=[O:8])[CH2:5][CH2:4]/[CH:3]=[C:2](\[Cl:1])/[CH3:9]
Reactant: C=[N+]=[N-]
Reactant: C/C(Cl)=C/CCC(=O)O
Solvent: CCOCC
Product: COC(=O)CC/C=C(/C)Cl

Procedure:
A solution of 10.4 g. of the carboxylic acid prepared according to (c) in 50 ml. of ether was combined with such an amount of ethereal diazomethane solution that there was no longer any liberation of nitrogen during the addition of the reagent and the yellow coloring of the reaction solution remained. Excess diazomethane and solvent were then removed under vacuum, and the residue was distilled with the aid of a water jet aspirator, thus obtaining 10.6 g. of final product, b.p. 87°-89° (18 mm.).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21](Br)=[C:15]3[N:14]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[F:23][C:24]1[C:25]([O:33][CH3:34])=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[C:25]=4[O:33][CH3:34])=[C:15]3[N:14]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: COc1c(F)cccc1B(O)O
Reactant: CC(C)OC(=O)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Product: COc1c(F)cccc1-c1cnn2ccc(N3CCN(C(=O)OC(C)C)CC3)nc12
Yield: 33.8 %

Procedure:
Prepared similarly to the preparation of example 5.6.9 from 4-(3-bromo-pyrazolo[1,5-a]pyrimidin-5-yl)-piperazine-1-carboxylic acid isopropyl ester (389.9 mg, 1.1 mmol) and 3-fluoro-2-methoxyphenylboronic acid [762287-59-2] (216.2 mg, 1.3 mmol) to afford 153.8 mg of light yellow powder as a free base, mp. 52-53° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (d, J=6.32 Hz, 6 H) 3.49-3.56 (m, 4 H) 3.75 (dd, J=6.44, 4.17 Hz, 4 H) 3.83 (d, J=1.01 Hz, 3 H) 4.82 (spt, J=6.23 Hz, 1H) 6.81 (d, J=8.08 Hz, 1 H) 7.06 (ddd, J=11.37, 8.08, 1.52 Hz, 1 H) 7.16 (td, J=8.08, 5.81 Hz, 1 H) 8.23 (dt, J=7.89, 1.36 Hz, 1 H) 8.42 (s, 1 H). 19F NMR (377 MHz, DMSO-d6) δ ppm −131.42. 13C NMR (100 MHz, DMSO-d6) δ ppm 21.95, 42.83, 44.05, 60.38, 68.16, 97.24, 99.94, 99.98, 112.72, 112.90, 123.22, 124.06, 127.98, 136.39, 143.40, 143.51, 144.25, 144.49, 154.28, 154.63, 155.53, 157.04. LRMS (ESI) m/z 414.1 [(M+H)]+, calc'd for C21H24FN5O3: 413.46.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[N:4]=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][C:9](=[O:13])[C:7]=2[N:8]=1.[C:16](=O)([O-])[O-].[Na+].[Na+].F[B-](F)(F)F.C[O+](C)C.O>ClCCl>[CH3:16][O:13][C:9]1[C:7]2[N:8]=[C:3]([C:2]([F:1])([F:14])[F:15])[N:4]=[CH:5][C:6]=2[CH2:12][CH2:11][N:10]=1
Reactant: O=C1NCCc2cnc(C(F)(F)F)nc21
Reactant: O=C([O-])[O-]
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC1=NCCc2cnc(C(F)(F)F)nc21
Reaction time: 5.5 h

Procedure:
To a vigorously stirred mixture of 336 mg (1.33 mmol) of 2-(trifluoromethyl)-6,7-dihydropyrido[3,4-d]pyrimidin-8(5H)-one and 2.94 g (27.7 mmol) of anhydrous sodium carbonate in 15 mL of dichloromethane was added 979 mg (6.6 mmol) of trimethyloxonium tetrafluoroborate. Vigorous stirring was continued at room temperature for 5.5 h. Then 15 mL of water was added, and the mixture was shaken. After separation of the phases, the aqueous layer was extracted twice with dichloromethane. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (0-2% methanol in dichloromethane) yielded the title compound as a yellow solid. LC-MS 232 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N+:12]([O-])=O)[C:9]([CH3:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CO.[Cl-].[NH4+]>[Zn].O>[NH2:12][C:10]1[C:9]([CH3:15])=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([CH3:1])[CH:11]=1
Reactant: COC(=O)c1cc(C)c([N+](=O)[O-])cc1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(C)c(N)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
To a stirred solution of methyl 2,5-dimethyl-4-nitrobenzoate (523 mg, 2.5 mmol) in a 9:1 mixture of methanol and water (25 mL total) at 0° C. was added ammonium chloride (401 mg, 7.5 mmol). Zinc (1.63 g, 25 mmol) was added portionwise and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then filtered through Celite and the Celite pad was washed with methanol. The filtrate was concentrated under reduced pressure and the resulting residue was dissolved in ethyl acetate. This solution was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide methyl 4-amino-2,5-dimethylbenzoate (450 mg) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 2.14 (s, 3H), 2.53 (s, 3H), 3.83 (s, 3H), 3.85 (br s, 2H), 6.48 (s, 1H), 7.72 (s, 1H).
Reaction SMILES: C[C@@]12[C@H]3[C@@H](O)C[C@]4(C)[C@@](O)(C(CO)=O)CC[C@H]4[C@@H]3CCC1=CC(=[O:6])CC2.C(N(CCC)C(=O)CCC(O)=O)CC.[CH:41]1([N:47]=[C:48]=[N:49][CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]2)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1.ClCCl>N1C=CC=CC=1>[C:48]([NH:47][CH:41]1[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]1)([NH:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1)=[O:6]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCN(CCC)C(=O)CCC(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.17 h
Yield: 78.3 %

Procedure:
To a solution of hydrocortisone (5 g, 0.014 mole) and N,N-di-n-propylsuccinamic acid (2.78 g, 0.014 mole) in 25 ml pyridine at room temperature was added dicyclohexylcarbodiimide (2.85 g, 0.014 mole). After the reaction was stirred 10 minutes, 25 ml dichloromethane was added to it to keep the suspension which had formed sufficiently fluid for stirring. After the reaction was stirred overnight, it was filtered. The residue was washed twice with CH2Cl2 and dried in the air to give 2.46 g (91% yield) dicyclohexylurea. The filtrate was concentrated in vacuo to a residue which was dissolved in 25 ml hot THF. After the THF solution was filtered while hot, the resulting filtrate was diluted to 150 ml with Et2O. The product crystallized overnight and was filtered and dried to give 3.49 g of light brown crystals, which a preliminary NMR showed to be contaminated with solvent. The crystals were dried in vacuo (50° C., 2 hours) to give 2.81 g (37% yield) of the desired product: mp 157°-162° C.; NMR (CDCl3) δ5.64 (s, 1, O=C-CH=), 4.98 (m, 2, O=C-CH2O), 4.46 (m, 1, CHOH), 3.8-4.2 (m, 2, OH), 3.24 (t, 4, J=7 Hz, N CH2), 2.70 (s, 4, OCCH2CH2CO), 1.46 (s, 3, C-CH3), 0.96 (s, 3, C-CH3), 0.94 (m, 6, N(CH2CH2CH3)2), 2.9-0.8 (m, 21, CH, CH2); TLC (silica gel, 10% MeOH/Et2O) Rf 0.56; [α]25D=+127° (C=0.5, dioxane); IR (KBr) 3400 cm-1 (s) (OH), 1730, 1710, 1640 and 1610 cm-1 (s) (C=O).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.C([O-])(=O)C.[NH4+].[N+:16]([CH3:19])([O-:18])=[O:17].C(O)(=O)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:19][N+:16]([O-:18])=[O:17]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])C=Cc1cccc(Cl)c1Cl
Reaction time: 0.5 h

Procedure:
28.0 g of 2,3-dichlorobenzaldehyde, 13.9 g of ammonium acetate, 13.9 ml of nitromethane and 120 ml of glacial acetic acid are refluxed for 2 hours. After cooling, the reaction mixture is poured onto ice and stirred for 30 minutes. The formed precipitate is then filtered off, washed with water and dried in vacuo to thus obtain the product in the form of slightly yellowish crystals, m.p. 89°-91° C. IR (CHCl3) in cm-1 : 1650 (C=C); 1530 and 1350 (NO2). NMR (CDCl3) in ppm: 7.2-7.7 (m, 4H); 8.50 (d, J=15 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[CH3:48][C:49]1[O:50][CH:51]=[CH:52][C:53]=1[C:54](O)=[O:55]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:54]([C:53]2[CH:52]=[CH:51][O:50][C:49]=2[CH3:48])=[O:55])[CH2:42][CH2:41]1
Reactant: Cc1occc1C(=O)O
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cc1occc1C(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 60 %

Procedure:
The desired compound was prepared according to the procedure of Example A27, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 2-methyl-3-furoic acid as starting materials in 60% yield. LCMS for C30H31ClN7O3 (M+H)+: m/z=572.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:8]([NH2:12])[CH2:9][CH2:10][CH3:11]>O>[CH2:8]([NH:12][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCN
Reactant: Clc1ccncc1
Solvent: O
Product: CCCCNc1ccncc1

Procedure:
A solution of 4-chloropyridine (2.0 g, 17.6 mmol), 50% butylamine in water (30 mL) was heated at 150° C. in a sealed tube for 24 h. The reaction mixture was evaporated, partitioned between 0.1 N NaOH and CH2Cl2, dried (Na2SO4) and evaporated. Crystallization in ether/petroleum ether 4:1 afforded 2.4 g of the title product 113 as a white powder (LCMS analysis).
Reaction SMILES: [C:1]1([N:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:8]([O:10][C:11]2[C:12]3[N:13]=[CH:14][N:15]([C:24]=3[N:25]=[C:26]([NH:28][C:29](=[S:32])[NH:30][CH3:31])[N:27]=2)[C@@H:16]2[O:23][C@H:20]([CH2:21][OH:22])[C@@H:18]([OH:19])[CH2:17]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:39][O:40][C:41]1[CH:62]=[CH:61][C:44]([C:45](Cl)([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:46]2[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=2)=[CH:43][CH:42]=1.O.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH3:53][O:52][C:49]1[CH:48]=[CH:47][C:46]([C:45]([O:22][CH2:21][C@H:20]2[O:23][C@@H:16]([N:15]3[C:24]4[N:25]=[C:26]([NH:28][C:29](=[S:32])[NH:30][CH3:31])[N:27]=[C:11]([O:10][C:8](=[O:9])[N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[C:12]=4[N:13]=[CH:14]3)[CH2:17][C@@H:18]2[OH:19])([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:44]2[CH:61]=[CH:62][C:41]([O:40][CH3:39])=[CH:42][CH:43]=2)=[CH:51][CH:50]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CNC(=S)Nc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@H]3C[C@H](O)[C@@H](CO)O3)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: CNC(=S)Nc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@H]3C[C@H](O)[C@@H](COC(c4ccccc4)(c4ccc(OC)cc4)c4ccc(OC)cc4)O3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.4 %

Procedure:
The above-obtained 6-O-diphenylcarbamoyl-2-N-methylthiocarbamoyldeoxyguanosine (400 mg, 0.744 mmol) was azeotroped with anhydrous pyridine three times and dissolved in anhydrous pyridine (8.0 mL), and 4,4′-dimethoxytrityl chloride (278 mg, 0.818 mmol) was added thereto. The mixture was stirred at room temperature for 3 hours, and then sodium bicarbonate water (3 mL) was added thereto to terminate the reaction. The reaction solution was extracted with ethyl acetate (150 mL)/sodium bicarbonate water (120 mL) once and with ethyl acetate (150 mL)/brine (100 mL) twice. Then, the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (N60: spherical neutral silica gel) with methanol/3% to 4% chloroform containing 1% triethylamine to give 5′-O-(4,4′-dimethoxytrityl)-6-O-diphenylcarbamoyl-2-N-methylthiocarbamoyldeoxyguanosine (570 mg, 78%).
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[N:10][C:11](Cl)=[N:12][CH:13]=1.[CH3:15][S:16][C:17]1[C:25]2[C:20](=[CH:21][C:22]([C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])=[CH:23][CH:24]=2)[NH:19][CH:18]=1>CN(C=O)C.C(OCC)(=O)C>[Br:7][C:8]1[CH:9]=[N:10][C:11]([N:19]2[C:20]3[C:25](=[CH:24][CH:23]=[C:22]([C:26]([N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)=[O:27])[CH:21]=3)[C:17]([S:16][CH3:15])=[CH:18]2)=[N:12][CH:13]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CSc1c[nH]c2cc(C(=O)N3CCOCC3)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Temperature: 120 °C
Reaction time: 16 h

Procedure:
Potassium tert-butoxide (9.75 g, 86.95 mmol, 1.5 eq) and 5-bromo-2-chloropyrimidine (11.21 g, 57.97 mmol, 1.0 eq) were added to (3-(methylthio)-1H-indol-6-yl)(morpholino)methanone (16.0 g, 57.97 mmol, 1.0 eq) in DMF (100 mL). The mixture was stirred at 120° C. for 16 h, then cooled to room temperature, diluted with ethyl acetate (100 mL), and filtered through a pad of celite. The filtrate was washed with water (2×100 mL) and brine (50 mL), and dried over sodium sulphate. The solvents were distilled off and the residue was purified by silica gel column chromatography [100-200 mesh; ethyl acetate/petrolether=1:1]. Yield: 8.0 g (32% over two steps).