Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=O.[F:3][C:4]([F:23])([F:22])[C:5]1[CH:6]=[C:7]([S:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][NH2:21])[CH2:16][CH2:15]2)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1.[C:24](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[CH3:24][NH:21][O:20][CH:17]1[CH2:16][CH2:15][N:14]([S:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:4]([F:3])([F:22])[F:23])[CH:6]=2)(=[O:13])=[O:12])[CH2:19][CH2:18]1
Reactant: NOC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CNOC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
Formaldehyde (166 mg, 5.55 mmol) was added to a solution of O-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yl) hydroxylamine (200 mg, 0.617 mmol) in 1,2-dichlorethane (5 ml) and stirred at room temperature for 3 hours. Sodium triacetoxyborohydride was added and stirred at room temperature for 12 hours. The reaction mixture was diluted with of ethyl acetate (30 ml), washed with H2O and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (the residue was purified by preparative TLC (ethyl acetate/petroleum ether: 67/33) to give N-methyl-O-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yl)hydroxylamine (125 mg, 60%) as a white solid.
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][NH:9][CH2:10][C:11]([OH:13])=O)[N:4]=[CH:3]1.[NH2:14][C@@H:15]([CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)=[O:17]>>[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][NH:9][CH2:10][C:11]([NH:14][C@@H:15]([CH2:33][O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[CH:23][CH:24]=2)=[O:17])=[O:13])[N:4]=[CH:3]1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)CNCCc1c[nH]cn1
Agent: Cl
Product: O=C(CNCCc1c[nH]cn1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 26.3 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2-(1H-imidazol-4-yl)ethylamino)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 216, (S)-2-(2-(2-(1H-imidazol-4-yl)ethylamino)acetamido)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide (11.2 mg, 26.3%). 1H-NMR (400 MHz, DMSO-D6): σ 10.24 (s, 1H), 8.25 (d, 1H), 7.61 (d, 2H), 7.51 (s, 1H), 7.28 (m, 6H), 7.19 (t, 2H), 7.02 (m, 4H), 6.78 (s, 1H), 4.70 (m, 1H), 4.52 (s, 2H), 3.68 (m, 3H), 3.20 (s, 2H), 2.75 (m, 2H), 2.64 (m, 2H). MS (EI) for C29H30FN5O4: 532.6 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[N:20]1[C:21]([C:32](O)=[O:33])=[CH:22][N:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[S:25][C:24]=12>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:32]([C:21]1[N:20]=[C:24]2[N:23]([CH:22]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[S:25]2)=[O:33]
Reactant: O=C(O)c1cn2c(n1)sc1ccccc12
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1cn2c(n1)sc1ccccc12

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with benzo[d]imidazo[2,1-b]thiazole-2-carboxylic acid. MS: 460.4 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:26][C@H:27]([CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([O:42][CH3:43])[CH:35]=3)[CH2:28][C:29]([OH:31])=[O:30])=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C.O1CCOCC1>[NH:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:26][C@H:27]([CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([O:42][CH3:43])[CH:35]=3)[CH2:28][C:29]([OH:31])=[O:30])=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1
Reactant: COc1ccc(CC[C@H](CC(=O)O)NC(=O)[C@@H]2CCCN(C(=O)/C=C/C3CCN(C(=O)OC(C)(C)C)CC3)C2)cc1OC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(CC[C@H](CC(=O)O)NC(=O)[C@@H]2CCCN(C(=O)/C=C/C3CCNCC3)C2)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
To a solution of N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-3(R)-(3,4-dimethoxyphenethyl)-β-alanine (1.33 g) in ethyl acetate (10 ml) was added 4N HCl in 1,4-dioxane (5.53 ml) at 0° C., and the reaction mixture was stirred for 3 hours at room temperature. The precipitates were filtered, washed with diethyl ether and resolved in water, neutralized with saturated aqueous NaHCO3, desalted by using the resin of HP-20 eluting with isopropanol:H2O=(1:1), then freeze-dried to give N-[(R)-1-[3-(4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-3(R)-(3,4-dimethoxyphenethyl)-β-alanine as a white powder (0.88 g, 79.4%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][NH:16][CH2:17][CH2:18][OH:19])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][NH:16][CH2:17][CH2:18][O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCNCc1cccc(OCc2ccccc2)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OCCNCc1cccc(OCc2ccccc2)c1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
Next, to toluene (50 ml) were added 2-[(3-benzyloxyphenyl)methylamino]ethanol (10.3 g, 39.9 mmol), pivaloyl chloride (9.6 g, 79.8 mmol), and pyridine (7.6 g, 95.8 mmol). The mixture was stirred at room temperature for 1 hour and further at 85° C. for 2 hours. After pyridine hydrochloride was removed by filtration, the filtrate was concentrated. The product was purified by silica gel chromatography to give 2,2-dimethylpropionic acid 2-[(3-benzyloxyphenyl)methylamino]ethyl ester as a colorless oily matter (yield: 8.9 g (65.1%)).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl>[C:10]([O:9][C:7]([N:5]1[CH2:6][C@H:2]([NH:1][S:32]([C:29]2[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH2:3][C@H:4]1[C:14]([O:16][CH3:17])=[O:15])=[O:8])([CH3:11])([CH3:12])[CH3:13]
Reactant: COC(=O)[C@@H]1C[C@@H](N)CN1C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a solution of (2S,4R)-4-amino-1-t-butoxycarbonyl-2-methoxycarbonylpyrrolidine (6.04 g) in dichloromethane (60 ml) were added triethylamine (3.44 ml) and p-chlorobenzenesulfonyl chloride (6.26 g) in an ice bath. After being stirred at room temperature overnight, the solution was washed successively with diluted hydrochloric acid, saturated aqueous sodium bicarbonate and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was crystallized from n-hexane to give (2S,4R)-1-t-butoxycarbonyl-4-(4-chlorophenylsulfonylamino)-2-methoxycarbonylpyrrolidine (9.13 g) as a pale yellow crystal.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.C(N(CC)CC)C.[CH2:29]([Si:31]([CH2:36][CH3:37])([CH2:34][CH3:35])[C:32]#[CH:33])[CH3:30]>[Cu]I.C1COCC1>[F:21][C:5]1[CH:4]=[CH:3][C:2]([C:30]#[C:29][Si:31]([CH2:36][CH3:37])([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:7][C:6]=1[C@:8]1([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]1
Reactant: NC1=N[C@](CF)(c2cc(Br)ccc2F)C[C@@H](C(F)(F)F)O1
Reactant: C#C[Si](CC)(CC)CC
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[Si](C#Cc1ccc(F)c([C@]2(CF)C[C@@H](C(F)(F)F)OC(N)=N2)c1)(CC)CC
Temperature: 110 °C
Reaction time: 0.42 h
Yield: 76 %

Procedure:
A 25 mL microwave vial was charged with (4S,6S)-4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (1.465 g, 3.93 mmol), triethylamine (2.74 mL, 19.63 mmol), 10 mL of THF, triethyl(ethynyl)silane (2.176 mL, 11.78 mmol), Pd(0) tetrakis(triphenylphosphine) (0.343 g, 0.297 mmol), and copper(I) iodide (0.112 g, 0.589 mmol). The resulting mixture was then heated at 110° C. for 30 min in a Biotage microwave synthesizer (waited for 25 min to get on the instrument). The solids were filtered off and the solvent was removed under vacuum and the residue was redissolved in 60 mL of EtOAc, washed with 50 mL of saturated NH4Cl solution twice, dried (Na2SO4) and concentrated to give an oil that was purified by Shoko silica gel instrument (pre-packed GRACE column 120 g, with EtOAc in hexane as eluent, 0-10% 17 min; 10% 8 min; 10-30% 5 min; 30% 10 min) to give the titled compound as a light yellow oil, 1.285 g, 76% yield. MS m/z=433.0 [M+H]+. Calculated for C20H25F5N2OSi: 432.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[N:10]#[C:11]Br>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:11]([NH2:10])[NH:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: N#CBr
Solvent: CO
Product: Nc1nc2ccc(Br)cc2[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 144.5 %

Procedure:
4-bromobenzene-1,2-diamine (1.02 g, 5.45 mmol) was taken into 50% aqueous methanol (25 mL) followed by slow addition of cyanogen bromide (1.73 g, 16.35 mmol) and the mixture was allowed to stir at room temperature over 12 h. The mixture was then concentrated to approximately 50% volume, diluted with water and brought to neutral pH by addition of 2 M aqueous sodium hydroxide. The aqueous mixture was then partitioned with ethyl acetate and the organic solution washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 6-bromo-1H-benzimidazol-2-amine (1.67 g) as a red amorphous residue. MS (EI) for C7H6BrN3: 213 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12]O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[CH:8]=2)[N:3]=1.S(Cl)([Cl:23])=O>C(Cl)Cl>[Cl:1][C:2]1[C:11]([CH2:12][Cl:23])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[CH:8]=2)[N:3]=1
Reactant: Cc1ccccc1-c1ccc2nc(Cl)c(CO)cc2c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1ccccc1-c1ccc2nc(Cl)c(CCl)cc2c1
Reaction time: 0.25 h

Procedure:
A mixture of (6-bromo-2-chloroquinolin-3-yl)methanol (19.8 g, 72.5 mmol, prepared as in example 2, step 2), o-tolylboronic acid (10.4 g, 76.1 mmol), potassium acetate (21.3 g, 217.4 mmol) and dichlorobis(4-(di-tert-butylphosphino)-N,N-dimethylaniline)palladium (II) (0.51 g, 0.72 mmol) in CH3CN (300 ml) and water (100 ml) was heated in to reflux. After 2 h, the reaction was allowed to cool to RT and the aqueous phase was discarded. The organics were washed with 2×50% brine/water, and then 2× brine. The organics were concentrated to ˜100 mL, at which point the precipitate was filtered off to afford a pale yellow solid of (2-chloro-6-o-tolylquinolin-3-yl)methanol. Step 2: (2-chloro-6-o-tolylquinolin-3-yl)methanol (13.9 g, 49.0 mmol) was treated with DCM (100 ml) and thionyl chloride (106 ml, 1456 mmol) at ambient temperature. After 15 min, the solution was concentrated and azeotroped with 2×100 mL toluene, to afford a yellow solid of 2-chloro-3-(chloromethyl)-6-o-tolylquinoline.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([CH:13]([CH3:15])[CH3:14])[C:6]=2[CH:16]=1.Cl[C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH:12][C:18]3[N:26]=[CH:25][N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][NH:22]4)[CH3:11])[N:7]([CH:13]([CH3:15])[CH3:14])[C:6]=2[CH:16]=1
Reactant: CC(C)n1c([C@H](C)N)nc2ccc(F)cc21
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1C(C)C
Temperature: 100 °C
Yield: 27 %

Procedure:
(S)-1-(6-Fluoro-1-isopropyl-1H-benzoimidazol-2-yl)ethylamine (0.5 g, 2.26 mmol) was dissolved in n-butanol (5 mL) and 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.54 g, 2.26 mmol) and DIPEA (2 mL, 11.3 mmol) added. The resultant dark red solution was heated to 100° C. overnight. The mixture was allowed to cool to RT and was concentrated in vacuo. The residue was purified by column chromatography (silica gel, gradient 0-10% MeOH in DCM) to afford 379 as a pale red solid (207 mg, 27%). LCMS (Method K): RT 2.68 min [M+H]+ 340.1 1H NMR (DMSO-d6, 400 MHz): δ 8.24 (1H, s), 8.15 (1H, s), 8.00-7.90 (1H, m), 7.64-7.55 (2H, m), 7.02 (1H, td, J=9.31, 2.40 Hz), 5.96-5.77 (1H, m), 4.98-4.85 (1H, m), 1.67 (3H, d, J=6.71 Hz), 1.57 (3H, d, J=6.91 Hz), 1.46 (3H, d, J=6.78 Hz)
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6](S(C)(=O)=O)[CH:7]=[C:8]([C:10](=[N:20][NH2:21])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])[CH:9]=1)=[O:4].Br[C:27]#[N:28]>CO>[NH2:28][C:27]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])[C:10]([C:8]2[CH:9]=[C:5]([C:3]([OH:2])=[O:4])[NH:6][CH:7]=2)=[N:20][N:21]=1
Reactant: N#CBr
Reactant: COC(=O)c1cc(C(=NN)Nc2cccc(Cl)c2Cl)cn1S(C)(=O)=O
Solvent: CO
Product: Nc1nnc(-c2c[nH]c(C(=O)O)c2)n1-c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-[N-(2,3-dichloro-phenyl)-N′-amino-carbamimidoyl]-1-methanesulfonyl-1H-pyrrole-2-carboxylic acid methyl ester (Prepared by the same method described above for the preparation of the corresponding difluoro compound) (150 mg, 0.37 mmol) in MeOH (2 mL) was added BrCN (60 mg, 0.57 mmol) at RT. The mixture was stirred at RT for 12 h. The solvent was removed by evaporation, the residue was dissolved in MeOH (4 mL), and the resulting solution was treated with 6N NaOH (1 mL) at 50° C. for 4 h. After cooling to RT, the solution was acidified with 6N HCl. The organic solvent was evaporated, the remaining aqueous solution was diluted with CH3CN, and the inorganic salt was removed by filtration. The filtrate was concentrated under vacuum to give a crude product, which was purified by HPLC for next reaction. MS (ES+): m/e=338.0 (M+H); LC: 2.44 min.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].Cl[CH2:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22].C(N(CC)CC)C>C(OCC)C>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: CC(=O)CCCCl
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)CCCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The thio of Example 2 (5.0 g, 0.021 M) was reacted with 5-chloro-2-pentanone (2.87 ml) and triethylamine (3.0 ml) in ethyl ether (50 ml) by the method of Example 8 to give the title compound, m.p. ca. 65-67° C.
Reaction SMILES: [Br:1][C:2]1[S:24][C:5]2[CH2:6][CH2:7][C:8]3[C:9]([C:21](O)=[O:22])=[N:10][N:11]([C:13]4[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=4[Cl:20])[C:12]=3[C:4]=2[CH:3]=1.[NH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[N:26]1([NH:25][C:21]([C:9]2[C:8]3[CH2:7][CH2:6][C:5]4[S:24][C:2]([Br:1])=[CH:3][C:4]=4[C:12]=3[N:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:10]=2)=[O:22])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(O)c1nn(-c2ccc(Cl)cc2Cl)c2c1CCc1sc(Br)cc1-2
Reactant: NN1CCCCC1
Product: O=C(NN1CCCCC1)c1nn(-c2ccc(Cl)cc2Cl)c2c1CCc1sc(Br)cc1-2
Yield: 42 %

Procedure:
The same procedure described in the preparations a) and b) of Example 3.1. was used to react the 7-bromo-1-(2′,4′-dichlorophenyl)-4,5-dihydro-1H-thieno[2,3-g] indazol-3-carboxylic acid prepared in the Example 2.2 with 1-aminopiperidine. The purification by flash chromatography (oil ether/ethyl acetate 6/4) has given the compound N-piperidinyl-7-bromo-1-(2′,4′-dichlorophenyl)-4,5-dihydro-1H-thieno[2,3-g]indazol-3-carboxamide as white solid with a 42% yield. Rf=0.33 (oil ether/ethyl acetate 6/4); m.p.: 145° C.;
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[O:47]1[CH:51]=[CH:50][CH:49]=[C:48]1[C:52](Cl)=[O:53].C(N(CC)CC)C>O1CCCC1>[O:47]1[CH:51]=[CH:50][CH:49]=[C:48]1[C:52]([NH:46][C:42]1[CH:43]=[CH:44][CH:45]=[C:40]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:16]4[N:20]=[CH:19][N:18]([C:21]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:17]=4)[CH:11]=3)[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=2)[CH:41]=1)=[O:53]
Reactant: O=C(Cl)c1ccco1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)c1ccco1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.125 g, 0.207 mmol), in tetrahydrofuran (5 mL), were added, 2-furoyl chloride (0.041 g, 0.315 mmol, 0.031 mL) and triethyl amine (0.107 g, 1.06 mmol, 0.147 mL). The reaction mixture was stirred at room temperature for 12 hours. After evaporation of the solvent, the residue was dissolved in 10 mL of ethyl acetate and was washed 3 times with water (5 mL). The crude was used without further purification (0.150 g, 99% yield): ES-MS (m/z) 697 [M+1]+.
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.[CH:18]([C:20]1[N:25]2[CH:26]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:28]=[C:24]2[CH:23]=[CH:22][CH:21]=1)=[O:19]>C1(C)C=CC=CC=1>[CH2:3]([O:2][P:1]([CH:18]([OH:19])[C:20]1[N:25]2[CH:26]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:28]=[C:24]2[CH:23]=[CH:22][CH:21]=1)([O:5][CH2:6][CH3:7])=[O:8])[CH3:4]
Reactant: CCOC(=O)c1cn2c(C=O)cccc2n1
Reactant: CCOP([O-])OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn2c(C(O)P(=O)(OCC)OCC)cccc2n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
Diethyl phosphite (1.7 g, 12.3 mmol, Aldrich), N,N-diisopropylethylamine (1.63 g, 12.4 mmol, Aldrich) and toluene (60 mL) were combined in a 100 mL flask equipped with a N2 inlet and condensor. After warming this solution to 60° C., the product from Example 54 was added. After stirring at 75°-80° C. for 3 h, all solvent was removed from this mixture and the residue was chromatographed (7.5/92.4/0.1 isopropanol/CH2Cl2 /HOAc) to give 1.2 g (66%) of the title product.
Reaction SMILES: C([Mg]Cl)(C)C.[CH:6]([S:9]([N:12]1[C:16]2[CH:17]=[C:18](I)[CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[NH2:22])(=[O:11])=[O:10])([CH3:8])[CH3:7].CN(OC)[C:25](=[O:41])[CH:26]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Cl-].[NH4+]>O1CCCC1>[CH:6]([S:9]([N:12]1[C:16]2[CH:17]=[C:18]([C:25](=[O:41])[CH:26]([O:33][Si:34]([C:37]([CH3:39])([CH3:38])[CH3:40])([CH3:36])[CH3:35])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[NH2:22])(=[O:11])=[O:10])([CH3:8])[CH3:7]
Reactant: CON(C)C(=O)C(O[Si](C)(C)C(C)(C)C)c1ccccc1
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(I)cc21
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)n1c(N)nc2ccc(C(=O)C(O[Si](C)(C)C(C)(C)C)c3ccccc3)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
Add isopropylmagnesium chloride (2.0 M in THF, 235 mL, 470 mmol) over 15 minutes to a solution of 1-isopropylsulfonyl-2-amino-6-iodobenzimidazole (42.9 g, 118 mmol) in tetrahydrofuran (850 mL) at −70° C. under a nitrogen atmosphere. Stir for 1 hour at 0° C. and then add a solution of N-[methyl] N-[methoxy] 2-(tert-butyldimethylsilyl)oxy-2-(phenyl)acetamide (90.0 g, 294 mmol) (Tius, et al., Tetrahedron, 56, 3339-3351-(2000)) in tetrahydrofuran (150 mL) via cannula. Stir the resulting slurry at 0-5° C. for 1 hour and then at room temperature for 1.5 hours. Cool the mixture to 10° C. and then add saturated aqueous ammonium chloride. Stir the mixture 15 minutes and separate the layers. Extract the aqueous layer with ethyl acetate (400 mL), dry the combined organic layers over sodium sulfate, and concentrate under reduced pressure. Purify the residue by silica gel chromatography, eluting with 1-10% acetonitrile in dichloromethane containing 0.5% triethylamine to provide a 50% yield of the title compound as a white solid. MS(ES+): m/z=488.1 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[C:12]1[CH:11]=[C:10]([N:18]([CH3:20])[CH3:19])[CH:9]=[CH:8][C:7]=1[S:6]2(=[O:22])=[O:21])#[N:2].[CH2:23](N)[CH2:24][NH2:25].C[O-].[Na+].O.[ClH:31]>CO>[ClH:31].[ClH:31].[CH3:19][N:18]([CH3:20])[C:10]1[CH:9]=[CH:8][C:7]2[S:6](=[O:22])(=[O:21])[C:5]3[C:14](=[CH:15][CH:16]=[C:3]([C:1]4[NH:25][CH2:24][CH2:23][N:2]=4)[CH:4]=3)[C:13](=[O:17])[C:12]=2[CH:11]=1
Reactant: CN(C)c1ccc2c(c1)C(=O)c1ccc(C#N)cc1S2(=O)=O
Reactant: NCCN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN(C)c1ccc2c(c1)C(=O)c1ccc(C3=NCCN3)cc1S2(=O)=O

Procedure:
A mixture of 6-cyano-2-dimethylaminothioxanthen-9-one 10,10-dioxide, 2.0 g (0.006 mol), ethylenediamine, 3 g, 0.05 mol, and sodium methoxide, 0.1 g (0.002 mol) in methanol, 30 ml, was refluxed for 48 hr. The mixture was poured into H2O and the resultant precipitate was dissolved in boiling in 1N HCl. This solution was cooled and the dihydrochloride salt was filtered and recrystallized from 95% ethanol to yield 2-dimethylamino-6-(2-imidazolin-2-yl)thioxanthen-9-one 10,10-dioxide dihydrochloride 0.3 g with m.p. 330°-335° C. (dec); TLC on silica gel (ethylacetate:ethanol:acetic acid/80:15:5), Rf =0.4.