Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:13])[CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:3].[SH2:14]>C(O)C>[CH2:2]([O:4][C:5](=[O:13])[CH2:6][CH:7]([SH:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:3]
Reactant: S
Reactant: CCCCCC=CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCCCCC(S)CC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.2 g of sodium are dissolved in 10 ml of absolute ethyl alcohol. After completed alcoholate-formation, 5 g of 2-octenoic acid ethyl ester are added and the solution is cooled to -70°. At this temperature, 10 ml of hydrogen sulphide are condensed into the solution. Subsequently, the whole mixture is immediately transferred into an autoclave, pre-cooled to about -30°, and left by itself overnight at room temperature in the sealed pressure vessel. On the next morning, the autoclave is heated at 50° for a further 2 hours. After cooling to room temperature, the excess hydrogen sulphide is vented off, the reaction product washed with saturated common salt solution, dried and distilled. There are obtained 1.6 g of 3-mercapto-octanoic acid ethyl ester of boiling point 74°/0.4 mm Hg, nD20 1.4538.
Reaction SMILES: [CH2:1]([C:4]1[S:8][C:7]([CH2:9][O:10][C:11]2[C:12]([F:21])=[C:13]([C:17]([F:20])=[CH:18][CH:19]=2)[C:14]([NH2:16])=[O:15])=[N:6][C:5]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[CH:2]=[CH2:3]>CO>[F:21][C:12]1[C:11]([O:10][CH2:9][C:7]2[S:8][C:4]([CH2:1][CH2:2][CH3:3])=[C:5]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[N:6]=2)=[CH:19][CH:18]=[C:17]([F:20])[C:13]=1[C:14]([NH2:16])=[O:15]
Reactant: C=CCc1sc(COc2ccc(F)c(C(N)=O)c2F)nc1-c1ccc(OC)cc1
Solvent: CO
Product: CCCc1sc(COc2ccc(F)c(C(N)=O)c2F)nc1-c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 239 %

Procedure:
To a solution of 3-[5-allyl-4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide (0.1 g, 0.02 mmol) in 5 ml of anhydrous methanol was added dry 50 mg of dry Pd—C. The reaction mixture was stirred at 25° C. for 12 h under hydrogen atmosphere. The reaction mixture was filtered over the bed of celite. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400μ) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.02 g, 2%). 1H NMR (DMSO-d6, 400 MHz); δ 0.92 (t, 3H, J=7.2 Hz), 1.63-1.65 (m, 2H), 2.8 (t, 2H, J=7.6 Hz (o-coupling), 3.79 (s, 3H), 5.47 (s, 2H), 7.02 (d, 2H, J=8.8 Hz (o-coupling), 7.11 (m, 1H), 7.42 (m, 1H), 7.53 (d, 2H, J=8.8 Hz (o-coupling), 7.88 (s, 1H), 8.16 (s, 1H), 8.38 (d, 1H, J=8.4 Hz (o-coupling). MS ES+ (419.14), HPLC (method 5) Rt=16.58
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([NH:20][C:21]([NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=S)[NH:17][N:16]=2)=[C:11]([F:36])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[CH:48]1([NH2:53])[CH2:52][CH2:51][CH2:50][CH2:49]1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([NH:20][C:21]([NH:53][CH:48]3[CH2:52][CH2:51][CH2:50][CH2:49]3)=[N:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[NH:17][N:16]=2)=[C:11]([F:36])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC(=S)Nc1cc(-c2ccc(OCc3ccccc3)cc2F)n[nH]1)c1ccc(C(F)(F)F)cc1
Reactant: NC1CCCC1
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Product: O=C(N=C(Nc1cc(-c2ccc(OCc3ccccc3)cc2F)n[nH]1)NC1CCCC1)c1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 53 %

Procedure:
N-((3-(4-(Benzyloxy)-2-fluorophenyl)-1H-pyrazol-5-yl)carbamothioyl)-4-(trifluoromethyl)benzamide (154 mg, 0.3 mmol) and EDCI (63 mg, 0.33 mmol) were suspended in THF (4 mL) and cyclopentylamine (0.044 mL, 0.45 mmol) was added. The resulting mixture was stirred at 50° C. for 45 minutes, then concentrated onto silica gel and purified by chromatography (gradient: 9:1 hexanes:EtOAc to 6:4 hexanes:EtOAc) to provide the title compound in 53% yield.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[CH2:13]([C:15]1[CH:27]=[C:26]([C:28]2[N:32]=[C:31]([C:33]3[CH:38]=[C:37]([O:39][CH3:40])[N:36]=[C:35]([CH:41]([CH2:44][CH3:45])[CH2:42][CH3:43])[CH:34]=3)[O:30][N:29]=2)[CH:25]=[C:24]([CH3:46])[C:16]=1[O:17][CH2:18][C@@H:19]([OH:23])[CH2:20][NH:21][CH3:22])[CH3:14].[C:47]([OH:51])(=O)[CH2:48][OH:49].C1C=CC2N(O)N=NC=2C=1>C1COCC1>[CH2:13]([C:15]1[CH:27]=[C:26]([C:28]2[N:32]=[C:31]([C:33]3[CH:38]=[C:37]([O:39][CH3:40])[N:36]=[C:35]([CH:41]([CH2:44][CH3:45])[CH2:42][CH3:43])[CH:34]=3)[O:30][N:29]=2)[CH:25]=[C:24]([CH3:46])[C:16]=1[O:17][CH2:18][C@@H:19]([OH:23])[CH2:20][N:21]([CH3:22])[C:47](=[O:51])[CH2:48][OH:49])[CH3:14]
Reactant: O=C(O)CO
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C(CC)CC)c3)n2)cc(C)c1OC[C@@H](O)CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C(CC)CC)c3)n2)cc(C)c1OC[C@@H](O)CN(C)C(=O)CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.1 %

Procedure:
EDC hydrochloride (144 mg, 753 μmol) is added to a stirred solution of (2S)-1-(2-ethyl-4-{5-[2-(1-ethyl-propyl)-6-methoxy-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenoxy)-3-methylamino-propan-2-ol (294 mg, 627 μmol), glycolic acid (57 mg, 753 μmol) and HOBt (101 mg, 753 μmol) in THF (10 mL). The mixture is stirred at rt for 2 h before it is concentrated. The crude product is purified by prep. HPLC, then on prep. TLC plates using DCM containing 10% of 7 N NH3 in methanol to give the title compound (149 mg) as a white solid; LC-MS: tR=1.14 min, [M+H]+=527.17; 1H NMR (CDCl3): δ0.84 (t, J=7.5 Hz, 6H), 1.33 (t, J=7.5 Hz, 3H), 1.69-1.88 (m, 4H), 2.40 (s, 3H), 2.57-2.66 (m, 1H), 2.76 (q, J=7.5 Hz, 2H), 3.10 (s, 3H), 3.76 (d, J=5.3 Hz, 2H), 3.80-3.88 (m, 1H), 3.89-3.94 (m, 1H), 4.02 (s, 3H), 4.25 (s, 2H), 4.28-4.36 (m, 1H), 7.33 (s, 1H), 7.45 (s, 1H), 7.88 (s, 1H), 7.89 (s, 1H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]1[N:12]=[C:11]([CH2:13][O:14][C:15]2[CH:32]=[CH:31][C:18]([CH2:19][N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:30])=[CH:17][CH:16]=2)[O:10][N:9]=1.[NH:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1[S:42](Cl)(=[O:44])=[O:43]>>[NH:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1[S:42]([N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]1[N:12]=[C:11]([CH2:13][O:14][C:15]2[CH:32]=[CH:31][C:18]([CH2:19][N:20]3[C:21](=[O:30])[C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:28]3=[O:29])=[CH:17][CH:16]=2)[O:10][N:9]=1)(=[O:43])=[O:44]
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(OCc2nc([C@@H]3CCCCN3)no2)cc1
Reactant: O=S(=O)(Cl)c1nc2ccccc2[nH]1
Agent: Cl
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(OCc2nc([C@@H]3CCCCN3S(=O)(=O)c3nc4ccccc4[nH]3)no2)cc1

Procedure:
The title compound was prepared by a similar method to Example 1 from 2-[4-(3-[(2S)-2-piperidyl]-1,2,4-oxadiazol-5-ylmethoxy)benzyl]-1,3-isoindolinedione hydrochloride [see Preparation 15] and 1H-benzo[d]imidazole-2-sulfonyl chloride [see Preparation 8] to afford 2-[4-(3-[(2S)-1-(1H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]-1,2,4-oxadiazol-5-ylmethoxy)benzyl]-1,3-isoindolinedione (956 mg).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]([F:33])([F:32])[C:10]1[N:14]2[N:15]=[C:16]([N:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH2:17][CH2:18][C:13]2=[N:12][N:11]=1>C(Cl)Cl>[N:19]1([C:16]2[CH2:17][CH2:18][C:13]3[N:14]([C:10]([C:9]([F:8])([F:32])[F:33])=[N:11][N:12]=3)[N:15]=2)[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2=Nn3c(nnc3C(F)(F)F)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1nnc2n1N=C(N1CCNCC1)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
TFA (5 mL) was added to tert-butyl 4-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazine-1-carboxylate (1.88 g, 5.02 mmol) in DCM (5 mL). The resulting solution was stirred at ambient temperature for 30 minutes then added to a SCX column. The desired product was eluted from the column using 2M ammonia in methanol and the solvents were evaporated to dryness to give 6-(piperazin-1-yl)-3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine (1.360 g, 99%) as a solid.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][OH:7])[CH:2]=[CH2:3].[H-].[Na+].Br[CH2:11][C:12]([O:14][CH3:15])=[O:13]>C1COCC1>[CH3:15][O:14][C:12](=[O:13])[CH2:11][O:7][CH2:6][CH2:5][O:4][CH2:1][CH:2]=[CH2:3]
Reactant: COC(=O)CBr
Reactant: C=CCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOCCOCC(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 56.1 %

Procedure:
To a stirred solution of 2-allyloxy-ethanol 7 (10.9 mL, 100 mmol, 1.0 equiv.) in THF (200 mL) was carefully added NaH (60%, 4.8 g, 120 mmol, 1.2 equiv.) in small portions at room temperature. The reaction was then refluxed for 1 h (until H2 release ceased) then cooled to 0° C. Methyl bromoacetate (11.4 mL, 120 mmol, 1.2 equiv.) was then added dropwise. After 15 min at 0° C., the reaction was submitted to a EtOAc/H2O extraction. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered then evaporated under reduced pressure. Purification was achieved by Kugelrohr distillation under reduced pressure and provided 9.77 g (55%) of ester (8) as a colorless oil; bp=130-145° C. (water tap vacuum); 1H NMR (400 MHz, CDCl3) δ 5.91 (m, 1H), 5.28 (m, 1H), 4.99 (m, 1H), 4.19 (s, 2H), 4.02 (m, 2H), 3.76 (s, 3H), 3.75 (m, 2H), 3.64 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 171.1, 134.8, 117.3, 72.4, 71.2, 69.7, 68.9, 51.9; IR (neat) 1755 cm−1; HRMS (ESI, m/z) calcd. for C8H15O4 (MH+) 175.0964, found 175.0960.
Reaction SMILES: C([N:4]1[CH2:9][C:8](=[O:10])[NH:7][CH:6]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=2[O:20][CH3:21])[C:5]1=[O:22])(=O)C.O.NN>O1CCCC1>[CH3:21][O:20][C:13]1[C:14]([O:18][CH3:19])=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][CH:6]1[NH:7][C:8](=[O:10])[CH2:9][NH:4][C:5]1=[O:22]
Reactant: COc1cccc(CC2NC(=O)CN(C(C)=O)C2=O)c1OC
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(CC2NC(=O)CNC2=O)c1OC
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
To a suspension of 1-acetyl-3-(2,3-dimethoxybenzyl)-2,5-piperazinedione (2.49 g) in tetrahydrofuran (38 ml) was added hydrazine monohydrate (0.43 ml) at room temperature and the mixture was stirred at the same temperature for 30 minutes. The resulting precipitates were collected by filtration and washed with tetrahydrofuran to give powders of 3-(2,3-dimethoxybenzyl)-2,5-piperazinedione (1.40 g)
Reaction SMILES: [OH:1][C@H:2]([C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH:3]=[CH2:4].C(N(C(C)C)CC)(C)C.[CH3:30][O:31][CH2:32][CH2:33][O:34][CH2:35]Cl>C(Cl)Cl>[CH3:30][O:31][CH2:32][CH2:33][O:34][CH2:35][O:1][C@H:2]([C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)[CH:3]=[CH2:4]
Reactant: COCCOCCl
Reactant: C=C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C[C@H](OCOCCOC)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.1 %

Procedure:
To the resultant compound from Example 6 (2.51 g, 8.84 mmol) in methylene chloride (20 ml) was added diisopropylethylamine (4.60 ml, 26.4 mmol) and methoxyethoxychloromethane (3.00 ml, 26.3 mmol). After stirring at room temperature for 24 h the mixture was concentrated, diluted with ethyl acetate, washed with 0.5M H3PO4, saturated NaHCO3 solution, then brine, dried over Na2SO4, and evaporated. Chromatography on silica gel with ethyl acetate/ hexane mixtures afforded 2.63 g (80%) of the desired product as an oil. EI-MS: M+ =371.
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[BrH:13].N([O-])=O.[Na+]>C(#N)C.O.[Cu]Br>[Br:13][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: Br
Reactant: Nc1ccc2c(c1)C(=O)NCC2
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C1NCCc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a solution of 7-amino-3,4-dihydro-1(2H)-isoquinolinone, (for a synthesis see Girard, Yves; Atkinson, Joseph G.; Belanger, Patrice C.; Fuentes, Jose J.; Rokach, Joshua; Rooney, C. Stanley; Remy, David C.; Hunt, Cecilia A J. Org. Chem. (1983), 48(19), 3220) (0.773 g, 4.772 mmol) in acetonitrile (10 ml) at 0° C. was added 48% aqueous hydrobromic acid (10 ml, precooled to 0° C.). The mixture was stirred at 0° C. for 0.5 h before addition of a solution of sodium nitrite (0.379 g, 5.49 mmol) in water (2 ml) over 0.4 h. The reaction was then stirred at 0° C. for 0.5 h and then copper(I) bromide (0.822 g, 5.726 mmol) was added portionwise over 10 min. The reaction mixture was then warmed to room temperature, stirred at room temperature for 0.5 h and then at 70° C. for 1 h. The reaction mixture was then cooled to 0° C., water (60 ml) was added and the mixture stirred at 0° C. for 1 h before filtering and drying in vacuo. The residue was dissolved in 10% methanol/dichloromethane, dried with magnesium sulphate and evaporated to give the desired product (0.679 g, 63%).
Reaction SMILES: [C:1]([CH2:4][CH:5]([S:15]([OH:18])(=[O:17])=[O:16])[CH2:6][NH:7][C:8](=[O:14])/[CH:9]=[CH:10]\[C:11]([OH:13])=O)([OH:3])=[O:2].CC(N(C)C)=O.C[Si](N[Si](C)(C)C)(C)C>[Cl-].[Cl-].[Zn+2].C1(C)C=CC=CC=1>[O:13]=[C:11]1[CH:10]=[CH:9][C:8](=[O:14])[N:7]1[CH2:6][CH:5]([S:15]([OH:18])(=[O:17])=[O:16])[CH2:4][C:1]([OH:3])=[O:2]
Reactant: O=C(O)/C=C\C(=O)NCC(CC(=O)O)S(=O)(=O)O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: O=C(O)CC(CN1C(=O)C=CC1=O)S(=O)(=O)O
Reaction time: 6 h
Yield: 74.8 %

Procedure:
(Z)-4-(3-carboxy-2-sulfopropylamino)-4-oxobut-2-enoic acid (450 mg, 1.60 mmol) in mixture of 10 ml of dry DMA and 50 ml of dry toluene was heated. After the temperature reached at 80° C., HMDS (hexamethyldisilazane, 1.80 ml, 8.63 mmol,) and ZnCl2 (3.2 ml, 1.0 M in diethyl ether) were added. The mixture was continued heated to 115˜125° C. and toluene was collected through Dean-Stark trap. The reaction mixture was fluxed at 120° C. for 6 h. During this period, 2×20 ml of dry toluene was added to keep the mixture volume around 8˜10 ml. Then the mixture was cooled, 1 ml of 1:10 HCl (conc)/CH3OH was added, evaporated, purified on SiO2 chromatography eluted with 1:5:0.01 CH3OH/CH2Cl2/HAc to afford 315 mg (75%) of the title product. 1H NMR (DMF-d7) 6.96 (s, 2H), 4.04 (dd, 1H, J=4.3, 13.8 Hz), 3.47 (m, 1H), 3.23 (dd, 1H, J=7.4, 14.7 Hz), 2.99 (dd, 1H, J=3.3, 16.8 Hz), 2.35 (dd, 1H, J=8.1, 16.9 Hz); 13C NMR 173.58, 172.18, 135.54, 54.61, 40.24, 32.43, ESI MS m/z−261.70 (M−H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[NH:24][NH2:25]>CN(C=O)C>[C:28]([O:27][C:23]([NH:24][NH:25][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:11]=1[F:10])=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NNC(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 57.3 %

Procedure:
N,N-Diisopropylethylamine (14.1 ml, 0.081 mol) is added to 2-fluoro-4-nitrobenzoic acid (5 g, 0.027 mol) and O-(7-azabenzotriazol-1-yl)-N,N, N,N′-tetramethyluronium hexafluorophosphate (10.8 g, 0.0284 mol) in DMF (100 ml) and the mixture stirred at room temperature for 20 minutes. tert-Butyl carbazate (3.57 g, 0.0270 mol) is added in one portion and the reaction stirred overnight at room temperature. The mixture is concentrated and diluted with water (100 ml). The resulting precipitate is filtered, washed well with water, and dried under vacuum to give the title compound as a white solid (4.63 g, 57%), [M+H]+=300.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[CH:6]=[CH:5]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[F:36][C:37]1[CH:38]=[C:39](O)[CH:40]=[CH:41][CH:42]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:36][C:37]1[CH:42]=[C:41]([CH:40]=[CH:39][CH:38]=1)[O:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[CH:6]=[CH:5]1
Reactant: Oc1cccc(F)c1
Reactant: COC(=O)c1ccc2ccn(CCO)c2c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2ccn(CCOc3cccc(F)c3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.7 %

Procedure:
To a solution of methyl 1-(2-hydroxyethyl)-1H-indole-6-carboxylate (0.14 g, 0.64 mmol) and Ph3P (0.25 mL, 0.96 mmol) and 3-fluorophenol (0.11 g, 0.96 mmol) in THF (10 mL) was added DIAD (0.19 mL, 0.96 mmol). The solution was stirred 1 hr at room temperature, then concentrated and subjected to flash chromatography (25% ethyl acetate/hexane) to provide 0.22 g (˜100%) of methyl 1-(2-(3-fluorophenoxy)ethyl)-1H-indole-6-carboxylate as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11]Br)([CH3:4])([CH3:3])[CH3:2].[CH3:14][O:15][C:16](=[O:30])[CH2:17][C:18]1[C:19](=[O:29])[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([OH:28])[CH:22]=2>>[CH3:14][O:15][C:16](=[O:30])[CH2:17][C:18]1[C:19](=[O:29])[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([O:28][CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:13])[CH:22]=2
Reactant: CC(C)(C)OC(=O)NCCCCBr
Reactant: COC(=O)Cc1cc2ccc(O)cc2[nH]c1=O
Product: COC(=O)Cc1cc2ccc(OCCCCNC(=O)OC(C)(C)C)cc2[nH]c1=O

Procedure:
The title compound is prepared according to the procedure of Example 75 except that (4-bromobutyl)-carbamic acid tert-butyl ester is used in place of (3-bromopropyl)-carbamic acid tert-butyl ester and that (7-hydroxy-2-oxo-1,2-dihydro-quinolin-3-yl)-acetic acid methyl ester is used in place of (7-hydroxy-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-acetic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1.[S-:16][C:17]#[N:18].[K+]>CS(O)(=O)=O>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([C:17](=[S:16])[NH2:18])=[CH:5][CH:4]=1
Reactant: N#C[S-]
Reactant: COc1cccc2c1oc1ccccc12
Agent: CS(=O)(=O)O
Agent: [K+]
Product: COc1ccc(C(N)=S)c2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a mixture of 4-methoxydibenzo[b,d]furan (1 g, 5.05 mmol) in methane sulphonic acid (11 mL), potassium thiocyanate (1 g, 10.29 mmol) was added at 0-5° C. Subsequently the reaction mass was stirred at room temperature for 3 h. The reaction mixture was poured into crushed ice and filtered. The solid was washed with hexane and dried, to furnish the required product in 70% yield; Rf 0.25 (Ethyl acetate:Hexane (3:7); HPLC (purity); 1H-NMR (CDCl3) δ: 4.08 (s, 3H), 6.97 (d, 1H), 7.26-7.30 (m, 1H), 7.33-7.37 (m, 1H), 7.65 (d, 1H), 7.69 (d, 1H), 7.94 (d, 1H), 8.31 (d, 1H); 91.4%; MS m/z: 258.1 (M+1).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Br:18][C:19]([CH3:24])([CH3:23])[C:20](Br)=[O:21]>ClCCl>[Br:18][C:19]([CH3:24])([CH3:23])[C:20]([C:15]1[CH:14]=[CH:13][C:12]([O:11][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:17][CH:16]=1)=[O:21]
Reactant: CC(C)(Br)C(=O)Br
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(Br)C(=O)c1ccc(Oc2ccccc2)cc1

Procedure:
7.82 g of AlCl3 were added in about 30′ to a solution of 10 g (0.0587 mol) of diphenylether and 7.44 ml (0.0587 mol) of α-bromoisobutyrylbromide (97.5% w/w) in 100 ml of dichloromethane, maintaining the temperature between 0 e 5° C.
Reaction SMILES: [Cl:1][C:2]1[C:19]([Cl:20])=[CH:18][C:5]2[NH:6][C:7]([C:9]3([C:14]([F:17])([F:16])[F:15])[CH:13]=[CH:12][CH2:11][O:10]3)=[N:8][C:4]=2[CH:3]=1>CO.[Rh]>[Cl:1][C:2]1[C:19]([Cl:20])=[CH:18][C:5]2[NH:6][C:7]([C:9]3([C:14]([F:17])([F:15])[F:16])[CH2:13][CH2:12][CH2:11][O:10]3)=[N:8][C:4]=2[CH:3]=1
Reactant: FC(F)(F)C1(c2nc3cc(Cl)c(Cl)cc3[nH]2)C=CCO1
Agent: [Rh]
Solvent: CO
Product: FC(F)(F)C1(c2nc3cc(Cl)c(Cl)cc3[nH]2)CCCO1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 5,6-dichloro-2-(2-trifluoromethyl-2,5-dihydro-furan-2-yl)-1H-benzimidazole (95 mg) in methanol (5 mL) was added Rhodium on alumina (32 mg). The resulting mixture was stirred at room temperature under a H2 atmosphere via balloon for 5 hours. The reaction mixture was then filtered through a pad of Celite®, rinsed with Et2O, and concentrated to yield the title compound as a tan solid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2=[N:8][NH:9][C:10]([CH:11]3[CH2:14][CH:13]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)[CH:18]=[O:19])[CH2:12]3)=[C:5]2[CH:4]([C:23]2[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=2[F:31])[CH2:3]1.CO.[BH4-].[Na+]>C1COCC1>[OH:19][CH2:18][C:17]1[CH:16]=[C:15]([CH:13]2[CH2:12][CH:11]([C:10]3[NH:9][N:8]=[C:6]4[C:5]=3[CH:4]([C:23]3[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=3[F:31])[CH2:3][C:2](=[O:1])[NH:7]4)[CH2:14]2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1cccc(C2CC(c3[nH]nc4c3C(c3cc(F)c(F)cc3F)CC(=O)N4)C2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CC(c2cc(F)c(F)cc2F)c2c(n[nH]c2C2CC(c3cccc(CO)c3)C2)N1
Reaction time: 0.5 h

Procedure:
To 3-{3-[6-oxo-4-(2,4,5-trifluoro-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-cyclobutyl}-benzaldehyde (15 mg, 0.03 mmol) in THF:MeOH (3 mL 3:1) was added sodium borohydride (10 mg, 0.26 mmol). After 30 min, the reaction was quenched by the addition of 5 drops of aqueous NaOH (1N). The reaction mixture was concentrated under reduced pressure. Purification of this material was accomplished by preparative plated chromatography. The product band was collected, extracted with EtOAc, filtered, and concentrated to give the title compound. LRMS m/z (APCI+) 428 (M+1).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.C(OC([N:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[C:40]1B(O)O)=O)(C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[NH:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[C:40]1[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:13])=[O:14])[CH:9]=2)[NH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1
Yield: 40.8 %

Procedure:
N-[3-(1H-Indol-2-yl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 59 from 1 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 900 mg 1-(tert-butyloxycarbonyl)indole-2-boronic acid, 40 ml of dimethylformamide, 3.2 ml of saturated aqueous sodium hydrogencarbonate solution and 50 mg of tetrakis(triphenylphosphine)palladium[0]. 330 mg of N-[3-(1H-indol-2-yl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of a white solid melting above 260° C. (analysis C22H18N4O4S2 % calculated C, 56.63; H, 3.89; N, 12.01; O, 13.72; S, 13.75. % found C, 56.87; H, 4.10; N, 13.81; S, 12.65).