Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[N:6][C:7]=1[F:8].C([Li])CCC.Cl[Si](C)(C)CC[Si](Cl)(C)C.C([Li])(C)(C)C.C([Cu])#N.C(OC([N:48]1[C:52]2=[N:53][CH:54]=[C:55]([Cl:57])[CH:56]=[C:51]2[C:50]([CH2:58]Cl)=[CH:49]1)=O)(C)(C)C.Cl.N>O1CCCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][NH:9][C:5]2[CH:4]=[CH:3][C:2]([CH2:58][C:50]3[C:51]4[C:52](=[N:53][CH:54]=[C:55]([Cl:57])[CH:56]=4)[NH:48][CH:49]=3)=[C:7]([F:8])[N:6]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)n1cc(CCl)c2cc(Cl)cnc21
Reactant: Fc1nc(NCc2ccc(Cl)cc2)ccc1Br
Agent: N#C[Cu]
Agent: C[Si](C)(Cl)CC[Si](C)(C)Cl
Agent: Cl
Solvent: C1CCOC1
Product: Fc1nc(NCc2ccc(Cl)cc2)ccc1Cc1c[nH]c2ncc(Cl)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 0 %

Procedure:
To (5-bromo-6-fluoro-pyridin-2-yl)-(4-chloro-benzyl)-amine (537, 2.76 g, 8.75 mol) in tetrahydrofuran (90.0 mL), under an atmosphere of nitrogen at −78° C., n-butyllithium (2.50 M in hexane, 3.64 mL) was added slowly. After 60 minutes, 1,2-bis-(chloro-dimethyl-silanyl)-ethane (0.942 g, 4.38 mol) in tetrahydrofuran (8.0 mL) was added to the reaction. The reaction mixture was allowed to stir at room temperature for 2 hours. The reaction w,as cooled to −78° C., followed by addition of tert-butyllithium (1.70 M in hexane, 10.50 mL). The reaction was stirred for 30 minutes, followed by addition of 0.65 M of CuCN.2LiCl in tetrahydrofuran (14.0 mL). The reaction was stirred at −35° C. for 10 minutes, followed by addition of 5-chloro-3-chloromethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (535, 1.70 g, 5.64 mol, prepared as described in Example 49, Scheme 164) in tetrahydrofuran (10.0 mL). The reaction was allowed to warm to room temperature for 1 hour and 2 N HCl (30 mL) was added to the reaction mixture, then stirred for 30 minutes. The reaction was poured into aqueous ammonia and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified with silica gel column chromatography eluting with 30% ethyl acetate in hexane to give the desired compound (P-0132, 0.75 g, 33.1%). MS (ESI) [M+H+]+=401.1.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(NC1C=CC=CN=1)C.[F:16][C:17]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]2[C:18]=1[CH2:19][CH2:20][C:21](=[O:28])[CH2:22]2.Cl>C(OCC)C.C(Cl)(Cl)Cl.CO>[F:16][C:17]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]2[C:18]=1[CH2:19][CH2:20][C@@H:21]([OH:28])[CH2:22]2
Reactant: O=C1CCc2c(F)cc(F)cc2C1
Agent: CCNc1ccccn1
Agent: Cl
Agent: [Al+3]
Solvent: CCOCC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O[C@@H]1CCc2c(F)cc(F)cc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.7 %

Procedure:
A solution of (1R,2S)-N-methylephedrine (81.3 g, 0.454 mol) in 1.2 L of anhydrous diethyl ether was added to lithium aluminum hydride (1.0M in diethyl ether, 416 mL, 0.416 mol) over 45 minutes. The mixture was heated under reflux for 1 hour and then allowed to cool to room temperature. A solution of 2-ethylaminopyridine (110.7 g, 0.907 mol) in 100 mL of anhydrous diethyl ether was added over 45 minutes. The mixture was heated under reflux for 1 hour and then cooled to -65° C. A solution of 5,7-difluoro-1,2,3,4-tetrahydro naphthalen-2-one (23.0 g, 0.107 mol) in 100 mL of diethyl ether was added dropwise such that the reaction temperature did not exceed -60° C. The mixture was stirred at -65° C. to -68° C. for 3 hours and then 100 mL of methanol was added such that the reaction temperature did not exceed -60° C. The mixture was stirred at -65° C. to -68° C. for 10 minutes, then allowed to warm to -20° C., and 3.0 L of 3N hydrochloric acid was added such that the reaction temperature did not exceed 35° C. The diethyl ether layer was separated, washed with 200 mL of saturated sodium chloride, and dried over magnesium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure. Crystallization from 20 mL of diethyl ether and 200 mL of hexane and drying in vacuo gave (R)-5,7-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene (10.87 g, 0.05 mol), m.p. 85° C. [α]D25 =+36.03° (c=1.59, CHCl3).
Reaction SMILES: [CH3:1][N:2]([C:11](SC)=[N:12][C:13](=O)[CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[N:3]=CC1C=CC=CC=1.[CH3:22][N:23]([CH2:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[O:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH3:24]>C1(C)C=CC=CC=1.Cl>[CH3:22][N:23]([CH2:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[O:29][CH2:30][CH2:31][CH2:32][NH:33][C:11]1[N:2]([CH3:1])[N:3]=[C:13]([CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[N:12]=1)[CH3:24]
Reactant: CSC(=NC(=O)CS(C)(=O)=O)N(C)N=Cc1ccccc1
Reactant: CN(C)Cc1cccc(OCCCN)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: CN(C)Cc1cccc(OCCCNc2nc(CS(C)(=O)=O)nn2C)c1
Yield: 80.9 %

Procedure:
Methyl 1-methyl-N-[(methylsulphonyl)acetyl]-2-(phenylmethylene)hydrazinecarboximidothioate (1.3 g) and 3-[3-[(dimethylamino)methyl]phenoxy]propanamine (0.81 g) were heated at 70° under water vacuum for 1 h. After cooling, the reaction mixture was dissolved in toluene (10 ml) and 5N hydrochloric acid (6 ml), and stirred at 20° during 18 h. The acidic layer was washed with toluene and basified (pH 10) with potassium carbonate. The mixture was then extracted with ethyl acetate to give the title compound (1.2 g) as an oil. T.l.c. System A Rf 0.39.
Reaction SMILES: [Te].[BH4-].[Na+].[N:4]([CH:7]([C:9]1[C:10]([C:16]2[C:21]3[S:22][C:23]([C:25]4[C:30]([F:31])=[CH:29][N:28]=[C:27]([NH:32][CH2:33][CH2:34][N:35]5[CH:39]=[CH:38][N:37]=[N:36]5)[N:26]=4)=[CH:24][C:20]=3[CH:19]=[CH:18][CH:17]=2)=[CH:11][C:12]([F:15])=[N:13][CH:14]=1)[CH3:8])=[N+]=[N-]>C(O)C>[N:35]1([CH2:34][CH2:33][NH:32][C:27]2[N:26]=[C:25]([C:23]3[S:22][C:21]4[C:16]([C:10]5[C:9]([CH:7]([NH2:4])[CH3:8])=[CH:14][N:13]=[C:12]([F:15])[CH:11]=5)=[CH:17][CH:18]=[CH:19][C:20]=4[CH:24]=3)[C:30]([F:31])=[CH:29][N:28]=2)[CH:39]=[CH:38][N:37]=[N:36]1
Reactant: CC(N=[N+]=[N-])c1cnc(F)cc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12
Agent: [BH4-]
Agent: [Na+]
Agent: [Te]
Solvent: CCO
Product: CC(N)c1cnc(F)cc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.2 %

Procedure:
Combine tellurium (1.27 g, 10 mmol) and sodium tetrahydroborate (0.9 g, 2.4 mmol) in ethanol (20 mL) under nitrogen. Heat the mixture to refluxing until it becomes a clear red solution. Add 5 mL of the solution to a solution of (4-{7-[5-(1-azido-ethyl)-2-fluoro-pyridin-4-yl]-benzo[b]thiophen-2-yl}-5-fluoro-pyrimidin-2-yl)-(2-[1,2,3]-triazol-1-yl-ethyl)-amine (400 mg, 0.8 mmol) in ethanol (10 mL). Stir the mixture for 20 min at RT. Filter off the black solid. Wash the solid with methanol and DCM. Evaporate the combined mother liquor to give the crude product. Purify the crude product by FCC (chloroform/methanol/ammonium hydroxide, 7/3/0.05) to give the title compound as a yellow solid (200 mg, 52%). MS (ES) m/z 479 [M+1]+.
Reaction SMILES: [OH:1][C@@H:2]([CH2:13][NH:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)(=[O:17])=[O:16])[C@@H:3]([NH:5]C(=O)OC(C)(C)C)[CH3:4].O[C@H](CNS(C1C=CC=CN=1)(=O)=O)[C@@H](NC(=O)OC(C)(C)C)C.Cl.[C:48](=[O:81])(OC1C=CC([N+]([O-])=O)=CC=1)[O:49][C@H:50]([CH2:55][N:56]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][C:64]([C:67]([F:70])([F:69])[F:68])=[CH:63][CH:62]=2)=[N:57]1)[C:51]([CH3:54])([CH3:53])[CH3:52].C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(OCC)C>[OH:1][C@@H:2]([CH2:13][NH:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)(=[O:17])=[O:16])[C@@H:3]([NH:5][C:48](=[O:81])[O:49][C@H:50]([CH2:55][N:56]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][C:64]([C:67]([F:70])([F:68])[F:69])=[CH:63][CH:62]=2)=[N:57]1)[C:51]([CH3:53])([CH3:54])[CH3:52])[CH3:4]
Reactant: CC(C)(C)[C@@H](Cn1ccc(-c2ccc(C(F)(F)F)cc2)n1)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CNS(=O)(=O)c1ccccn1
Agent: C[C@H](NC(=O)OC(C)(C)C)[C@H](O)CNS(=O)(=O)c1ccccn1
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H](NC(=O)O[C@H](Cn1ccc(-c2ccc(C(F)(F)F)cc2)n1)C(C)(C)C)[C@@H](O)CNS(=O)(=O)c1ccccn1
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
To a solution of 0.101 g (0.29 mmol) of tert-butyl (1S,2S)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamate & tert-butyl (1S,2R)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamate in 2 mL of dioxane was added 2.0 mL of a 4.0 M solution of hydrochloric acid in dioxane. The reaction mixture was stirred for 30 min, and then concentrated. This residue was dissolved in 3.0 mL of dimethylformamide and this solution was added to 0.14 g (0.29 mmol) of (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl 4-(nitro)phenyl carbonate and 1.5 mL (0.87 mmol) of diisopropylethylamine. The reaction mixture was stirred at room temperature for 16 h. A saturated solution of sodium bicarbonate was then added, followed by diethyl ether. The layers were separated, and the organic layer was dried over anhydrous magnesium sulfate, and concentrated under vacuum to afford the crude product. This crude product was purified via silica gel chromatography eluting with ethyl acetate:hexane (1:1) to afford 0.138 g (81%) of (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl (1S,2S)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamate & (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl (1S,2R)-2-hydroxy-1-methyl-3-[(2-pyridinylsulfonyl)amino]propylcarbamate as a colorless oil. 1H-NMR (300 MHz, CDCl3): δ 8.64 (m, 1H), 7.98–7.88 (m, 5H), 7.64–7.47 (m, 4H), 6.60 (s, 1H), 5.01–4.81 (m, 3H), 4.46, 4.42 (2s br, 1H), 4.25–4.17 (m, 2H), 3.59–3.44 (m, 2H), 3.14 (m, 1H), 1.00 (m, 12H); LC-MS 584 (M+H).
Reaction SMILES: [C:1]([N:5]1[C:29](=[O:30])[C:28]2[N:13]3[CH2:14][CH2:15][C:16]4[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:20][C:21]=4[C:12]3=[C:11](Br)[C:10]=2[CH2:9][O:8][CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[N:38]1[CH:43]=[CH:42][CH:41]=[C:40](B(O)O)[CH:39]=1.[OH-].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)C.C(COC)OC>[C:1]([N:5]1[C:29](=[O:30])[C:28]2[N:13]3[CH2:14][CH2:15][C:16]4[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:20][C:21]=4[C:12]3=[C:11]([C:40]3[CH:39]=[N:38][CH:43]=[CH:42][CH:41]=3)[C:10]=2[CH2:9][O:8][CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccnc1
Reactant: COc1cc2c(cc1OC(C)C)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCOC3
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOCC
Product: COc1cc2c(cc1OC(C)C)-c1c(-c3cccnc3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCOC3
Yield: 56.2 %

Procedure:
A solution of 50 mg of 18d, 60 mg of K2CO3, 20 mg of 3-pyridylboronic acid and 15 mg of Pd(PPh3)4 in 2.5 ml of degassed 90% aq. dimethoxyethane was heated at 95° C. under N2 for 16 hr. The reaction mixture was cooled and poured into 1N NaOH. The product was extracted with ethyl acetate. The organic extract was washed twice with water, dried, concentrated and the residue was chromatographed over silica gel, using a gradient of heptane/acetone as eluent. The product thus isolated was treated with diethyl ether, to provide 28 mg of 18e as white crystalline material. Mp 193-194° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:15][CH2:14]1.[C:25]1([Mg]Br)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1.[Cl-].[NH4+]>C1COCC1>[F:21][C:20]([F:23])([F:22])[C:19]([N:16]1[CH2:17][CH2:18][N:13]([C:4]2[CH:5]=[C:6]([S:9]([C:33]3[C:34]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:30]=[CH:31][CH:32]=3)(=[O:11])=[O:10])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:14][CH2:15]1)=[O:24]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1N1CCN(C(=O)C(F)(F)F)CC1
Reactant: Br[Mg]c1cccc2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)c2cccc3ccccc23)cc1N1CCN(C(=O)C(F)(F)F)CC1
Reaction time: 1 h

Procedure:
To a solution of 4-methoxy-3-[4-(2,2,2-trifluoro-acetyl)-piperazin-1-yl]-benzenesulfonyl chloride (0.19 g; 0.5 mmol) in THF (0.5 mL) at 0° C. under argon atmosphere was added dropwise a solution of 1-naphthylmagnesium bromide in THF (0.5M, 2 mL; 1 mmol). After stirring at this temperature for 1 h, a saturated solution of ammonium chloride was added and the mixture was extracted into ethyl acetate (20 mL). The organic phase was dried (Na2SO4) and concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with hexane-ethyl acetate (7:3, v/v) to give 2,2,2-trifluoro-1-{4-[2-methoxy-5-(naphthalene-1-sulfonyl)-phenyl]-piperazin-1-yl}-ethanone (1) as a white solid (0.110 g; 47%), MS, MH+ 479.
Reaction SMILES: CN(C)N=[C:4]([CH2:6][CH:7]([OH:29])[CH:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:20][N:19]=2)=[CH:13][CH:12]=1)[CH3:9])[CH3:5].I([O-])(=O)(=O)=[O:32].[Na+]>CO.P([O-])([O-])([O-])=O.O>[OH:29][CH:7]([CH:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:20][N:19]=2)=[CH:13][CH:12]=1)[CH3:9])[CH2:6][C:4](=[O:32])[CH3:5]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(CC(O)C(C)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)=NN(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)CC(O)C(C)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
The above hexanone hydrazone (1 mmol) is dissolved in 10 ml of methanol with 2 ml of 2M pH 7 phosphate buffer, and a solution of sodium periodate (2.2 mmol) in 2 ml of water is added, with stirring. The mixture is stirred for 3 hours, after which the solvent is removed and the residue is extracted with chloroform. The extract is washed with water and dried and the solvent is removed to give 4-hydroxy-5-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy]-2-hexanone (C'; Q1 is N, Y is chloro, Z is trifluoromethyl, R1 is methyl and R2 is methyl).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:8]([C:10]1[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][CH:11]=1)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:2]1([NH:1][CH2:8][C:10]2[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)c1cccc(C=O)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cccc(CNc2ccccc2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.7 %

Procedure:
A mixture of aniline (128 mg, 1.38 mmol), methyl 6-formylpyridine-2-carboxylate (217 mg, 1.31 mmol) and acetic acid (75 μL, 1.31 mmol) in dichloromethane (10 mL) was stirred at room temperature for 24 h. After this time, sodium triacetoxyborohydride (695 mg, 3.28 mmol) was added in one portion and the resulting mixture was stirred at room temperature for 18 h. The reaction was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, passed through a hydrophobic fit and the solvent was removed in vacuo to afford the title compound (310 mg, 97%) as yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH:13]=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1([CH:21]([Mg]Br)[CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH:13]([OH:14])[CH:23]([CH2:22][CH2:21][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Br[Mg]C(CCCCc1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC1C=O
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1C(O)C(CCc1ccccc1)CCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 17 %

Procedure:
To a solution of 0.5 g (2.5 mmol) of 2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester in anhydrous THF (20 mL) was added 5.0 mL (2.5 mmol) of 4a, and the mixture was stirred at an ambient temperature for 16 hours. The solution was poured over a 1N solution of hydrochloric acid and was extracted with EtOAc (2×100 mL). The organic phase was washed with saturated sodium bicarbonate, dried (MgSO4) and evaporated to a clear oil which was subject to column chromatography (EtOAc/Hexanes, 1:3) to yield 0.18 g (16.7%) of 10a as a clear oil. TLC Rf=0.6 (EtOAc/Hexanes, 1:3)
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[O:17][C:13]=3[CH:12]=2)[CH:2]=1.[CH2:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:25]([NH2:32])[C@@H:24]1[OH:33].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16]([NH:32][C@@H:25]4[C:26]5[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH2:23][C@H:24]4[OH:33])[O:17][C:13]=3[CH:12]=2)[CH:2]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cccnc43)cc2o1
Reactant: N[C@@H]1c2ccccc2C[C@H]1O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1Cc2ccccc2[C@H]1Nc1nc2ccc(Cn3cnc4cccnc43)cc2o1
Temperature: 120 °C
Yield: 25.5 %

Procedure:
A stirred mixture of 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole (108 mg, 0.346 mmol) from Step 5 of Example 56, (1R,2R)-(−)-trans-1-amino-2-indanol (104 mg, 0.698 mmol), and DIEA (90 mg, 0.698 mmol) in anhydrous DMA (1.5 mL) was sealed and heated in a Biotage microwave synthesizer at 120° C. for 30 min. The reaction mixture was cooled to rt and purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford (1R,2R)-1-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol (35 mg, 26%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.36-8.45 (m, 2H), 8.09 (dd, J=1.3, 8.1 Hz, 1H), 7.47 (s, 1H), 7.29 (dd, J=4.7, 8.1 Hz, 1H), 7.12-7.25 (m, 6H), 5.52 (s, 2H), 5.47 (d, J=5.1 Hz, 1H), 5.02 (m, 1H), 4.34 (m, 1H), 3.15 (dd, J=7.2, 15.6 Hz, 1H), 2.73 (dd, J=7.6, 15.4 Hz, 1H). LCMS (ESI) m/z 398 (M+H)+.
Reaction SMILES: Cl.[CH:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]([C:22]1[CH:23]=[CH:24][C:25]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:26]([NH:28][CH:29]=O)[CH:27]=1)[OH:21].[H-].[Al+3].[Li+].[H-].[H-].[H-].CO.C(Cl)(Cl)Cl>O1CCCC1>[CH:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]([C:22]1[CH:23]=[CH:24][C:25]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[C:26]([NH:28][CH3:29])[CH:27]=1)[OH:21]
Reactant: O=CNc1cc(C(O)CNCCOc2ccc3c(c2)[nH]c2ccccc23)ccc1OCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CNc1cc(C(O)CNCCOc2ccc3c(c2)[nH]c2ccccc23)ccc1OCc1ccccc1

Procedure:
According to the method reported by Carl Kaiser et al in J. Med. Chem., 17, 49-57 (1974), a solution of 500 mg of the compound of Example 22 in 1 ml of tetrahydrofuran was added dropwise to a suspension of 50 mg of lithium aluminum hydride in 2 ml of tetrahydrofuran to cause reaction, followed by after-treatment, whereby 381 mg of the above-identified compound were obtained. Rf=0.13 (methanol/chloroform of 1/10).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[C:12]1[NH:16][C:15]([CH3:17])=[N:14][CH:13]=1>CO.[OH-].[Na+]>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:12]1[N:16]=[C:15]([CH3:17])[NH:14][CH:13]=1
Reactant: COC(=O)c1ccc(C)c(-c2cnc(C)[nH]2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(-c2cc(C(=O)O)ccc2C)c[nH]1
Temperature: 50 °C
Yield: 62.3 %

Procedure:
Methyl 4-methyl-3-(2-methyl-1H-imidazol-5-yl)benzoate (compound 7.1, 219 mg, 0.95 mmol) was dissolved in a mixture of methanol (20 mL) and aqueous sodium hydroxide (5 mL, 2M). The resulting solution was heated at 50° C. for 16 hrs, then the reaction was cooled to room temperature and the organic solvent was removed under reduced pressure. The resulting aqueous residue was acidified to pH 3-4 with aqeuous HCl (2 M). The resulting solids were collected and dried to yield 128 mg (62%) of the title compound as a white solid. m/z (ES−) 215 (M−H)−.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C[Al](C)C.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:20]#[N:21]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[F:16][C:17]1[CH:18]=[C:19]([C:20](=[NH:21])[NH:9][C:8]2[CH:10]=[CH:11][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: COc1ccc(C#N)cc1F
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)cc1F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline (2.82 g, 16.5 mmol) in toluene (150 mL), trimethylaluminum (2M solution in toluene, 12.5 mL, 24.7 mmol) was added over 15 minutes. The reaction mixture was warmed to room temperature and stirred for 2.5 hours. A solution of 3-fluoro-4-methoxybenzonitrile (5 g, 33 mmol) in toluene (100 mL) was added over 10 minutes and the reaction mixture was heated to 80°-85° C. After 20 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the reside was washed with a mixture of methylene chloride/methanol (2/1). The combined filtrates were concentrated in vacuo and the resulting yellowish solid was stirred with a mixture of hexane/ether (2/1, 1000 mL). The intermediate was filtered and washed with more hexane/ether (2/1). The pale yellow solid 3-fluoro-4-methoxy-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (3.95 g, 74%) was used in the next reaction without further purification: mp (DSC) 195° C. Anal. Calc'd. for C15H15N2SO3F: C, 55.89, H, 4.69, N, 8.69. Found: C, 55.92, H, 4.74, N, 8.53.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([OH:15])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:19]1[CH:20]=[C:21]([F:23])[CH:22]=[C:17]([F:16])[C:18]=1[N+:24]([O-:26])=[O:25])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CCOC(=O)c1cc2c(O)cccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Oc3cc(F)cc(F)c3[N+](=O)[O-])cccc2[nH]1
Temperature: 25 °C

Procedure:
4-Hydroxy-1H-indole-2-carboxylic acid ethyl ester (1 g, 4.87 mmol) and 2,4-Difluoro-1-nitro-benzene (0.534 ml, 4.87 mmol) are dissolved in 20 ml of dimethylformamide. After addition of potassium carbonate (1.3 g, 9.74 mmol) the mixture is stirred over night at room temperature. Then the reaction mixture is evaporated under reduced pressure, dissolved with ethyl acetate and washed with water. The organic layers are dried over sodium sulfate and evaporated. The crude product is used in the next step without further purification.