Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10](=O)[CH3:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>C(O)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10](=[N:14][OH:15])[CH3:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: NO
Reactant: CC(=O)c1ccc2[nH]ncc2c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=NO)c1ccc2[nH]ncc2c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 71 %

Procedure:
To a suspension of 1-(1H-indazole-5-yl)-ethanone (334 mg, 2.09 mmol) in EtOH-H2O (4:1, 10 ml) were added hydroxylamine hydrochloride (444 mg, 6.39 mmol) and sodium acetate (449 mg, 5.47 mmol). The reaction mixture was stirred at 80° C. for 15 hours and concentrated in vacuo. The residue was stirred with H2O at room temperature for 10 min. The solid obtained was collected by filtration, and rinsed with H2O. After drying, the title compound (260 mg, 71%) was obtained as a white solid. 1H NMR (270 MHz, DMSO-d6) δ ppm 2.22 (3H, s), 7.52 (1H, d, J=8.6 Hz), 7.79 (1H, d, J=8.6 Hz), 7.98 (1H, s), 8.10 (1H, s), 11.05 (1H, s), 13.13 (br.s, 1H). MS (ESI) m/z 176 (M+H)+, 174 (M−H)−.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([N:19]3[CH2:24][CH2:23][C:22]4([CH2:33][C:32](=[O:34])[C:31]5[C:26](=[CH:27][CH:28]=[C:29]([C:35]6[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=6)[CH:30]=5)[O:25]4)[CH2:21][CH2:20]3)=[O:18])=[CH:14][CH:15]=2)[NH:10][N:9]=1.[CH3:41][O:42][C:43]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)=[O:44]>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([N:19]3[CH2:20][CH2:21][C:22]4([CH2:33][C:32](=[O:34])[C:31]5[C:26](=[CH:27][CH:28]=[C:29]([C:35]6[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=6)[CH:30]=5)[O:25]4)[CH2:23][CH2:24]3)=[O:18])=[CH:14][CH:15]=2)[N:10]([C:48]2[CH:49]=[CH:50][C:45]([C:43]([O:42][CH3:41])=[O:44])=[CH:46][CH:47]=2)[N:9]=1
Reactant: Cc1n[nH]c2cc(C(=O)N3CCC4(CC3)CC(=O)c3cc(-c5cnn(C)c5)ccc3O4)ccc12
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(-n2nc(C)c3ccc(C(=O)N4CCC5(CC4)CC(=O)c4cc(-c6cnn(C)c6)ccc4O5)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyridine (0.080 ml, 0.988 mmol) was added to a stirred mixture of 1′-[(3-methyl-1H-indazol-6-yl)carbonyl]-6-(1-methyl-1H-pyrazol-4-yl)spiro[chroman-2,4′-piperidin]-4-one (150 mg, 0.329 mmol), [4-(methoxycarbonyl)phenyl]boronic acid (119 mg, 0.659 mmol), Cu(OAc)2 (90 mg, 0.494 mmol) in CH2Cl2 (1.5 ml) and the mixture was stirred at room temperature overnight. The mixture was filtered and the solvent was evaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/EtOAc) to give intended compound as colorless oil.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:13]=[C:12]3[C:7]([C:8]([CH:15]([O:17][CH2:18][C:19]4([C:32]5[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=5)[CH2:24][CH2:23][N:22]([C:25](OC(C)(C)C)=O)[CH2:21][CH2:20]4)[CH3:16])=[CH:9][C:10]([CH3:14])=[CH:11]3)=[N:6]2)[CH2:3][CH2:2]1.C([BH3-])#N.[Na+].C=O>FC(F)(F)C(O)=O.C(O)(=O)C>[CH:1]1([CH2:4][N:5]2[CH:13]=[C:12]3[C:7]([C:8]([CH:15]([O:17][CH2:18][C:19]4([C:32]5[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=5)[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)[CH3:16])=[CH:9][C:10]([CH3:14])=[CH:11]3)=[N:6]2)[CH2:3][CH2:2]1
Reactant: Cc1cc(C(C)OCC2(c3ccc(F)cc3)CCN(C(=O)OC(C)(C)C)CC2)c2nn(CC3CC3)cc2c1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Cc1cc(C(C)OCC2(c3ccc(F)cc3)CCN(C)CC2)c2nn(CC3CC3)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(±)-tert-Butyl 4-((1-(2-(cyclopropylmethyl)-5-methyl-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (15 mg, 0.03 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 1 mL) and stirred at room temperature for 1 h. The reaction was concentrated, loaded onto a strong cation exchange cartridge in methanol, and flushed with several volumes of methanol which were discarded. The crude secondary amine was eluted in 2 M ammonia in methanol and concentrated. The resulting residue was dissolved in acetonitrile (1 mL), cooled to 0° C., and treated with sodium cyanoborohydride (9 mg, 0.14 mmol) and formalin (79 μL). After 5 min, the reaction was treated with a few drops of acetic acid. The ice bath was removed and stirring continued for 1 h. The reaction was concentrated and purified by flash chromatography on silica gel (10% methanolic ammonia/methylene chloride) to afford 5 mg (40%) as a clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.89 (s, 1H), 7.32-7.34 (m, 2H), 7.23 (m, 1H), 6.99-7.02 (m, 2H), 6.66 (m, 1H), 4.94 (q, J=6.4 Hz, 1H), 4.22-4.24 (m, 2H), 3.34-3.41 (m, 2H), 2.57 (m, 2H), 2.29 (s, 3H), 2.21 (s, 3H), 2.09-2.25 (m, 6H), 2.01-2.04 (m, 1H), 1.44 (d, J=6.4 Hz, 3H), 0.64 (m, 2H), 0.40-0.43 (m, 2H). Mass spec.: 436.53(MH)+.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.N1C=CC=CC=1.C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19].Cl>>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:17][C:18]([OH:20])=[O:19]
Reactant: O=C(O)CC(=O)O
Reactant: Cc1ccccc1C=O
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccccc1C=CC(=O)O
Temperature: 0 °C
Yield: 84.3 %

Procedure:
To a stirred solution of o-methylbenzaldehyde (50 g, 417 mmol) in pyridine (2 equiv, 65 mL) was added malonic acid (86.6 g, 834 mmol) and the mixture was refluxed for 4-5 h. The reaction mixture was then poured into ice-water followed by 1N HCl. The white solid precipitated out was filtered, washed with water and concentrated under high vacuum for 3-4 h to get the desired product (57 g, 87%).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]2[C:11]3[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:15][C:16]=3[CH2:17][C@H:6]12)=[O:4].[O:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1>>[F:1][C:2]([F:27])([F:26])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]2[C:11]3[CH:12]=[C:13]([C:30]4[CH:31]=[CH:32][O:28][CH:29]=4)[CH:14]=[CH:15][C:16]=3[CH2:17][C@H:6]12)=[O:4]
Reactant: O=C(N1CCC[C@@H]2c3cc(OS(=O)(=O)C(F)(F)F)ccc3C[C@@H]21)C(F)(F)F
Reactant: OB(O)c1ccoc1
Product: O=C(N1CCC[C@@H]2c3cc(-c4ccoc4)ccc3C[C@@H]21)C(F)(F)F
Yield: 61 %

Procedure:
The title compound is prepared from trifluoro-methanesulfonic acid cis-1-(2,2,2-trifluoro-acetyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-6-yl ester and furan-3-yl-boronic acid following a procedure analogous to that described in Step 2 of Intermediates 17 and 18. Yield: 61% of theory; LC (method 1): tR=4.60 min; Mass spectrum (ESI+): m/z=336 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[CH:10][C:5]=2[S:4][CH:3]=1.BrN1C(=[O:17])CCC1=O>C(Cl)(Cl)(Cl)Cl>[N:7]1[C:6]2[C:2]([CH:1]=[O:17])=[CH:3][S:4][C:5]=2[CH:10]=[N:9][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1csc2cncnc12
Solvent: ClC(Cl)(Cl)Cl
Product: O=Cc1csc2cncnc12
Yield: 61 %

Procedure:
A mixture of 7-methyl-thieno[3,2-d]pyrimidine (1.2 g) and N-bromosuccinimide (2.9 g) in carbon tetrachloride (50 mL) was heated at reflux for 1 hour. The reaction mixture was then cooled, the solid formed was filtered off and the filtrate was concentrated under reduced pressure. The residue was suspended in water (10 mL) and the suspension was heated at reflux for 1 hour. The resulting mixture was basified by addition of a saturated aqueous solution of sodium bicarbonate and extracted twice with dichloromethane (100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The solid residue was triturated with ethyl acetate and hexane and then collected by filtration to give 0.8 g of thieno[3,2-d]pyrimidine-7-carbaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:37])[C:10]=1[CH2:11][S:12][C:13]1[N:14]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:15]([C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([O:28][CH3:29])[CH:22]=2)([CH3:20])[CH3:19])=[CH:16][N:17]=1)[C:5](O)=[O:6].[NH2:38][C@@H:39]([CH2:47][CH2:48][CH2:49][NH:50][C:51]([NH2:53])=[NH:52])[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:37])[C:10]=1[CH2:11][S:12][C:13]1[N:14]([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[C:15]([C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([O:28][CH3:29])[CH:22]=2)([CH3:19])[CH3:20])=[CH:16][N:17]=1)[C:5]([NH:38][C@@H:39]([CH2:47][CH2:48][CH2:49][NH:50][C:51]([NH2:53])=[NH:52])[C:40]([O:42][C:43]([CH3:46])([CH3:44])[CH3:45])=[O:41])=[O:6]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C(=O)O)cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCCNC(=N)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C(=O)N[C@@H](CCCNC(=N)N)C(=O)OC(C)(C)C)cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of 3-chloro-4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-5-fluorobenzoic acid (0.96 g, 1.70 mmol) and (S)-tert-butyl 2-amino-5-guanidinopentanoate (0.54 g, 1.79 mmol) in DMF (4 mL) at 0° C. was added HATU (0.69 g, 1.79 mmol) and DIPEA (0.82 mL, 5.27 mmol). The reaction was stirred at room temperature for 1 h, quenched with satd NaHCO3 and diluted with EtOAc. The mixture was washed with water (10 mL), brine (10 mL) and dried with Na2SO4. The residue was purified by column chromatography (silica, MeOH/DCM) to afford (S)-tert-butyl 2-(3-chloro-4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-5-fluorobenzamido)-5-guanidinopentanoate (1.2 g) as a white solid. The solids were dissolved in 4N HCl in dioxane (8 mL) and stirred for 3 h. The reaction was concentrated and purified by chromatography (silica, MeOH/DCM) to yield the title compound (380 mg) as a white solid. 1H-NMR (DMSO-d6, 400 MHz) δ 8.84 (d, J=7.6 Hz, 1H), 7.81 (s, 1H), 7.64-7.61 (m, 1H), 7.46-7.43 (m, 1H), 7.21 (d, J=8.30 Hz, 1H), 7.18 (s, 1H), 7.01-6.93 (m, 2H), 6.61-6.57 (m, 1H), 6.54-6.49 (m, 3H), 4.37-4.31 (m, 1H), 4.07 (s, 2H), 3.68 (s, 3H), 3.15-3.11 (m, 2H), 1.88-1.70 (m, 2H), 1.61-1.54 (m, 2H), 1.47-1.46 (m, 6H), 1.42 (s, 9H); MS (EI) m/z 719 [MH]+.
Reaction SMILES: [O:1]=[C:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:9][C:10]([CH3:15])([CH2:13]O)[CH2:11][OH:12].B(F)(F)F.CCOCC>C(#N)C>[CH3:8][C:2]1([C:3]([O:5][CH2:6][CH3:7])=[O:4])[O:12][CH2:11][C:10]([CH3:15])([CH3:13])[CH2:9][O:1]1
Reactant: CCOC(=O)C(C)=O
Reactant: CC(C)(CO)CO
Agent: FB(F)F
Solvent: CC#N
Solvent: CCOCC
Product: CCOC(=O)C1(C)OCC(C)(C)CO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.3 %

Procedure:
To a solution of ethyl 2-oxopropanoate (0.581 g, 5 mmol) and 2,2-dimethylpropane-1,3-diol (0.521 g, 5.00 mmol) in acetonitrile (5 mL) cooled to 0° C. was added BF3.OEt2 (0.063 mL, 0.500 mmol), and the mixture was allowed to warm to rt and stirred at rt for 18 h. The reaction mixture was quenched with sat. NaHCO3 (5 mL) and diluted with ether/hexane (1:1, 20 mL). The organic layer was washed with water, brine and dried (MgSO4). The solvent was evaporated to yield ethyl 2,5,5-trimethyl-1,3-dioxane-2-carboxylate as a clear oil (681 mg). 1H NMR (500 MHz, CDCl3) δ ppm 4.31 (2H, q, J=7.07 Hz), 3.48-3.58 (4H, m), 1.55 (3H, s), 1.35 (3H, t, J=7.17 Hz), 1.22 (3H, s), 0.69-0.75 (3H, m). Ethyl 2,5,5-trimethyl-1,3-dioxane-2-carboxylate (90 mg) was saponified (1 N NaOH, MeOH-THF) to afford Cap P-24 (69 mg). 1H NMR (500 MHz, CDCl3) δ ppm 3.53-3.64 (4H, m), 1.63 (3H, s), 1.23 (3H, s), 0.78 (3H, s).
Reaction SMILES: [C:1](=[O:8])([O-])[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[Si:9]([O:16][C@H:17]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=1)[C@@H:18]1[NH:22][CH:21]([CH2:23][C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>>[NH2:28][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][CH:21]2[CH2:20][CH2:19][C@H:18]([C@H:17]([O:16][Si:9]([C:12]([CH3:13])([CH3:15])[CH3:14])([CH3:10])[CH3:11])[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=3)[N:22]2[C:1]([O:2][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:8])=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)O[C@H](c1cccc(Cl)c1)[C@H]1CCC(Cc2ccc(N)cc2)N1
Product: CC(C)(C)OC(=O)N1C(Cc2ccc(N)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of 33 mg (0.07 mmol) of 4-({(5R)-5-[(R)-([tert-butyl(dimethyl)silyl]oxy}(3-chlorophenyl)methyl]pyrrolidin-2-yl}methyl)aniline in 1 mL of anhydrous THF (from Step A) was added tert-butyl carbonate (15.3 mg, 0.07 mmol), followed by TEA (13 uL, 0.07 mmol) and the resulting solution stirred at room temperature under nitrogen atmosphere overnight. The reaction mixture was put directly on a preparative plate (500 uM) and eluted with 30% ethyl acetate in hexane to afford the title compound (25 mg, 78%). m/z (ES) 530, 532 (M, M+2)+, 430, 432 (M-Boc, M-Boc+2)+.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[C:4]([N+:16]([O-])=O)[CH:3]=1.Cl[Sn]Cl>>[NH2:16][C:4]1[CH:3]=[C:2]([CH3:1])[CH:15]=[CH:14][C:5]=1[O:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1
Reactant: Cc1ccc(Oc2ccc(O)cc2)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Product: Cc1ccc(Oc2ccc(O)cc2)c(N)c1
Yield: 85.6 %

Procedure:
The product from Example 122a (1.89 g, 7.71 mmol) was reduced with SnCl2 following the procedure from Example 1f giving the title compound as a white solid (1.42 g, 86%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[N+:13]([CH3:16])([O-:15])=[O:14].[OH-].[Na+].Cl>CO.O>[N+:13](/[CH:16]=[CH:5]/[C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[C:2]([F:12])([F:11])[F:1])([O-:15])=[O:14]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccccc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])/C=C/c1ccccc1C(F)(F)F
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 41.3 %

Procedure:
2-(Trifluoromethyl)benzaldehyde (0.758 mL, 5.74 mmol) was dissolved in MeOH (5 mL) and nitromethane (0.370 mL, 6.89 mmol) was added. The mixture was cooled to −10° C. and a solution of NaOH (0.241 g, 6.03 mmol) in Water (2 mL) was added slowly keeping the temperature below −5° C. The mixture stirred at −5° C. for 15 minutes then warmed to 0° C. and stirred for two hours. Ice water (6 mL) was added followed by HCl (6 N, 3 mL). The mixture was extracted with DCM (×2) and washed with brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give (E)-1-(2-nitrovinyl)-2-(trifluoromethyl)benzene (1.12 g, 2.373 mmol, 41%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8](/[N:10]=[C:11](\N)/[C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH2:19][C:20]2[N:28]([CH3:29])[C:27]3[CH:26]=[CH:25][C:24]([C:30]([N:32]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][N:45]=4)[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[O:31])=[CH:23][C:22]=3[N:21]=2)=[CH:16][CH:17]=1)=[O:9].CS(O)(=O)=[O:49].CS(O)(=O)=O>O>[CH2:6]([O:7][C:8]([NH:10][C:11]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH2:19][C:20]2[N:28]([CH3:29])[C:27]3[CH:26]=[CH:25][C:24]([C:30]([N:32]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][N:45]=4)[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:31])=[CH:23][C:22]=3[N:21]=2)=[CH:16][CH:17]=1)=[O:49])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCOC(=O)/N=C(\N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Reactant: CS(=O)(=O)O
Solvent: O
Product: CCCCCCOC(=O)NC(=O)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)O)c4ccccn4)ccc3n2C)cc1
Temperature: 55 °C
Reaction time: 168 h
Yield: 28.4 %

Procedure:
25 g of dabigatran etexilate mesylate were suspended in 180 mL of deionized water. 1.32 g of methanesulfonic acid were added. The reaction mixture was heated to 55° C. and stirred at this temperature for 7 days. The resulting mixture was filtered, and the solid was dried under vacuum. The solid was purified by column chromatography, eluting with dichloromethane:methanol (10:1 v/v) mixture. After solvent evaporation of the selected fractions containing the desired compound, 5.9 g of 3-{[(2-{[(4-{[({hexyloxy}carbonyl)amino]carbonyl}phenyl)-amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoic acid were obtained.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([N:7]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[O:29][CH3:30])[S:8]([C:11]2[CH:16]=[CH:15][C:14](F)=[C:13]([C:18]#[N:19])[CH:12]=2)(=[O:10])=[O:9])=[N:4][CH:3]=1.[I:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[OH:39].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[S:6][C:5]([N:7]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[O:29][CH3:30])[S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:39][C:33]3[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:32]=3[I:31])=[C:13]([C:18]#[N:19])[CH:12]=2)(=[O:10])=[O:9])=[N:4][CH:3]=1
Reactant: Oc1ccc(F)cc1I
Reactant: COc1ccc(CN(c2ncc(Cl)s2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CN(c2ncc(Cl)s2)S(=O)(=O)c2ccc(Oc3ccc(F)cc3I)c(C#N)c2)c(OC)c1

Procedure:
N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-N-(2,4-dimethoxybenzyl)-4-fluorobenzenesulfonamide (Preparation 207, 410 mg, 0.876 mmol), 2-iodo-4-fluorophenol (Preparation 218, 229 mg, 0.964 mmol) and potassium carbonate (363 mg, 2.63 mmol) in dimethyl sulphoxide (20 ml) were stirred at room temperature under nitrogen for 18 hours. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (3×30 ml). The combined organics were washed with saturated aqueous sodium chloride solution (30 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound as an off-white solid, 670 mg, quantitative yield.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[O:31][CH3:32])[C:8]2[NH:13][N:12]=[C:11]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19]Cl)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.CCN(CC)CC>C(#N)C>[CH2:1]([C:5]1[N:6]=[C:7]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[O:31][CH3:32])[C:8]2[NH:13][N:12]=[C:11]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(C#CCCCCCl)c2n1
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(C#CCCCCN3CCCC3)c2n1
Temperature: 70 °C
Yield: 72.2 %

Procedure:
A solution of 5-butyl-3-(6-chlorohex-1-yn-1-yl)-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine (30 g, 65.8 mmol), pyrrolidine (16.32 mL, 197 mmol) and Et3N (27.5 mL, 197 mmol) in Acetonitrile (400 mL) was heated at 70° C. for 16 hours. Further pyrrolidine (7 g) was added and the solution was heated at 70° C. for 8 hours. The cooled solution was evaporated and the residue was purified on a silica cartridge (750 g) eluted with EtOAc (2 column volumes) followed by 20-30% MeOH (+1% Et3N)/EtOAc (16 column volumes) to give the title compound as a yellow gum (23.3 g).
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[CH3:5][C:6]1[CH:11]2[CH2:12][CH:8]([CH2:9][CH2:10]2)[C:7]=1[CH2:13][CH:14]=[O:15].Cl>C1COCC1>[CH3:5][C:6]1[CH:11]2[CH2:12][CH:8]([CH2:9][CH2:10]2)[C:7]=1[CH2:13][CH:14]([OH:15])[C:1]#[CH:2]
Reactant: CC1=C(CC=O)C2CCC1C2
Reactant: C#C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: C#CC(O)CC1=C(C)C2CCC1C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
Ethynylmagnesium bromide in THF (0.5 M, 210.0 ml, 105.0 mmol) was placed in a reactor under a nitrogen atmosphere at room temperature and (3-Methyl-bicyclo[2.2.1]hept-2-en-2-yl)-acetaldehyde (12.15 g, 80.9 mmol) in THF (200 ml) was introduced over a 90 minutes period and the mixture turned orange. The mixture was further stirred at room temperature for 30 minutes and was hydrolyzed with aqueous HCl 5% at room temperature. The mixture was extracted twice with Et2O and the combined organic layers were washed twice with a saturated aqueous solution of NaHCO3, H2O, and brine and dried over Na2SO4. Solvents were removed under vacuum to give a crude which was purified by flash chromatography with cyclohexane/AcOEt (95/5) as eluent to afford the title compound (11.32 g) in 79% yield.
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH:14]=[CH:13]1)(C)C.F.C(=O)(O)[O-].[Na+]>C(#N)C>[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH:14]=[CH:13]1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCC1C=CCC1
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: OCCCCCC1C=CCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-(5-[(1,1-Dimethylethyl)dimethylsiloxy]pent-1-yl)cyclopentene (300 g, 1.170 moles) is diluted with acetonitrile (3000 ml) and a 40% stock solution of hydrofluoric acid (166 ml) is added. The reaction is stirred at room temperature for 10 minutes and then slowly neutralized with a saturated solution of sodium bicarbonate. The reaction is partitioned between ether (1500 ml) and the aqueous phase extracted with ether (1×1000 ml). The organic layers are combined and the solvent volume is reduced under vacuum. The residue is dried over anhydrous sodium sulfate and the remaining solvent removed leaving a clear, colorless oil. The product is kugelrohred under vacuum leaving a product sufficiently pure for the next reaction (171 g, 1.11 moles).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[NH:8][C:9]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:19][CH:18]=2)=[CH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2].[N+:31]([O-])([OH:33])=[O:32].O>C(OC(=O)C)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:30])=[N:8][C:9]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:19][CH:18]=2)=[C:10]([N+:31]([O-:33])=[O:32])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1cc(-c2ccc(OCOCCOC)cc2)[nH]c(=O)c1C(=O)OCC
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1c(O)nc(-c2ccc(OCOCCOC)cc2)c([N+](=O)[O-])c1C(=O)OCC
Temperature: -20 °C
Reaction time: 1 h

Procedure:
In 3 ml of acetic anhydride was dissolved 1.0 g of 3,4-diethoxycarbonyl-6-(4-methoxyethoxymethoxyphenyl)-2-pyridone, and the mixture was cooled to -20° C. and thereafter 0.2 ml of fuming nitric acid was added dropwise. After the mixture was stirred for 1 hour, water was added. After 2 hours' stirring at room temperature, the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium hydrogencarbonate, water and a saturated aqueous solution of sodium chloride, and dried. After the solvent was distilled off the resulting crystals were collected by filtration with diethyl ether.
Reaction SMILES: OO.[NH2:3][C:4]1([CH2:18][NH:19][C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH2:8][CH2:7][N:6]([C:9]2[C:14]([C:15]#[N:16])=[C:13]([NH2:17])[N:12]=[CH:11][N:10]=2)[CH2:5]1.C(=O)([O-])[O-:31].[K+].[K+]>CS(C)=O>[NH2:17][C:13]1[C:14]([C:15]([NH2:16])=[O:31])=[C:9]([N:6]2[CH2:7][CH2:8][C:4]([NH2:3])([CH2:18][NH:19][C:20](=[O:29])[C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])[CH2:5]2)[N:10]=[CH:11][N:12]=1
Reactant: N#Cc1c(N)ncnc1N1CCC(N)(CNC(=O)c2ccc(F)cc2F)C1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1c(N)ncnc1N1CCC(N)(CNC(=O)c2ccc(F)cc2F)C1
Temperature: 40 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
Hydrogen peroxide (0.38 ml; 4.29 mmol; 40.0 eq.) was added dropwise to the mixture of N-{[3-amino-1-(6-amino-5-cyanopyrimidin-4-yl)pyrrolidin-3-yl]methyl}-2,4-difluorobenzamide (40.0 mg; 0.11 mmol; 1.0 eq.) and potassium carbonate (118.45 mg; 0.86 mmol; 8.0 eq.) in DMSO (3.0 ml) at room temperature. The resulting mixture was then stirred at 40° C. for 2 hours. The reaction mixture was workup and the crude was purified by reverse phase chromatography (Yamazen, acetonitrile/0.1% NH4OH in water) to yield the title compound in 40% yield. LC-MS: (M+1=392, obsd.=392).