Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]#[N:11])[C:4]=2[CH:3]=[CH:2]1.[NH2:12][OH:13]>CO>[OH:13][N:12]=[C:10]([C:5]1[C:4]2[CH:3]=[CH:2][NH:1][C:9]=2[CH:8]=[CH:7][CH:6]=1)[NH2:11]
Reactant: N#Cc1cccc2[nH]ccc12
Reactant: NO
Solvent: CO
Product: NC(=NO)c1cccc2[nH]ccc12

Procedure:
In a 50 ml reaction vessel, to a solution of 1H-indole-4-carbonitrile (5.00 g) in CH3OH (100 ml) was added hydroxylamine (50% aqueous solution) at room temperature, followed by refluxing for 15 hours (completion of the reaction was confirmed by TLC). The reaction solution was concentrated under reduced pressure, and azeotroped with toluene three times. The obtained solid was washed with IPE. N′-Hydroxy-1H-indole-4-carboximidamide (6.12 g) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[S:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.[CH2:38]([P:47](=[O:54])([O:51][CH2:52][CH3:53])[O:48][CH2:49][CH3:50])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)[S:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:38]/[P:47](=[O:54])([O:48][CH2:49][CH3:50])[O:51][CH2:52][CH3:53])=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(N2CCOCC2)sc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(N3CCOCC3)sc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 50.5 %

Procedure:
To a mixture of 3-({3-methoxy-4-[(5-methyl-2-morpholin-4-yl-1,3-thiazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (0.52 g), tetraethyl methylenediphosphonate (0.32 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.050 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-[3-({3-methoxy-4-[(5-methyl-2-morpholin-4-yl-1,3-thiazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazol-4-yl]ethenylphosphonate as colorless crystals (0.33 g, yield 51%) from a fraction eluted with ethyl acetate-hexane (9:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 88-90° C.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8](/[N:10]=[CH:11]/[N:12]([CH3:14])[CH3:13])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1.[I-].[Na+]>CN(C)C=O>[C:1]([C:5]1[CH:9]=[C:8](/[N:10]=[CH:11]/[N:12]([CH3:14])[CH3:13])[N:7]([CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)/C=N/c1cc(C(C)(C)C)n[nH]1
Reactant: BrCC1CCCCO1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)/C=N/c1cc(C(C)(C)C)nn1CC1CCCCO1
Temperature: 65 °C
Reaction time: 16 h
Yield: 53.9 %

Procedure:
To a solution of Example 63A (1.0 g, 5.2 mmol) in N,N-dimethylformamide (10 mL) were added sodium hydride (0.52 g, 12.9 mmol, 60% in mineral oil, Aldrich), 2-(bromomethyl)tetrahydro-2H-pyran (0.8 mL, 6.2 mmol) and sodium iodide (0.23 g, 1.5 mmol). After stirring at 65° C. for 16 hours, the reaction mixture was cooled and quenched with saturated NaHCO3 (10 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-10% methanol in dichloromethane) to provide 0.82 g (55%) of the title compound. 1H NMR (501 MHz, CDCl3) δ ppm 1.22-1.33 (m, 1H), 1.27 (s, 9H), 1.34-1.49 (m, 3H), 1.51-1.62 (m, 1H), 1.72-1.83 (m, 1H), 2.87 (s, 3H), 2.95 (s, 3H), 3.36-3.49 (m, 1H), 3.73-3.83 (m, 1H), 3.95 (dd, J=11.3, 3.0 Hz, 1 H), 4.02 (dd, J=13.4, 7.7 Hz, 1H), 4.17 (dd, J=13.4, 5.8 Hz, 1H), 5.55 (s, 1H), 8.00 (s, 1H). MS (ESI+) m/z 293 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]([NH:15][C:16](=[O:39])[CH2:17][CH:18]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[NH:19][S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1)(=[O:22])=[O:21])[CH2:10][CH2:9][CH2:8]2)=[CH2:4].CCN(CC)CC.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>C(Cl)Cl>[C:33]1([CH:18]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=2)(=[O:22])=[O:21])[CH2:17][C:16]([NH:15][CH:11]2[CH2:10][CH2:9][CH2:8][C:7]3[CH:6]=[C:5]([C:3](=[CH2:4])[CH2:2][O:1][S:48]([CH3:47])(=[O:50])=[O:49])[CH:14]=[CH:13][C:12]2=3)=[O:39])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CS(=O)(=O)Cl
Reactant: C=C(CO)c1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(COS(C)(=O)=O)c1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccccc1
Temperature: 0 °C

Procedure:
To a flask charged with N-[6-(1-hydroxymethyl-vinyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-3-phenyl-3-(3-trifluoromethyl-benzenesulfonylamino)-propionamide (Step F, 558 mg, 1.0 mmol, 1.0 eq) was added CH2Cl2 (7 mL) and Et3N (0.18 mL, 1.3 mmol, 1.3 eq). The suspension was cooled to 0° C., purged with N2, and then added the CH2Cl2 solution (1 mL) of methanesulfonyl chloride (Aldrich, 0.1 mL, 1.3 mmol, 1.3 eq). The mixture was concentrated in vacuo after 1 h. The crude was dried on vacuum and used for next step directly.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:42]([OH:43])[C@@H:41]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:40]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[O:39][C@H:10]1[O:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][C@H:18]([C@@H:20]1[C@:37]2([CH3:38])[C@H:23]([C@H:24]3[C@H:34]([CH2:35][CH2:36]2)[C@:32]2([CH3:33])[CH:27]([CH2:28][CH2:29][CH2:30][CH2:31]2)[CH2:26][CH2:25]3)[CH2:22][CH2:21]1)[CH3:19])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:60](OC(=O)C)(=[O:62])[CH3:61].C1(C)C=CC=CC=1>N1C=CC=CC=1>[C:60]([O:43][C@H:42]1[C@@H:41]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:40]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:57])([CH3:56])[CH3:58])[O:39][C@@H:10]([O:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][C@H:18]([C@@H:20]2[C@:37]3([CH3:38])[C@H:23]([C@H:24]4[C@H:34]([CH2:35][CH2:36]3)[C@:32]3([CH3:33])[CH:27]([CH2:28][CH2:29][CH2:30][CH2:31]3)[CH2:26][CH2:25]4)[CH2:22][CH2:21]2)[CH3:19])[CH3:14])[C@@H:9]1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:62])[CH3:61]
Reactant: CC(=O)OC(C)=O
Reactant: CC(CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CCCC[C@]4(C)[C@H]3CC[C@]12C)CO[C@@H]1O[C@H](COC(=O)C(C)(C)C)[C@H](OCc2ccccc2)[C@H](O)[C@H]1OCc1ccccc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)O[C@H]1[C@@H](OCc2ccccc2)[C@@H](COC(=O)C(C)(C)C)O[C@@H](OCC(C)CCC[C@@H](C)[C@H]2CC[C@H]3[C@@H]4CCC5CCCC[C@]5(C)[C@H]4CC[C@]23C)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
Compound 27 (10 mg, 12.3 μmol) was dissolved in pyridine (1 mL). To the solution, acetic anhydride (0.5 mL) was added, and the mixture was stirred at the room temperature for 1 hour. The solvent was subjected to azeotropy with toluene, and the residue was purified with Sephadex LH-20 (CHCl3:MeOH=1:2) to obtain Compound 28 (9 mg, 85.4%).
Reaction SMILES: [CH3:1][S-:2].[Na+].[Cl:4][C:5]1[CH:10]=[C:9](Cl)[N:8]=[C:7]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:6]=1>C1COCC1>[Cl:4][C:5]1[CH:10]=[C:9]([S:2][CH3:1])[N:8]=[C:7]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:6]=1
Reactant: C[S-]
Reactant: Clc1cc(Cl)nc(OCc2ccccc2)n1
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1cc(Cl)nc(OCc2ccccc2)n1

Procedure:
Aqueous sodium thiomethoxide (15%, 2.75 g, 0.0059×1.0 mol) was added dropwise in 4,6-dichloro-2-(phenylmethoxy)pyrimidine (Compound No. II-26) (1.5 g, 0.0059 mol) dissolved in THF at room temperature. After allowed to react for 2 hours, the reaction solution was partitioned between ethyl acetate and aqueous saturated sodium hydrogen carbonate. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated, then purified on a silica gel column to obtain 4-chloro-6-methylthio-2-(phenylmethoxy)pyrimidine (Compound No. II-15) as an intermediate.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:10]1[N:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[C:12]([NH2:14])=[O:13]>CN(C=O)C>[Cl:19][C:17]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[C:10]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:18]=1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Reactant: OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Cl)nc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a solution of cyclopentanol (1.42 mL, 15.70 mmol) in DMF (5 mL) at 0° C. was added sodium hydride (95% in mineral oil, 0.39 g, 15.70 mmol) in portions and stirred for 1 h at room temperature. This mixture was slowly added to a solution of 2,6-dichloro-nicotinamide (2.0 g, 10.47 mmol) in DMF (10 mL) at 0° C. The reaction mixture was stirred at room temperature overnight. DMF was removed under reduced pressure, and the resulting mixture was diluted with EtOAc (100 mL), washed with water (2×25 mL) and brine (2×25 mL) solution, dried over anhyd. Na2SO4, filtered, and concentrated to give yellow oil, which was purified by flash chromatography on silica gel using 10-25% EtOAc/hexanes as eluent to yield the title compound (1.94 g, 51%) as a transparent oil. 1H NMR (400 MHz, CDCl3) δ 8.44 (d, J=7.8 Hz, 1H), 7.65 (br. s., 1H), 7.03 (d, J=8.2 Hz, 1H), 5.74 (br. s., 1H), 5.70-5.57 (m, 1H), 2.25-1.95 (m, 2H), 1.90-1.66 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[N+:8]([C:4]1[CH:3]=[C:2]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(Br)c1
Reactant: C1CCNC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc(N2CCCC2)c1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 78 %

Procedure:
To a solution of 3-bromonitrobenzene (2.02 g, 10 mmol) in toluene (33 mL) and pyrrolidine (1.0 mL, 12 mmol) was added sodium t-butoxide (1.92 g, 20 mmol) and the solution was deoxygenated by passing a nitrogen through the solution at room temperature for 15 minutes. BINAP and tris(dibenzylideneacetone)dipalladium(0) complex were subsequently added as a solid and the nitrogen bubbling was continued for an additional 5 minutes. The mixture was heated at 100° C. overnight. The reaction mixture was then cooled and partitioned between water and ethyl acetate. The organic layer was washed once with brine solution and dried over anhydrous sodium sulfate. The ethyl acetate was decanted and evaporated under reduced pressure to give the desired 1-(3-nitrophenyl)pyrrolidine as a red oil (1.5 g, 79%).
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:15](=[O:17])[CH3:16])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH3:21][N:22]([CH:24](N(C)C)N(C)C)[CH3:23]>C1(C)C=CC=CC=1>[CH2:18]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:15](=[O:17])[CH:16]=[CH:21][N:22]([CH3:24])[CH3:23])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:19][CH3:20]
Reactant: CN(C)C(N(C)C)N(C)C
Reactant: CCCN(CCC)C1CCc2cccc(C(C)=O)c2C1
Solvent: Cc1ccccc1
Product: CCCN(CCC)C1CCc2cccc(C(=O)C=CN(C)C)c2C1
Reaction time: 2 h
Yield: 107.9 %

Procedure:
A solution of 2-di-n-propylamino-8-acetyl-1,2,3,4-tetrahydronaphthalene (0.3 g, 1.1 mmol), prepared as in Example 5, and tris(dimethylamino)methane (0.32 g, 2.2 mmol) in toluene was heated to reflux for 5 hours and at 60° for 18 hours. An additional aliquot of tris(dimethylamino)methane (0.16 g, 1.1. mmol) was added and the reaction stirred at 60° for an additional 2 hours. The reaction was concentrated to give 2-di-n-propylamino-8-(1-oxo-3-(dimethylamino)-prop-2-enyl)-1,2,3,4-tetrahydronaphthalene (0.39 g) as a viscous, orange oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:10]3=[N:11][CH:12]=[C:13]([NH:15][NH:16]C(OC(C)(C)C)=O)[N:14]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.Cl.O1CCOCC1>CCOC(C)=O>[NH:15]([C:13]1[N:14]=[C:9]2[CH:8]=[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:10]2=[N:11][CH:12]=1)[NH2:16]
Reactant: Cn1cc(-c2cc3nc(NNC(=O)OC(C)(C)C)cnc3n2COCC[Si](C)(C)C)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cc3nc(NN)cnc3n2COCC[Si](C)(C)C)cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a flask was added tert-butyl 2-(6-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate (0.152 g, 0.331 mmol, Preparation #O.1), HCl (4.0 M in 1,4-dioxane, 0.827 mL, 3.31 mmol) and 1,4-dioxane (5 mL). The mixture was heated to about 60° C. for about 1 h then stirred at rt overnight. The mixture was diluted with EtOAc (10 mL), washed with aqueous saturated NaHCO3, dried over anhydrous MgSO4 and concentrated in vacuo to give 2-hydrazinyl-6-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (0.100 g, 84%): LC/MS (Table 2, Method c) Rt=1.43 min; MS m/z 360 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14](Br)=[CH:15][CH:16]=2)[CH2:11][CH:10]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]1([OH:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Cu](I)I>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:15][CH:16]=2)[CH2:11][CH:10]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: O=S(=O)(NC1Cc2cc(Br)ccc2N(Cc2ccccc2)C1)c1ccccc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S(=O)(NC1Cc2cc(Oc3ccccc3)ccc2N(Cc2ccccc2)C1)c1ccccc1
Temperature: 200 °C
Reaction time: 16 h
Yield: 7.1 %

Procedure:
A suspension of 87B (55 mg, 0.12 mmol), phenol (33.9 mg, 0.36 mmol), K2CO3 (50 mg, 0.36 mmol) and copper iodide (17.1 mg, 0.09 mmol) in DMF (1.0 mL) was heated at 200° C. in a sealed tube with stirring for 16 h. After cooling to RT, the reaction mixture was filtered, the filtrate purified using preparative HPLC (YMC S5 ODS 20×100 mm) eluting with MeOH (70-100%) in 1120 for 8 min, and then 100% MeOH in H2O for 7 min to give the title compound (4 mg) as a light brownish solid. HPLC: 91% at 6.99 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A=90% H2O−10% MeOH−0.1% H3PO4 and B=10% H2O−90% MeOH−0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). MS (ES): m/z 471 [M+H]+.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:13][C:14]([F:27])([F:26])[C:15](=O)/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1.O>C(O)(=O)C>[NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[CH2:16][C:15]([C:14]([F:13])([F:26])[F:27])=[N:12]2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1ccc(/C=C/C(=O)C(F)(F)F)cc1
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(C2CC(C(F)(F)F)=NN2c2ccc(S(N)(=O)=O)cc2)cc1
Yield: 45 %

Procedure:
A solution of 4-(aminosulphonyl)phenylhydrazine chlorohydrate (0.82 g, 3.69 mmoles) and (E)-1,1,1-trifluoro-4-(4-methylphenyl)-3-butene-2-one (0.79 g, 3.69 mmoles) in 15 ml of acetic acid is refluxed for 3 hours under a nitrogen atmosphere. It is cooled, poured over water and extracted with AcOEt. The organic solution is washed with water, dried over anhydrous sodium sulphate and evaporated to dryness under vacuum. The crude product thus obtained is crystallised from EtOH-petrol ether to give 1-(4-aminosulphonylphenyl)-4,5-dihydro-5-(4-methylphenyl)-3-trifluoromethyl-1H-pyrazole (0.65 g, yield: 45%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH2:7][CH2:6]2.O.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCN=C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)CCNC2

Procedure:
In methanol (100 ml), 6-methoxy-3,4-dihydroisoquinoline (10.4 g) was dissolved. After the addition of water (10 ml) and then sodium borohydride (6.10 g), the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane. The resulting solution was washed with water. The organic layer so separated was dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (dichloromethane˜dichloromethane:methanol=100:15), whereby the title compound (7.95 g, 76%) was obtained.
Reaction SMILES: [NH2:1][C@H:2]([CH3:22])[CH2:3][C:4]1[C:12]2[C:7](=[C:8]([O:13][CH2:14][C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[O:16])[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.FC(F)(F)C([O-])=O.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C@@H:36]2[CH2:38][O:37]2)[CH:31]=1.CCN(C(C)C)C(C)C>C(#N)C>[OH:37][C@H:36]([C:32]1[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=1)[CH2:38][NH:1][C@H:2]([CH3:22])[CH2:3][C:4]1[C:12]2[C:7](=[C:8]([O:13][CH2:14][C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[O:16])[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: c1cncc([C@@H]2CO2)c1
Reactant: C[C@@H](N)Cc1c[nH]c2c(OCC(=O)NS(C)(=O)=O)cccc12
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@H](Cc1c[nH]c2c(OCC(=O)NS(C)(=O)=O)cccc12)NC[C@H](O)c1cccnc1

Procedure:
A mixture of (R)—N-{2-[3-(2-aminopropyl)-1H-indol-7-yloxy]-acetyl}methanesulfonamide.trifluoroacetate (40 mg, 0.091 mmol), (R)-(pyridin-3-yl)oxirane (48 mg, 0.36 mmol) and iPr2NEt (24 μL, 0.137 mmol) in acetonitrile (1 mL) is refluxed for 3 hours. After cooling, the mixture is concentrated and purified by preparative reversed phase HPLC (trifluoroacetic acid/water/acetonitrile) to give the desired N-(2-{3-[(2R)-2-((2R)-2-hydroxy-2-pyridin-3-ylethylamino)propyl]-1H-indol-7-yloxy}acetyl)methanesulfonamide.2 trifluoroacetate (3 mg, yield: 3%).
Reaction SMILES: Br[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][N:12]3[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1.[CH3:27][CH:28]1[O:33][CH:32]([CH3:34])[CH2:31][NH:30][CH2:29]1>ClCCl>[Cl:17][C:15]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][N:12]2[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:19])=[O:20])=[C:8]([C:6]2[O:7][C:3]([CH2:2][N:30]3[CH2:29][C@@H:28]([CH3:27])[O:33][C@H:32]([CH3:34])[CH2:31]3)=[CH:4][N:5]=2)[CH:16]=1
Reactant: CC1CNCC(C)O1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3ncc(CBr)o3)cc(Cl)cc21
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2cnc(-c3cc(Cl)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)C[C@@H](C)O1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
To a solution of 4-[5-(bromomethyl)-1,3-oxazol-2-yl]-6-chloro-1-(phenylsulfonyl)-1H-indazole (750 mg, 1.657 mmol) in dichloromethane (50 mL) stirred in air at room temp, was added neat 2,6-dimethylmorpholine (191 mg, 1.657 mmol, available from Aldrich as a mixture of isomers). The reaction mixture was stirred at 20° C. for 20 hr. Volatiles were removed using a rotary evaporator then the crude material was pre-absorbed onto Fluorosil™ and purified by column chromatography on silica (100 g) using a 0-100% ethyl acetate-cyclohexane gradient over 60 mins. Two diastereoisomers were isolated. Appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow oil (226 mg).
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C([O-])(=O)C.[NH4+:15]>C(O)C>[NH2:15]/[C:3](/[CH2:2][Cl:1])=[CH:4]\[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: [NH4+]
Reactant: CCOC(=O)CC(=O)CCl
Agent: CC(=O)[O-]
Solvent: CCO
Product: CCOC(=O)/C=C(\N)CCl

Procedure:
A solution of ethyl 4-chloroacetoacetate (7.02 ml) and ammonium acetate (11.8 g) in absolute ethanol (180 ml) is refluxed for 3 hours. After a night at room temperature the solution is concentrated to dryness by distillation under reduced pressure and the resulting residue is purified by flash chromatography (silica gel, 200 g; eluent CH2Cl2/MeOH/TEA 15/5/02), to give 6.53 g of ethyl (Z)-3-amino-4-chloro-2-butenoate as dark oil which is used without further purifications.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1.O>CN(C)C=O>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[S:1][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=2)=[N:17][CH:18]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: Oc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(Oc2ccccc2Sc2ccc(Cl)cn2)nc1

Procedure:
To a mixture of 3.0 grams (0.023 mole) of 2-mercaptophenol and 7.0 grams of potassium carbonate stirring in 50 ml of dimethylformamide, 9.0 grams of 2,5-dichloropyridine is added and the stirred mixture heated at 130° overnight. After pouring into excess H2O, the aqueous mixture is extracted with ethyl ether (200 ml) and the extract washed with H2O, saturated NaHCO3, and brine, dried (MgSO4), filtered, and the solvent evaporated to give the crude product which is recrystallized from 1-chlorobutane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11](=O)[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][C:7]=1[F:8].Cl.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[NH:29][NH2:30]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:29]([C:23]3[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=3[F:21])[N:30]=[C:11]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NNc1ccc(F)cc1F
Reactant: O=C(C=Cc1ccc(F)c(Br)c1)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: CC(=O)O
Product: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2ccc(F)c(Br)c2)c(F)c1
Temperature: 125 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
1-(3-Bromo-4-fluoro-phenyl)-4,4,5,5,5-pentafluoro-pent-1-en-3-one (2.5 g, 7.1 mmol) prepared in Step 4 and 2,4-difluorophenylhydrazine hydrochloride (1.4 g, 7.8 mmol) were added to acetic acid (35.0 mL). The reaction mixture was stirred at 125° C. for 2 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The mixture was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/30) to give 2.1 g of the titled compound as a yellow liquid.