Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]([CH2:6][C:7]2[C:8]([O:26][CH3:27])=[N:9][C:10]3[C:15]([C:16]=2[Cl:17])=[CH:14][C:13]([C:18]([C:20]2[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=2)=[O:19])=[CH:12][CH:11]=3)=[CH:4][C:3]2[CH:28]=[CH:29][CH:30]=[CH:31][C:2]1=2.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[Mg]Br>C1COCC1>[S:1]1[C:5]([CH2:6][C:7]2[C:8]([O:26][CH3:27])=[N:9][C:10]3[C:15]([C:16]=2[Cl:17])=[CH:14][C:13]([C:18]([C:20]2[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=2)[OH:19])=[CH:12][CH:11]=3)=[CH:4][C:3]2[CH:28]=[CH:29][CH:30]=[CH:31][C:2]1=2
Reactant: Br[Mg]c1ccccn1
Reactant: COc1nc2ccc(C(=O)c3cncn3C)cc2c(Cl)c1Cc1cc2ccccc2s1
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccccn3)c3cncn3C)cc2c(Cl)c1Cc1cc2ccccc2s1
Reaction time: 0.08 h

Procedure:
LaCl3-2LiCl (0.6 M in THF, 0.78 mL, 0.47 mmol) was added dropwise by syringe to a solution of (3-(benzo[b]thiophen-2-ylmethyl)-4-chloro-2-methoxyquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone (101.4 mg, 0.226 mmol, Intermediate 40: step b) in dry THF (2 mL). After 5 minutes, the solution was cooled in an ice bath and pyridin-2-ylmagnesium bromide (2.8 mL, 0.7 mmol) was added dropwise via syringe. The reaction was stirred for 3 hours, then quenched with saturated aqueous ammonium chloride and removed from the cold bath. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (silica gel, 0-5% MeOH-DCM) followed by reverse-phase chromatography (acetonitrile/H2O+0.05% TFA). The isolated product fractions were basified with saturated aqueous sodium bicarbonate, extracted with DCM, dried (Na2SO4), filtered, and concentrated to dryness to provide the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 8.63-8.59 (m, 1H), 8.13 (d, J=2.0 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.71-7.60 (m, 4H), 7.49 (d, J=1.1 Hz, 1H), 7.30-7.18 (m, 4H), 7.08 (d, J=1.0 Hz, 1H), 6.32 (d, J=1.1 Hz, 1H), 4.50 (d, J=1.1 Hz, 2H), 4.13 (s, 3H), 3.41 (s, 3H); MS m/e 527.2 [M+H]+.
Reaction SMILES: CN(C)C=O.[CH2:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13]Cl)[CH:7]=[CH2:8].[OH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)[CH:7]=[CH2:8]
Reactant: C=CCOCCCCCl
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOCCCCOc1ccc(C(=O)O)cc1
Yield: 123 %

Procedure:
A dimethylformamide (50 ml) solution of allyl(4-chlorobutyl) ether 14 g, 4-hydroxybenzoic acid 14 g and potassium carbonate 14 g was stirred at 90° C. for 3 hours. Water was added thereto, and the solution was extracted with toluene. The toluene layer was washed well with water, and then toluene was distilled off. Sodium hydroxide 20 g, water 50 ml and ethanol 200 ml were added to the resulting residue and refluxed for 2 hours. Ethanol was distilled off, and then hydrochloric acid was added to the residue to acidify the solution. The solution was extracted with diethyl ether, and the extract was dried on anhydrous magnesium sulfate. A residue obtained by distilling the solvent off was recrystallized from a mixed solvent of ethanol and water to obtain 29 g of 4-(4-allyloxybutyloxy)benzoic acid. Phase transition temperature: C94N107I.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.[O:10]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11]1>>[O:10]1[CH:14]=[CH:13][C:12]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=2)=[CH:11]1
Reactant: O=Cc1ccc(Br)nc1
Reactant: OB(O)c1ccoc1
Product: O=Cc1ccc(-c2ccoc2)nc1

Procedure:
Synthesized using compound 43c (976 mg, 5.25 mmol) and 3-furanboronic acid (881 mg, 7.87 mmol) according to Method C. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (10:1) as eluent. White solid. Yield: 770 mg, 85%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=6.94 (dd, J=1.9, 0.9 Hz, 1H), 7.51-7.55 (m, 1H), 7.58 (dd, J=8.2, 0.6 Hz, 1H), 8.11-8.17 (m, 2H), 9.00 (dd, J=2.2, 0.9 Hz, 1H), 10.06 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=108.5, 120.0, 126.5, 129.6, 136.3, 143.2, 144.4, 152.6, 156.8, 190.1; MS (ESI): m/z=174.26 [M+H]+.
Reaction SMILES: ClC1C=CC(C(O[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=O)=CC=1.[C:19]([C:22]1[CH:29]=[C:28]([Cl:30])[C:25]([C:26]#[N:27])=[C:24]([CH:31]=[CH2:32])[C:23]=1[O:33][CH2:34][CH3:35])(=[O:21])[CH3:20].C(=O)([O-:38])N>O.C(#N)C.[Os](=O)(=O)(=O)=O>[C:19]([C:22]1[C:23]([O:33][CH2:34][CH3:35])=[C:24]([CH:31]([OH:38])[CH2:32][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:25]([C:26]#[N:27])=[C:28]([Cl:30])[CH:29]=1)(=[O:21])[CH3:20]
Reactant: NC(=O)[O-]
Reactant: C=Cc1c(C#N)c(Cl)cc(C(C)=O)c1OCC
Reactant: CC(C)(C)OC(=O)NOC(=O)c1ccc(Cl)cc1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CC#N
Product: CCOc1c(C(C)=O)cc(Cl)c(C#N)c1C(O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.2 M Osmium tetraoxide in water (0.5 mL) was added to a solution of tert-butyl [(4-chlorobenzoyl)oxy]carbamate (Ref. Lawrence Harris, J. Org. Chem., 2011, 76, 358-372). (0.91 g, 3.3 mmol) in acetonitrile (10 mL) and stirred for 10 minutes. 4-Acetyl-6-chloro-3-ethoxy-2-vinylbenzonitrile (0.56 g, 2.2 mmol) as a solution in acetonitrile (10 mL) was added to the carbamate solution followed by the addition of water (2 mL) and the reaction was stirred for 3 hours at room temperature. The reaction was quenched with saturated 10 M dipotassium disulfite in water (12 mL) and stirred for 5 minutes. Water was added and the reaction mixture was extracted with ethyl acetate. The extracts were washed with saturated sodium bicarbonate solution, brine and dried over sodium sulfate, filtered and evaporated. Purification on silica gel using ethyl acetate in hexane (0-100%) gave the desired compound as a racemic mixture, 610 mg, 72%. LCMS calculated for C18H24ClN2O5 (M+H)+: m/z=383.1; found: 383.1. 1H NMR (400 MHz, DMSO-d6): δ 7.62 (s, 1 H), 7.03 (br s, 1 H), 5.68 (br s, 1 H), 3.96 (m, 1 H), 3.69 (m, 1 H), 3.31 (m, 1 H), 3.19 (m, 1 H), 2.60 (s, 3 H), 1.30 (m, 12 H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][C:5]([CH3:18])=[CH:6][C:7](=[O:17])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CS(C)=O.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:2]([C:3]1[O:4][C:5]([CH3:18])=[CH:6][C:7](=[O:17])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:1]
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(CO)o1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cc(=O)c(OCc2ccccc2)c(C=O)o1
Temperature: 4 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
To a solution of 2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1h)-one (5.28 g, 21.5 mmol, 1 eq) in 100 ml chloroform was added 27 ml of dimethyl sulfoxide and 18.5 ml of triethylamine and the reaction mixture was cooled with an ice-bath to an internal temperature of 3-5° C. Then sulfur trioxide pyridine complex (17.1 g 107 mmol, 5 eq) was added and the mixture was allowed to thaw to room temperature. After stirring for overnight at room temperature, the reaction mixture was washed with water (2×50 ml) and the organic phase was dried over Na2SO4, filtered and concentrated in vacuo to yield an organe oil. Further purification by column chromatography on silica gel (eluant: Et2O) furnished the pure product (4.6 g, 87.7%) as a white crystalline solid. m.p. 78-81 ° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.C(N(CC)CC)C.[CH:17]1([CH2:23][NH2:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CO>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH:24][CH2:23][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:7]=1
Reactant: NCC1CCCCC1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CO
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)cc(NCC2CCCCC2)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 66.5 %

Procedure:
To 4,6-dichloro-2-pyrimidinamine (1.64 g, 10 mmol) in CH3OH (20 mL) were added triethylamine (2.02 g, 20 mmol) and cyclohexylmethanamine (1.36 g, 12 mmol), and the reaction mixture was stirred for 3 hours at 60° C. The mixture was evaporated under vacuum, and the resulting residue was subjected to SiO2 chromatography (gradient: EtOAc/petroleum ether 1:4 to 1:2) to afford the title compound (1.6 g, 66%) as light yellow solid. LC-MS (ES) m/z=241, 243 [M+H]+.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH2:11][C:12]#[N:13].Br[CH2:15][CH2:16][CH2:17]Br>C1(C)C=CC=CC=1.O>[Br:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1([C:12]#[N:13])[CH2:17][CH2:16][CH2:15]1
Reactant: BrCCCBr
Reactant: N#CCc1ccc(F)cc1Br
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC1(c2ccc(F)cc2Br)CCC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 31.6 %

Procedure:
Add potassium hydroxide (8.39 g, 150 mmol) and tetrabutylamine bromide (0.3 g, catalytic) to a solution of 2-(2-bromo-4-fluorophenyl)acetonitrile (4 g, 18.69 mmol) and 1,3-dibromopropane (4.15 g, 20.5 mmol) in toluene (20 mL). Stir it at 100° C. temperature for 2 h. Dilute the mixture with water and extract with ethyl acetate. Wash the organic layer with 1 N HCl and aqueous saturated sodium chloride. Dry over magnesium sulfate. Remove the organic solvent to give the crude product. Distill to give 1-(2-bromo-4-fluorophenyl)cyclobutanecarbonitrile (boiling point 110-120° C./0.3 Torr.) (1.5 g, 31%). MS (GC) m/z 253 [M]+.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18].[CH2:22](O)C>>[CH2:1]([N:19]([CH2:20][CH3:21])[CH2:17][CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:22]
Reactant: CCNCC
Reactant: C=CCCCCCCCCCCCCCC
Reactant: CCO
Product: CCCCCCCCCCCCCCCCCN(CC)CC

Procedure:
A 40 ml ethanol solution containing 0.015 g of RhCl3.3H2O, 35 g of 1-hexadecene, and 18 g of diethylamine was charged in an autoclave of 200 ml capacity, and the reaction was conducted under the conditions described in Example 1. Upon completion of the reaction, the contents separated into a product amine phase and a yellow solvent phase. To this solvent phase again were added 1-hexadecene and diethylamine in the same amounts as used in the first run, followed by phase separation. Further, the starting materials were added to the resulting solvent phase to conduct the reaction. In such a manner, the reaction was repeated. The olefin conversions and the yields of heptadecyldiethylamine thus obtained are as follows.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25]([C:29](O)=[O:30])=[CH:26][CH:27]=3)[C:22]([CH3:32])=[C:21]2[CH3:33])=[CH:17][C:16]=1[O:36][C@H:37]([CH:42]([CH3:44])[CH3:43])[C:38]([O:40][CH3:41])=[O:39]>>[Cl:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25]([C:29](=[O:30])[NH:13][C@H:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=4)[CH3:12])=[CH:26][CH:27]=3)[C:22]([CH3:32])=[C:21]2[CH3:33])=[CH:17][C:16]=1[O:36][C@H:37]([CH:42]([CH3:43])[CH3:44])[C:38]([O:40][CH3:41])=[O:39]
Reactant: COC(=O)[C@H](Oc1cc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)ccc1Cl)C(C)C
Reactant: CC(C)c1cccc([C@H](C)N)c1
Agent: Cl
Product: COC(=O)[C@H](Oc1cc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)ccc1Cl)C(C)C

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (R)-1-(4-chloro-3-((1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][N:20]([CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].[CH2:51]([Cl:53])[Cl:52]>C(O)(=O)C>[NH3:1].[CH2:51]([Cl:53])[Cl:52].[CH3:19][N:20]([CH2:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH:21]1[CH2:22][CH2:23][N:24]([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][CH:13]=2)[CH2:25][CH2:26]1
Reactant: CN(CCc1ccccc1)C1CCNCC1
Reactant: O=Cc1ccc(OCCCN2CCCCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(CCc1ccccc1)C1CCN(Cc2ccc(OCCCN3CCCCC3)cc2)CC1
Product: N
Reaction time: 16 h

Procedure:
A solution of the product of Example 9 (152 mg), methyl-phenethyl-piperidin-4-yl-amine (128 mg), and acetic acid (0.11 mL) in DCM (3 mL) was treated with sodium triacetoxyborohydride (190 mg). After 16 h, the resulting mixture was treated with 10% sodium hydroxide (5 mL) and extracted with DCM (3×10 mL). The combined organic phases were dried (sodium sulfate) and evaporated. Chromatography of the residue (1-5% 2 M methanolic ammonia/DCM) gave the title compound as a colorless oil (148 mg). 1H NMR (400 MHz, CDCl3): 7.29-7.25 (m, 2H), 7.21-7.16 (m, 5H), 6.83 (j, J=8.6 Hz, 2H), 3.99 (d, J=6.3 Hz, 2H), 3.41 (s, 2H), 2.92 (m, 2H), 2.77-2.66 (m, 4H), 2.47 (m, 2H), 2.40 (m, 4H), 2.34 (s, 3H), 2.00-1.88 (m, 4H), 1.71 (m, 2H), 1.62-1.55 (m, 6H), 1.44 (m, 2H).
Reaction SMILES: CC(N1CCN(CC(O)=O)CCN(C(C)C(O)=O)CCN(C(C)C(O)=O)CC1)C(O)=O.C1(C[O:39][CH2:40][CH:41]([N:45]2[CH2:56][CH2:55][N:54]([CH2:57][C:58]([OH:60])=[O:59])[CH2:53][CH2:52][N:51]([CH:61]([CH2:65][O:66]CC3C=CC=CC=3)[C:62]([OH:64])=[O:63])[CH2:50][CH2:49][N:48]([CH:74]([CH2:78][O:79]CC3C=CC=CC=3)[C:75]([OH:77])=[O:76])[CH2:47][CH2:46]2)[C:42]([OH:44])=[O:43])C=CC=CC=1>>[OH:66][CH2:65][CH:61]([N:51]1[CH2:52][CH2:53][N:54]([CH2:57][C:58]([OH:60])=[O:59])[CH2:55][CH2:56][N:45]([CH:41]([CH2:40][OH:39])[C:42]([OH:44])=[O:43])[CH2:46][CH2:47][N:48]([CH:74]([CH2:78][OH:79])[C:75]([OH:77])=[O:76])[CH2:49][CH2:50]1)[C:62]([OH:64])=[O:63]
Reactant: O=C(O)CN1CCN(C(COCc2ccccc2)C(=O)O)CCN(C(COCc2ccccc2)C(=O)O)CCN(C(COCc2ccccc2)C(=O)O)CC1
Agent: CC(C(=O)O)N1CCN(CC(=O)O)CCN(C(C)C(=O)O)CCN(C(C)C(=O)O)CC1
Product: O=C(O)CN1CCN(C(CO)C(=O)O)CCN(C(CO)C(=O)O)CCN(C(CO)C(=O)O)CC1

Procedure:
By way of example of the huge potentialities given by this synthetic route, the synthesis of the novel compound, α,α',α"-tris(methyl)-1,4,7,10-tetraazacyclododecane--1,4,7,10-tetraacetic acid, is reported in Experimental section: ##STR12## as well as that of α,α',α"-tris[(phenylmethoxy)methyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid ##STR13## which, by catalytic hydrogenation, as described in example 6 of the cited Patent, yields α,α',α"-tris(hydroxymethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid. ##STR14##
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[C:11]([C:21]([NH2:23])=[O:22])[CH:12]=[C:13]([C:16]4[CH:17]=[N:18][NH:19][CH:20]=4)[CH:14]=3)[NH:9][N:8]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[CH3:33][N:34]1[CH:38]=[C:37]([S:39](Cl)(=[O:41])=[O:40])[N:36]=[C:35]1[CH3:43]>CN(C1C=CN=CC=1)C>[CH3:33][N:34]1[CH:38]=[C:37]([S:39]([N:1]2[CH2:2][CH2:3][CH:4]([C:7]3[C:15]4[C:10](=[C:11]([C:21]([NH2:23])=[O:22])[CH:12]=[C:13]([C:16]5[CH:17]=[N:18][NH:19][CH:20]=5)[CH:14]=4)[NH:9][N:8]=3)[CH2:5][CH2:6]2)(=[O:41])=[O:40])[N:36]=[C:35]1[CH3:43]
Reactant: NC(=O)c1cc(-c2cn[nH]c2)cc2c(C3CCNCC3)n[nH]c12
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(S(=O)(=O)N2CCC(c3n[nH]c4c(C(N)=O)cc(-c5cn[nH]c5)cc34)CC2)cn1C
Yield: 27.4 %

Procedure:
Following the general procedure of Example 11, 3-(4-piperidinyl)-5-(1H-pyrazol-4-yl)-1H-indazole-7-carboxamide (Example 75) (0.07 mmol), diisopropyl-ethylamine (100 uL, 0.56 mmol), DMAP (25 mg, 0.014 mmol) and 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride (33 mg, 0.17 mmol) were reacted to give the title compound (9 mg, 27% for 3 steps). LC/MS: 469.4 Rt: 1.33 min.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:44])[CH2:21][NH:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:33]=[C:34]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:35]=[CH:36][CH:37]=3)=[CH:27][CH:26]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)C1C=CC=CC=1.C(O)(=O)C>[OH-].[Pd+2].[OH-].O1CCCC1>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:44])[CH2:21][NH:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:33]=[C:34]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:35]=[CH:36][CH:37]=3)=[CH:27][CH:26]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2
Reactant: O=c1ccc2c([C@@H](O)CNCCc3ccc(Oc4cccc(-c5ccccc5)c4)cc3)ccc(OCc3ccccc3)c2[nH]1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=c1ccc2c([C@@H](O)CNCCc3ccc(Oc4cccc(-c5ccccc5)c4)cc3)ccc(O)c2[nH]1
Yield: 18 %

Procedure:
A slurry of the the product of step (e) (105 mg) and palladium hydroxide (100 mg) in a solution of 1:1 acetic acid:tetrahydrofuran (10 mL) was stirred under an atmosphere of hydrogen for 24 h. The catalyst was filtered off, the filtrate evaporated and the residue purified by reverse phase HPLC to afford the title compound (16 mg) in the form of a white solid as a trifluoroacetate salt. m/z: [M+H+] calcd for C31H28N2O4, 493.2. found 493.5. 1H NMR (300 MHz, DMSO-d6): 10.40 (d, 1H, J=20 Hz), 8.60 (br s, 1H), 8.01 (d, 1H, J=8.8 Hz), 7.49 (d, 2H, J=8.2 Hz), 7.14-7.34 (m, 7H), 7.03 (d, 1H, J=7.4 Hz), 6.93 (d, 2H, J=7.4 Hz), 6.86-6.82 (m, 2H), 6.46 (d, 1H, J=9.9 Hz), 6.07 (s, 1H), 5.18 (m, 1H), 3.19-2.82 (m, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH:10]([CH3:12])[C:9]([OH:18])([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[CH2:8][CH:7]1[CH3:19])=[O:5])[CH3:2].[Br:20]N1C(=O)CCC1=O.S([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O.O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH:10]([CH3:12])[C:9]([C:13]2[S:14][C:15]([Br:20])=[CH:16][N:17]=2)([OH:18])[CH2:8][CH:7]1[CH3:19])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1CC(C)C(O)(c2nccs2)CC1C
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CC(C)C(O)(c2ncc(Br)s2)CC1C
Temperature: 55 °C
Reaction time: 3 h
Yield: 34.5 %

Procedure:
To a solution of the product of Step 1 (3.84 g, 8.54 mmol) in dimethylformamide (33.5 mL) was added N-bromosuccinimide (1.75 g, 9.82 mmol) and the solution stirred at 55° C. for 3 hours. A solution of sodium sulfite (0.538 g, 4.27 mmol) in water (60 mL) was added dropwise to the reaction. The mixture was diluted with ethyl acetate (100 mL) and washed the organic extract with water (2×100 mL). The combined aqueous layers were back extracted with ethyl acetate (3×100 mL) and the combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography provided a solid, which was triturated with hexanes, to give 4-(5-bromo-thiazol-2-yl)-4-hydroxy-2,5-dimethyl-cyclohexanecarboxylic acid ethyl ester (1.07 g, 2.95 mmol). MS ESI: [M]+ m/z 362.1.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]2[C:10]([C:13]([NH:15][C:16]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:17]=3[CH:18]=[N:19][N:20]4[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:14])=[CH:11][N:12]=[C:6]2[CH:5]=1)(=[O:3])[CH3:2].C1COCC1.CO.[BH4-].[Na+]>CO.C(Cl)Cl>[CH2:25]([N:20]1[C:21]2[C:17](=[C:16]([NH:15][C:13]([C:10]3[N:7]4[CH:8]=[CH:9][C:4]([CH:1]([OH:3])[CH3:2])=[CH:5][C:6]4=[N:12][CH:11]=3)=[O:14])[CH:24]=[CH:23][CH:22]=2)[CH:18]=[N:19]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)c1ccn2c(C(=O)Nc3cccc4c3cnn4Cc3ccccc3)cnc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CC(O)c1ccn2c(C(=O)Nc3cccc4c3cnn4Cc3ccccc3)cnc2c1
Reaction time: 8 h
Yield: 89.1 %

Procedure:
A solution of 7-acetyl-N-(1-benzyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 146; 10 mg, 0.024 mmol) in a 1:1 THF/MeOH mixture (0.2 mL) was treated at ambient temperature with excess sodium borohydride (3.7 mL, 0.10 mmol), and stirring continued overnight. The reaction was quenched with excess saturated aqueous sodium bicarbonate and the resulting suspension was extracted with EtOAc and DCM. The combined organic extracts were dried over anhydrous sodium sulfate, and concentrated to afford the crude product. The crude product was subjected to preparative thin-layer chromatography on silica with MeOH/DCM as eluent to afford 8.8 mg of the desired product as a white solid. MS (ES+APCI) m/z=412 (M+H) detected.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH:13]=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:15]C(C)([O-])C.[K+].C(OP(C=[N+]=[N-])(=O)OCC)C>CCOCC>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]#[CH:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Agent: CCOP(=O)(C=[N+]=[N-])OCC
Agent: [K+]
Solvent: CCOCC
Product: C#C[C@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
(R)-N-Boc-2-Ethynyl-pyrrolidine was prepared according to Method X above by the treatment of (R)-N-Boc-2-formyl-pyrrolidine (700 mg, 3.51 mmol) (Example 89A) with potassium tert-butoxide (510 mg, 4.56 mmol) and diazomethyl-phosphonic-acid-diethylester (820 mg, 4.56 mmol) (also prepared according to Method X). (R)-N-Boc-2-Ethynyl-pyrrolidine was obtained after silica gel cotoumn chromatography with 10% Et2O in hexanes. (Yield 150 mg, 25%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15]O)[O:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:20]>CCOCC>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][Cl:20])[O:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(CO)occ1OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: O=c1cc(CCl)occ1OCc1ccccc1
Reaction time: 1 h

Procedure:
To a suspension of 5-(benzyloxy)-2-(hydroxymethyl)-4H-pyran-4-one (18.5 g, 80 mmol) in Et2O (130 mL) was added SOCl2 (18 mL, 1 10 mmol) at r.t. and the mixture was stirred for 1 h. The reaction mixture was poured onto ice-water and more Et20 was added. Then the Et20 phase was collected and water phase was extracted by Et20 twice, the combined Et20 layer was washed with brine, dried over Na2S04, and concentrated. The residue was purified by silica gel chromatography to give 5-(benzyloxy)-2-(chloromethyl)-4H-pyran-4-one 1HNMR (DMSO, 400 MHZ) δ 8.27 (s, 1H), 7.32-7.41 (m, 5H)S 6.55 (s, 1H), 4.92 (s, 2H), 4.65 (s, 2H). MS (M+H)+250.1/252.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:27])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=2)[CH:17]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:59][CH:60]1[CH2:65][CH2:64][O:63][CH2:62][CH2:61]1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:27])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH:59][CH:60]3[CH2:65][CH2:64][O:63][CH2:62][CH2:61]3)=[O:24])=[CH:20][N:19]=2)[CH:17]=1
Reactant: NC1CCOCC1
Reactant: Cn1nnc(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)NC3CCOCC3)cn2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
To a solution of 6-(4-(4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (75 mg, 0.194 mmol) and TBTU (73 mg, 0.226 mmol) in DMF (2.0 mL) was added DIPEA (180 μL, 1.03 mmol). Then 4-aminotetrahydropyran (24 μL, 0.226 mmol) was added and the mixture was stirred at room temperature under Ar for 30 min. The mixture was then evaporated and purification by chromatography (reverse phase HPLC) afforded the title compound (71 mg, 77%) as a white solid. MS: m/e=448.2 [M+H]+.