Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:23]=[CH:22][C:10]([C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=2)=[O:12])=[CH:9][CH:8]=1.C(O)(=O)[CH2:27][C:28]([OH:30])=[O:29].N1C=CC=CC=1.N1CCCCC1.Cl>>[F:25][C:2]([F:24])([F:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:23]=[CH:22][C:10]([C:11]([O:13][C:14]2[CH:15]=[CH:16][C:17](/[CH:20]=[CH:27]/[C:28]([OH:30])=[O:29])=[CH:18][CH:19]=2)=[O:12])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(OC(=O)c2ccc(OCCCC(F)(F)F)cc2)cc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)/C=C/c1ccc(OC(=O)c2ccc(OCCCC(F)(F)F)cc2)cc1
Reaction time: 0.25 h
Yield: 92.9 %

Procedure:
5.00 g (14.2 mMol) of 4-formylphenyl 4-(4,4,4-trifluorobutoxy)benzoate and 3.00 g (28.4 mMol) of Malonic acid are dissolved in 18 ml (227.1 mMol) of Pyridin.1.21 g (14.2 mMol) of Piperidin are added to the suspension which is allowed to react at 100° C. under argon for 1.5 h. The yellow solution is then thrown on ice. The solution is carefully acidified to pH=1-2 with a 25% HCl solution and is stirred for 15 min. The product is filtrated off and dried at room temperature under vacuum for 10 h to give 5.2 g of (2E)-3-(4-{[4-(4,4,4-trifluorobutoxy)benzoyl]oxy}phenyl)acrylic acid as white powder.
Reaction SMILES: C([Li])(C)(C)C.[C:6]([O:10][C:11](=[O:22])[NH:12][CH:13]([C:15]1[CH:16]=[N:17][C:18]([Cl:21])=[CH:19][CH:20]=1)[CH3:14])([CH3:9])([CH3:8])[CH3:7].[I:23]I>C1COCC1>[C:6]([O:10][C:11](=[O:22])[NH:12][CH:13]([C:15]1[CH:16]=[N:17][C:18]([Cl:21])=[CH:19][C:20]=1[I:23])[CH3:14])([CH3:7])([CH3:8])[CH3:9]
Reactant: II
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Cl)nc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(NC(=O)OC(C)(C)C)c1cnc(Cl)cc1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.2 %

Procedure:
Add tert-butyllithium (35 mL, 59.6 mmol) to a solution of [1-(6-chloro-pyridin-3-yl)-ethyl]-carbamic acid tert-butyl ester (5.1 g, 19.87 mmol) in THF (60 mL) under N2 at −78° C. After 30 min, add iodine (7.6 g, 29.8 mmol) in THF (20 mL) over 30 min at −78° C. Stir for 1 hour and then warm up to room temperature. Quench with water, extract in ethyl acetate with saturated aqueous sodium chloride, dry over Na2SO4. Purify on column chromatography 5% to 20% ethyl acetate in hexanes to obtain product (1 g). MS (ES) m/z 383 [M+1]+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12](C2C=C3C(C(C4C=CC5C(=CC=CC=5)C=4)=NN3S(C3C(C)=CC(C)=CC=3C)(=O)=O)=CC=2)=[CH:11][C:10]=1[O:46][CH3:47])C1C=CC=CC=1.C(OC1C=CC([C:62]2[CH:70]=[C:69]3[C:65]([C:66]([C:71]4[CH:80]=[CH:79][C:78]5[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=5)[CH:72]=4)=[N:67][NH:68]3)=[CH:64][CH:63]=2)=CC=1OC)C1C=CC=CC=1>C(OCC)(=O)C.CCCCCC>[CH:72]1[C:73]2[C:78](=[CH:77][CH:76]=[CH:75][CH:74]=2)[CH:79]=[CH:80][C:71]=1[C:66]1[C:65]2[C:69](=[CH:70][CH:62]=[CH:63][CH:64]=2)[N:68]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([O:46][CH3:47])[CH:11]=2)[N:67]=1
Reactant: COc1cc(-c2ccc3c(-c4ccc5ccccc5c4)nn(S(=O)(=O)c4c(C)cc(C)cc4C)c3c2)ccc1OCc1ccccc1
Reactant: COc1cc(-c2ccc3c(-c4ccc5ccccc5c4)n[nH]c3c2)ccc1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(-n2nc(-c3ccc4ccccc4c3)c3ccccc32)ccc1O

Procedure:
6-(4-Benzyloxy-3-methoxy-phenyl)-3-naphthalen-2-yl-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole was converted to 6-(4-benzyloxy-3-methoxy-phenyl)-3-naphthalen-2-yl-1H-indazole as described in Example 1(a), step (ix). Rf sm 0.40, p 0.17 (ethyl acetate-hexane 3:7); 1H NMR (CDCl3) δ 8.40 (s, 1H), 8.12 (d, 1H, J=8.5 Hz), 8.10 (dd, 1H, J=1.6, 8.4 Hz), 7.93 (d, 1H, J=8.3 Hz), 7.88 (m, 2H), 7.61 (m, 1H) 7.56 (s, 1H), 7.43 (m, 5H), 7.30 (m 3H), 7.15 (d, 1H, J=2.0 Hz), 7.08 (dd, 1H, J=2.1, 8.3 Hz), 6.91 (d, 1H, J=8.3 Hz), 5.16 (s, 2H), 3.91 (s, 3H).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][C@@H:19]2[CH2:21][C@H:16]1[CH2:17][N:18]2[S:22]([CH3:25])(=[O:24])=[O:23])=O)(C)(C)C>C(Cl)Cl>[CH3:25][S:22]([N:18]1[CH2:17][C@@H:16]2[CH2:21][C@H:19]1[CH2:20][NH:15]2)(=[O:23])=[O:24]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2S(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N1C[C@@H]2C[C@H]1CN2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Methanesulfonyl chloride (120 μL, 1.55 mmol) and DIPEA (187 μL, 1.07 mmol) were added to a solution of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (200 mg, 1.01 mmol) in DCM (20 mL) and the reaction mixture stirred at ambient temperature for 17 h, then partitioned between EtOAc and water. The organic layer was separated and washed with brine, then dried (MgSO4) and concentrated in vacuo to give (1S,4S)-5-methanesulfonyl-2,5-diazabicyclo[2.2.1]-heptane-2-carboxylic acid tert-butyl ester. TFA (3 mL) was added to a solution of (1S,4S)-5-methanesulfonyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester in DCM (10 mL) and the mixture stirred at ambient temperature for 30 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g); the cartridge was washed with MeOH before the desired product was eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a white solid (170 mg, 96%). 1H NMR (CDCl3, 400 MHz) δ 4.37 (d, J=2.0 Hz, 1H); 3.83 (d, J=2.0 Hz, 1H); 3.41 (dd, J=9.2, 2.19 Hz, 1H); 3.25 (d, J=9.2 Hz, 1H); 3.20 (d, J=10.3 Hz, 1H); 3.01 (dd, J=10.3, 2.14 Hz, 1H); 2.89 (s, 3H); and 1.79 (bs, 2H)
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][CH:13]=[C:12]2Cl)C1C=CC=CC=1>C(N(CC)CC)C.CN(C)C=O.[OH-].[Pd+2].[OH-]>[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][CH:13]=[CH:12]2
Reactant: COc1cc2nccc(Cl)c2cc1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc2ncccc2cc1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.1 %

Procedure:
6-Benzyloxy-4-chloro-7-methoxy-quinoline (525 mg) was dissolved in triethylamine/N,N-dimethylformamide (5 ml/20 ml) to prepare a solution. 20% palladium hydroxide (1.52 g) was added to the solution, and the mixture was stirred at room temperature under a hydrogen gas atmosphere for 6 hr. The reaction solution was filtered, and the solvent was then removed by distillation under the reduced pressure. Water was added to the residue, the mixture was extracted with chloroform, and the chloroform layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give 6-hydroxy-7-methoxyquinoline (258 mg, yield 84%).
Reaction SMILES: [NH2:1][CH:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])[OH:4].[F:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[CH:3]([OH:4])[CH:2]([NH:1][C:35]([C:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25]([F:24])=[CH:26][CH:27]=1)=[O:36])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1F)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(2,4-difluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (400 mg, 1.21 mmol) in acetonitrile (30 ml) were added 4-fluoronaphthalenecarboxylic acid (230 mg, 1.21 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (347 mg, 1.81 mmol) and 1-hydroxy-1H-benzotriazole (185 mg, 1.21 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (538 mg, 89%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH3:10]O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: CO
Reactant: O=C(O)CCCCCBr
Product: COC(=O)CCCCCBr
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a 1 L round bottom flask, charged with 20 g (102.5 mmol) of 6-bromohexanoic acid and 500 mL of methanol, was bubbled hydrogen chloride gas for 2-3 minutes. The mixture was stirred at room temperature for 4 hours and concentrated to afford 21.0 g of the product as a yellow oil (99%): 1H-NMR (200 MHz, d6-DMSO); 3.57 (s, 3H), 3.51 (t, 2H), 2.30 (t, 2H), 1.78 (pentet, 2H), and 1.62-1.27 (m, 4H) ppm.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([N:13]([CH3:33])[C:14](=[O:32])[C:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=3)([CH3:17])[CH3:16])=[C:9]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[CH3:41])[CH:8]=2)[CH2:3]1.C(N(CC)C(C)C)(C)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53]>ClCCl.CN(C1C=CN=CC=1)C>[F:27][C:24]([F:25])([F:26])[C:22]1[CH:23]=[C:18]([C:15]([CH3:16])([CH3:17])[C:14]([N:13]([C:10]2[CH:11]=[N:12][C:7]([N:4]3[CH2:5][CH2:6][C@H:2]([NH:1][S:52]([CH3:51])(=[O:54])=[O:53])[CH2:3]3)=[CH:8][C:9]=2[C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[CH3:41])[CH3:33])=[O:32])[CH:19]=[C:20]([C:28]([F:29])([F:30])[F:31])[CH:21]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(F)ccc1-c1cc(N2CC[C@H](N)C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1cc(N2CC[C@H](NS(C)(=O)=O)C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.3 %

Procedure:
To a solution of 600 mg (1.03 mmol) (S)—N-[6-(3-amino-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide in 6 ml dichloromethane were added 6 mg (0.05 mmol) 4-(N,N-dimethylamino)pyridine, 266 mg (2.06 mmol) N,N-diisopropylethylamine and 153 mg (1.34 mmol) methanesulfonyl chloride. After stirring at room temperature for 18 h the reaction mixture was diluted with 20 ml dichloromethane and washed with 20 ml of a saturated aqueous solution of sodium carbonate. The combined organic layers were dried over sodium sulfate, concentrated and purified by flash chromatography to give 553 mg (81%) of the title compound as an off-white foam.
Reaction SMILES: C(O)C.[F:4][C:5]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]1)[CH2:9]2.[H][H]>[C].[Pd].C(OCC)(=O)C>[F:4][C:5]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[C:10]2[C:6]=1[CH2:7][CH:8]([C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]1)[CH2:9]2
Reactant: [H][H]
Reactant: CCC[C@H]1CC[C@H](C2=Cc3c(cc(F)c(F)c3F)C2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCC[C@H]1CC[C@H](C2Cc3cc(F)c(F)c(F)c3C2)CC1

Procedure:
Ethanol (70 ml), ethyl acetate (30 ml) and 5% palladium-carbon (450 mg) were added to 4,5,6-trifluoro-2-(trans-4-propylcyclohexyl)indene (4.5 g), and stirred for 1 hour in a hydrogen atmosphere. The reaction solution was filtered with celite, the filtrate was concentrated, and the residue was purified with a silica gel short column (hexane) to obtain 4,5,6-trifluoro-2-(trans-4-propylcyclohexyl)indane (4.5 g). Moreover, this was then recrystallized from ethanol to obtain 4,5,6-trifluoro-2-(trans-4-propylcyclohexyl)indane (4.5 g, purity: 99.8%). The melting point of this compound was 52° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:21]2[CH2:26][CH2:25][O:24][C:23]3[CH:27]=[C:28]([S:31](=[O:48])(=[O:47])[N:32](CC4C=CC(OC)=CC=4)[C:33]4[S:34][CH:35]=[CH:36][N:37]=4)[CH:29]=[CH:30][C:22]2=3)=[C:6]([C:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH:9]=2)[CH:7]=1.N(OC(C)(C)C)=O.[N:56]([Si](C)(C)C)=[N+:57]=[N-].[C:63]([OH:69])([C:65]([F:68])([F:67])[F:66])=[O:64]>C(#N)C>[F:66][C:65]([F:68])([F:67])[C:63]([OH:69])=[O:64].[F:66][C:65]([F:68])([F:67])[C:63]([OH:69])=[O:64].[N:1]([C:2]1[CH:3]=[CH:4][C:5]([N:21]2[CH2:26][CH2:25][O:24][C:23]3[CH:27]=[C:28]([S:31]([NH:32][C:33]4[S:34][CH:35]=[CH:36][N:37]=4)(=[O:48])=[O:47])[CH:29]=[CH:30][C:22]2=3)=[C:6]([C:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]=2)[CH:7]=1)=[N+:56]=[N-:57]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccc(N)cc2C2=CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)(C)ON=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: [N-]=[N+]=Nc1ccc(N2CCOc3cc(S(=O)(=O)Nc4nccs4)ccc32)c(C2=CCNCC2)c1
Reaction time: 0.33 h
Yield: 25.7 %

Procedure:
To a solution of tert-butyl 4-(5-amino-2-(7-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (0.105 g, 0.152 mmol) in dry acetonitrile (1.522 mL) at 0° C. was added tert-butyl nitrite (0.026 mL, 0.213 mmol) followed by dropwise addition of azidotrimethylsilane (0.024 mL, 0.183 mmol). The resulting mixture was stirred for 20 minutes, at which time no conversion to the desired was observed. Additional tert-butyl nitrite (0.052 mL) and azidotrimethylsilane (0.048 mL) were added at 0° C. and the reaction was once again stirred at RT for 1 h. Conversion was observed, but starting material was still the major reaction component, so the reaction was recooled to 0° C. and 0.156 mL of t-Bu nitrite was added, followed by dropwise addition of 0.144 mL of TMS-azide. After 20 minutes at RT, the reaction was complete and was concentrated under a vacuum. DCM (1.0 mL) was added, followed by TFA (0.235 mL, 3.04 mmol), and the reaction was stirred at RT for 1 h. The material was concentrated under a vacuum and purified by reverse-phase preparative HPLC using a Phenomenex Luna column, 5 micron, C18(2), 100 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 25% to 90% over 20 min to provide 4-(4-azido-2-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide bis(2,2,2-trifluoroacetate) (0.028 g, 0.039 mmol) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.30-2.44 (m, 2 H) 3.19 (m, J=5.20 Hz, 2 H) 3.47-3.56 (m, 2 H) 3.62-3.70 (m, 2 H) 4.29 (t, J=4.25 Hz, 2 H) 5.76-5.83 (m, 1 H) 6.29 (d, J=8.31 Hz, 1 H) 6.79 (d, J=4.50 Hz, 1 H) 7.02 (d, J=2.74 Hz, 1 H) 7.08-7.15 (m, 2 H) 7.17 (dd, J=8.56, 2.69 Hz, 1 H) 7.22 (d, J=4.60 Hz, 1 H) 7.38 (d, J=8.51 Hz, 1 H) 8.76 (br. s., 2 H) 12.53 (br. s., 1H); m/z (ESI) 496.0 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:18]([O-:20])=[O:19])[S:9][C:6]2=[N:7][CH:8]=1.[C:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(N(CC)CC)C>C(#N)C>[N+:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[S:9][C:6]2[C:5]([N:11]=1)=[CH:4][C:3]([CH2:2][N:31]1[CH2:30][CH2:29][N:28]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:33][CH2:32]1)=[CH:8][N:7]=2)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccccc1-c1nc2cc(CBr)cnc2s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(Cc2cnc3sc(-c4ccccc4[N+](=O)[O-])nc3c2)CC1
Yield: 74 %

Procedure:
A solution of crude 6-(bromomethyl)-2-(2-nitrophenyl)thiazolo[5,4-b]pyridine (4.0 g), Boc-piperazine (1.99 g, 10.7 mmol), triethylamine (Et3N) (1.5 mL, 10.7 mmol) and acetonitrile (100 mL) was stirred at 50° C. (4 h) and then at room temperature (60 h). TLC demonstrated that the reaction was complete. The mixture was concentrated in vacuo and purified by silica gel chromatography (petroleum ether:ethyl acetate:Et3N=100:10:1) to afford tert-butyl 4-((2-(2-nitrophenyl)thiazolo[5,4-b]pyridin-6-yl)methyl)piperazine-1-carboxylate as a yellow solid (3.6 g, yield: 74% over 2 steps).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([CH3:36])=[C:8]([NH:14][C:15]([C:17]2[S:18][CH:19]=[CH:20][C:21]=2[S:22]([N:25]([C:29]2[O:33][N:32]=[C:31]([CH3:34])[C:30]=2[CH3:35])COC)(=[O:24])=[O:23])=[O:16])[C:9]([CH3:13])=[CH:10][C:11]=1[CH3:12])(=[O:3])[CH3:2]>C(O)(=O)C.O.S(=O)(=O)(O)O>[C:1]([O:4][CH2:5][C:6]1[C:7]([CH3:36])=[C:8]([NH:14][C:15]([C:17]2[S:18][CH:19]=[CH:20][C:21]=2[S:22](=[O:24])(=[O:23])[NH:25][C:29]2[O:33][N:32]=[C:31]([CH3:34])[C:30]=2[CH3:35])=[O:16])[C:9]([CH3:13])=[CH:10][C:11]=1[CH3:12])(=[O:3])[CH3:2]
Reactant: COCN(c1onc(C)c1C)S(=O)(=O)c1ccsc1C(=O)Nc1c(C)cc(C)c(COC(C)=O)c1C
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OCc1c(C)cc(C)c(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2C)c1C
Temperature: 80 °C
Yield: 27.9 %

Procedure:
To a solution of N2-(3-acetoxymethyl-2,4,6-trimethylphenyl)-3-[N-(3,4-dimethylisoxazol-5-yl)-N-methoxymethylaminosulfonyl]-2-thiophenecarboxamide (0.78 g, 1.46 mmol) in acetic acid (7 mL) and water (3 mL) was added 2 N sulfuric acid (3 drops). The reaction was heated at 80° C. for 4 hours, then allowed to cool to room temperature. The mixture was poured into ice water (50 mL), extracted with ethyl acetate (3×50 mL), washed with saturated sodium chloride (50 mL), dried (MgSO4), then concentrated. The residue was purified by reverse-phase HPLC (20-80% acetonitrile in water) which gave N2-(3-acetoxymethyl-2,4,6-trimethylphenyl)-3-[(3,4-dimethyl-5-isoxazolyl)sulfamoyl]-2-thiophenecarboxamide (0.2 g, 28%) as an off-white powder, mp 75-77° C. 1H NMR (400 MHZ, DMSO-d6) δ7.85 (d, J=5.12 Hz, 1H), 7.34 (d, J=5.12 Hz, 1H), 7.00 (s, 1H), 5.12 (s, 2H), 2.30 (s, 3H), 2.20 (s, 3H), 2.17 (s, 3H), 2.07 (s, 3H), 2.02 (s, 3H), 1.65 (s, 3H) ppm. IR (KBr) 3458, 1738, 1646, 1356, 1181 cm−1. And N2-(3-hydroxymethyl-2,4,6-trimethylphenyl)-3-[(3,4-dimethyl-5-isoxazolyl)sulfamoyl]-2-thiophenecarboxamide (45 mg, 6.9%), ratio 4:1 respectively, as a white powder, mp 100-115° C. 1H NMR (400 MHZ, DMSO-d6) δ7.84 (3, J=5.12 Hz, 1H), 7.34 (d, J=5.16 Hz, 1H), 6.92 (s, 1H), 4.48 (s, 2H), 2.33 (s, 3H), 2.23 (s, 3H), 2.14 (s, 3H), 2.07 (s, 3H), 1.65 (s, 3H). IR (KBr) 3439, 1651, 1341, 1181 cm−1.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:21]([NH2:23])=[N:20][CH:19]=[N:18][C:17]=3[NH:16][CH:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:26]([S:29](Cl)(=[O:31])=[O:30])([CH3:28])[CH3:27].O>CN(C)C=O>[CH:26]([S:29]([N:16]1[C:17]2[N:18]=[CH:19][N:20]=[C:21]([NH2:23])[C:22]=2[C:14]([C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:12]=2)=[CH:15]1)(=[O:31])=[O:30])([CH3:28])[CH3:27]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)n1cc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21

Procedure:
5-(4-Phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (1.57 g) was dissolved in dry dimethylformamide (30 ml) and then sodium hydride (0.22 g of a 60% dispersion in mineral oil) was added with stirring. The mixture was stirred for 30 minutes and then isopropylsulphonyl chloride (0.74 g) was added and the mixture was stirred at ambient temperature for 18 hours. Water was added to the mixture until no further precipitation occurred. The solid was collected by filtration and purified by flash column chromatography on silica using dichloromethane/methanol (9:1) as the mobile phase to give a solid which was further purified by flash column chromatography on silica using ethyl acetate as the mobile phase to give 7-isopropylsulphonyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, m.p. 162-162.5° C.
Reaction SMILES: [N:1]([C:4]1[S:8][C:7]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:6]=2[C:5]=1[C:14]([O:16]C)=O)=[C:2]=[S:3].[CH3:18][C:19]1[N:23]([CH2:24][CH2:25][CH2:26][NH2:27])[CH:22]=[N:21][CH:20]=1>>[CH3:18][C:19]1[N:23]([CH2:24][CH2:25][CH2:26][N:27]2[C:14](=[O:16])[C:5]3[C:6]4[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:7]=4[S:8][C:4]=3[NH:1][C:2]2=[S:3])[CH:22]=[N:21][CH:20]=1
Reactant: Cc1cncn1CCCN
Reactant: COC(=O)c1c(N=C=S)sc2c1CCCCC2
Product: Cc1cncn1CCCn1c(=S)[nH]c2sc3c(c2c1=O)CCCCC3

Procedure:
The compound was synthesized starting from methyl 5,6,7,8-tetrahydro-2-isothiocyanato-4H-cyclohepta[b]thiophene-3-carboxylate (0.10 g, 0.37 mmol) and 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (5) (0.052 g, 0.37 mmol) as described above.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16].O>CN(C)C=O>[F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[N:4]=[CH:14][N:15]([CH3:17])[CH3:16]
Reactant: Nc1ccc([N+](=O)[O-])cc1F
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C=Nc1ccc([N+](=O)[O-])cc1F
Reaction time: 1.5 h
Yield: 85 %

Procedure:
5 g of 2-fluoro-4-nitroaniline were dissolved in 35 ml of dry dimethylformamide, admixed at room temperature with 19.90 g of dimethylformamide dimethyl acetal and stirred for 90 min. For workup, 250 ml of water were added to the reaction mixture, and the precipitate was filtered off with suction, washed with water and dried. N′-(2-Fluoro-4-nitrophenyl)-N,N-dimethylformamidine was obtained in a yield of 85%. Molecular weight 211.07 (C9H10FN3O2); retention time Rt=0.49 min. [B]; MS (ESI):
Reaction SMILES: C(C1N(CC2C=CC=CC=2Cl)[C:7](/C=C(\CC2SC=CC=2)/C(O)=O)=[C:8]([CH2:10][OH:11])N=1)CCC.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][OH:38])=[CH:35][CH:34]=1>>[C:10]([O:38][CH2:37][C:36]1[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[CH:34][CH:35]=1)(=[O:11])[CH:8]=[CH2:7]
Reactant: CCCCc1nc(CO)c(/C=C(\Cc2cccs2)C(=O)O)n1Cc1ccccc1Cl
Reactant: COc1ccc(CO)cc1
Product: C=CC(=O)OCc1ccc(OC)cc1

Procedure:
(E)-3-[2-n-Butyl-1-[(2-chlorophenyl)methyl]-4-hydroxymethyl-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoic acid, prepared as in Example 19, is esterified with 4-methoxy-benzyl alcohol to give the p-methoxybenzyl propenoate. The 4-hydroxymethyl group in acetone is oxidized using an acidic aqueous solution containing chromic acid (Jones' reagent) and the ester is hydrolyzed using 10% sodium hydroxide to give the title compound.
Reaction SMILES: C[Si](C)(C)CC[O:5][C:6]([CH:8]=[CH:9][C:10](Cl)=[O:11])=[O:7].[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]([NH2:27])=[O:26])[C:20](=[O:28])[C:19]2=[C:29]([OH:35])[C:30]1[S:31][CH:32]=[CH:33][CH:34]=1.C(N(C(C)C)CC)(C)C>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]([NH2:27])=[O:26])[C:20](=[O:28])[C:19]2=[C:29]([O:35][C:10](=[O:11])[CH:9]=[CH:8][C:6]([OH:7])=[O:5])[C:30]1[S:31][CH:32]=[CH:33][CH:34]=1
Reactant: NC(=O)N1C(=O)C(=C(O)c2cccs2)c2cc(Cl)ccc21
Reactant: C[Si](C)(C)CCOC(=O)C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)N1C(=O)C(=C(OC(=O)C=CC(=O)O)c2cccs2)c2cc(Cl)ccc21

Procedure:
The title compound was prepared by the procedure of Example 1 with the exception the 3-(2-trimethylsilylethyloxycarbonyl)propenoyl chloride (1.3 equiv.), 5-chloro-2,3-dihydro-3-[hydroxy-(2-thienyl)methylene]-2-oxo-1H-indole-1-carboxamide and diisopropylethylamine were used. The crude product was purified by flash chromatography (using 98:2 CH2Cl2 /EtOAc as eluant) followed by recrystallization from acetonitrile.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[C:12]([CH3:20])[CH:11]=2)[CH:2]=1.[CH2:21]([N:23]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][C:28]=1[C:34]([F:37])([F:36])[F:35])[CH2:24][CH3:25])[CH3:22]>C(Cl)Cl.CO>[CH2:21]([N:23]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:17](=[O:19])[CH2:16][C:13]2[CH:14]=[CH:15][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:11][C:12]=2[CH3:20])=[CH:29][C:28]=1[C:34]([F:35])([F:36])[F:37])[CH2:24][CH3:25])[CH3:22]
Reactant: Cc1cc(-n2cnc3cccnc32)ccc1CC(=O)O
Reactant: CCN(CC)Cc1ccc(N)cc1C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)Cc1ccc(NC(=O)Cc2ccc(-n3cnc4cccnc43)cc2C)cc1C(F)(F)F

Procedure:
The title compound is prepared as described in Example 7 but using (4-imidazo[4,5-b]pyridin-3-yl-2-methyl-phenyl)-acetic acid and 4-diethylaminomethyl-3-trifluoromethyl-phenylamine (disclosed in WO2005/051366). Title compound: ES-MS: 496.0 [M+H]+; tR=3.31 min (System 1); Rf=0.43 (CH2Cl2/MeOH, 95:5+0.1% NH3aq).