Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:10]1([C:13]2[CH:14]=[N:15][N:16]([C:18]3[N:23]=[CH:22][C:21]([NH:24][CH:25]([C:29]4[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=4)[CH2:26][CH2:27][CH3:28])=[CH:20][CH:19]=3)[CH:17]=2)[CH2:12][CH2:11]1.O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl.O>[CH:10]1([C:13]2[CH:14]=[N:15][N:16]([C:18]3[N:23]=[CH:22][C:21]([NH:24][CH:25]([C:29]4[CH:37]=[CH:36][C:32]([C:33]([NH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:34])=[CH:31][CH:30]=4)[CH2:26][CH2:27][CH3:28])=[CH:20][CH:19]=3)[CH:17]=2)[CH2:12][CH2:11]1
Reactant: CCCC(Nc1ccc(-n2cc(C3CC3)cn2)nc1)c1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCC(Nc1ccc(-n2cc(C3CC3)cn2)nc1)c1ccc(C(=O)NCCC(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of ethyl 3-aminopropionate hydrochloride (31 mg, 0.27 mmol), (+/−)-4-(1-{[6-(4-cyclopropyl-1H-pyrazol-1-yl)pyridin-3-yl]amino}butyl)benzoic acid (0.050 g, 0.13 mmol), hydroxybenzotriazole hydrate (0.020 g, 0.13 mmol), and triethylamine (76 ul, 0.55 mmol) in dichloromethane (1.3 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (38.9 g, 201 mmol) (28 mg, 0.15 mmol) at rt. The mixture was stirred for 2 hours at ambient temperature. The reaction was diluted with water and the organic layer was separated. The aqueous layer was extracted with dichloromethane (2×) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([NH:11][NH2:12])=[O:10])=[CH:4][CH:3]=1.[CH2:15]=[C:16]1[O:19][C:18](=[O:20])[CH2:17]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([NH:11][NH:12][C:18](=[O:20])[CH2:17][C:16](=[O:19])[CH3:15])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)(C(=O)NN)c1ccc(Cl)cc1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NNC(=O)C(C)(C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.7 %

Procedure:
2-(4-chlorophenyl)-2-methylpropanehydrazide (9.0 g, 42.5 mmol) was dissolved in dry tetrahydrofuran (100 ml), and 4-methyleneoxetan-2-one (3.9 ml, 51 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 18 hours, then solvent removed under rescued pressure, and ethyl acetate was added. The solution was passed through a 120 g silica gel column eluting with ethyl acetate, to provide clean N′-(2-(4-chlorophenyl)-2-methylpropanoyl)-3-oxobutanehydrazide (12.2 g, 97%) as a viscous golden oil. TLC Rf=0.47 using 100% ethyl acetate as eluent on a glass backed silica gel plate.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[Cl:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:11][CH:10]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: Fc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Clc1ccc(CNc2ccccn2)cn1
Temperature: 230 °C

Procedure:
A mixture of 2-fluoropyridine (1.4 g, 15 mmol) and 6-chloro-3-pyridinemethanamine (alternatively named 5-aminomethyl-2-chloropyridine) (2.55 g, 18 mmol) in N-methylpyrrolidinone (5 mL) was heated at 230° C. in a microwave reactor for 30 min. This reaction was repeated four times using the same amounts of starting materials for each repetition. All five of the reaction mixtures were then poured into saturated aqueous sodium bicarbonate solution and extracted into ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over Na2SO4, and concentrated under reduced pressure. The crude product was then purified by chromatography on silica gel using 10% ethyl acetate in hexanes as the eluent to provide the title compound as an oil (5.1 g).
Reaction SMILES: [C:1]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)(=[O:4])[CH:2]=[CH2:3].C(#N)C.C(N(CC)CC)C.[Cl:31][CH2:32][CH2:33][C:34](N1C2C=CC=CC=2C(=O)NC2C=CC=NC1=2)=O>O1CCOCC1>[Cl:31][CH2:32][CH2:33][CH2:34][CH2:3][CH2:2][C:1]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4]
Reactant: O=C1Nc2cccnc2N(C(=O)CCCl)c2ccccc21
Reactant: C=CC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C1Nc2cccnc2N(C(=O)CCCCCCl)c2ccccc21

Procedure:
From the thus obtained 11-haloacyl-5,11-dihydro-6H-pyrido-[2,3-b][1,4]benzodiazepin-6-ones one can easily, as described above, obtain the intermediates having in 11-position an alkenylacyl group, which can subsequently be reacted with an amine of the formula III. Thus, for example, from 11-(3-chloropropionyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one in dioxane as solvent, 11-(acryloyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one, M.p.: 235° C. (decomp.) (from acetonitrile), was obtained with high yield after 1 hour of refluxing in the presence of an excess of triethylamine (see German Pat. No. 1,936,670).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.Cl[S:42]([C:45]1[O:49][C:48]([C:50]([O:52][CH3:53])=[O:51])=[CH:47][CH:46]=1)(=[O:44])=[O:43]>O1CCCC1.O>[C:19]([O:18][C:17]([N:16]([CH2:15][C:12]1[C:11]([F:25])=[C:10]([C:9]2[C:4]([F:3])=[N:5][CH:6]=[CH:7][CH:8]=2)[N:14]([S:42]([C:45]2[O:49][C:48]([C:50]([O:52][CH3:53])=[O:51])=[CH:47][CH:46]=2)(=[O:43])=[O:44])[CH:13]=1)[CH3:24])=[O:23])([CH3:21])([CH3:22])[CH3:20]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)o1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)o1
Reaction time: 0.25 h
Yield: 83 %

Procedure:
To a suspension of sodium hydride (60% in oil, 64.3 mg) in tetrahydrofuran (2 mL) was added a solution of tert-butyl {[5-(2-fluoropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (400 mg) in tetrahydrofuran (1 mL) at room temperature and the mixture was stirred for 15 min. 15-Crown-5 (354 mg) and methyl 5-(chlorosulfonyl)-2-furoate were added dropwise and the mixture was further stirred at room temperature for 30 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→2:1) to give the title compound as a pale-yellow oil (yield 522 mg, 83%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][NH:8][CH:9]=1)=[O:4].[H-].[Na+].Cl[C:13]1[CH2:17][C:16]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)([C:18]([F:21])([F:20])[F:19])[O:15][N:14]=1.N1C=CC=N1>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:13]2[CH2:17][C:16]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)([C:18]([F:19])([F:20])[F:21])[O:15][N:14]=2)[CH:9]=1)=[O:4]
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(Cl)=NO1
Reactant: COC(=O)c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Agent: c1cn[nH]c1
Solvent: CC#N
Product: COC(=O)c1cnn(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a solution of pyrazole-4-carboxylic acid methyl ester (756 mg) in acetonitrile (30 ml) under argon was added sodium hydride (240 mg). The reaction mixture was stirred at room temperature for 1 h. 15 mf of this solution was added dropwise to a solution of chloroisoxazoline of example 17.2 (630 mg) in acetonitrile (10 ml). It was then stirred at room temperature for 1 h; 15 ml of pyrazole solution was added again and the mixture was stirred over the weekend. The reaction was quenched by adding water and dichloromethane. The two layers were separated. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The crude residue was purified by column chromatography (from c-Hex (100%) to c-Hex:EtOAc (80:20)) to afford the title intermediate (810 mg) as a yellow solid. 1H-NMR (CDCl3, 400 MHz): 8.60 (s, 1H), 8.10 (s, 1H), 7.5 (m, 2H), 7.45 (m, 1H), 4.35 (d, 1H), 4.00 (d, 1H), 3.75 (s, 3H).
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[C:8]([N+:19]([O-:21])=[O:20])=[C:9]([C:12]([CH3:18])=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[CH2:10][OH:11])[CH2:4][CH3:5])[CH3:2].[Cl:22][C:23]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:24]=1[O:25][CH2:26][C:27](Cl)=[O:28]>C1C=CC=CC=1.CCOCC>[Cl:22][C:23]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:24]=1[O:25][CH2:26][C:27]([O:11][CH2:10][C:9]1[C:12]([CH3:18])=[CH:13][C:14]([N+:15]([O-:17])=[O:16])=[C:7]([NH:6][CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:8]=1[N+:19]([O-:21])=[O:20])=[O:28]
Reactant: CCC(CC)Nc1c([N+](=O)[O-])cc(C)c(CO)c1[N+](=O)[O-]
Reactant: O=C(Cl)COc1ccc(Cl)cc1Cl
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCC(CC)Nc1c([N+](=O)[O-])cc(C)c(COC(=O)COc2ccc(Cl)cc2Cl)c1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
3-[(1-Ethylpropyl)amino]-6-methyl-2,4-dinitrobenzyl alcohol (2.0 g; 0.007 mol) and 2,4-dichlorophenoxyacetyl chloride (used in excess over theory) are dissolved in benzene, and the solution stirred at 60° C. until tlc (silica gel-benzene) indicates the reaction to be complete. The reaction mixture is then cooled down, diluted with ether, and washed with dilute sodium bicarbonate solution until the washings became alkaline. The organic layer is then separated, dried over magnesium sulfate, and evaporated to afford a liquid residue, which solidifies gradually (3.3 g; 94%). Recrystallization of this solid from methanol affords 1.4 g of title product, melting point 103°-106° C.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH3:13])=[O:11])(OCC)=O)C.[H-].[Na+].[N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[CH:26]=O>C1COCC1>[N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1/[CH:26]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11]
Reactant: CCOP(=O)(CC(=O)OC)OCC
Reactant: O=Cc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 2-(diethoxyphosphoryl)acetate (4.41 g, 20.9 mmol) in THF (8 mL) was added NaH (0.91 g, 22 mmol) and the resultant solution was stirred for 20 min. The reaction mixture was cooled to 0° C. and quinoline-2-carbaldehyde (3.0 g, 19 mmol) in THF (4 mL) was added via syringe. The reaction was allowed to warm to room temperature and stirred for 3 h. The reaction was quenched with saturated sodium bicarbonate (10 mL) and the resulting mixture was extracted with DCM (100 mL). The DCM layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue obtained was purified by flash column chromatography on silica gel (0-30% EtOAc-heptane) to afford compound 79a. Mass spectrum (LCMS, ESI pos.) Calcd. For C13H11NO2 214.1 (M+H). found 214.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15]O)[CH:12]=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P([N:31]=[N+:32]=[N-:33])(C2C=CC=CC=2)=O)=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:31]([CH2:15][C:11]1[CH:12]=[N:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)=[N+:32]=[N-:33]
Reactant: OCc1cncc(OCc2ccccc2)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NCc1cncc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 20 h
Yield: 64.4 %

Procedure:
To a stirring solution of 250 mg (1.17 mmol) of (5-(benzyloxy)pyridin-3-yl)methanol in 8 mL of toluene was added 310 μL (1.44 mmol) of DPPA. The mixture was cooled to 0° C. and 210 μL (1.44 mmol) of 1,8-diazabicyclo[5.4.0]-undec-7-ene] (DBU) was added. The ice bath was removed, and stirring was continued with warming to room temperature. After about 20 h, the solution was diluted with EtOAc, and 1N HCl was added to a pH between 7 and 8. The organic layer was washed with water (2×15 mL) and brine (15 mL) and dried over Na2SO4. After filtration and concentration, the crude product was purified by flash silica gel chromatography (56-60% EtOAc/hexanes) to give 181 mg (65% yield) of 3-(azidomethyl)-5-(benzyloxy)pyridine as a colorless oil.
Reaction SMILES: [OH:1]C1C=CC2[C@H]3CC[C@H]4[C@H]([C@@H]3CCC=2C=1)CCC4.[CH3:19][O:20][C:21]1[CH:37]=[CH:36][C:35]2[C@H:27]3[CH2:28][CH2:29][C@H:30]4[C@H:34]([C@@H:26]3[CH2:25][CH2:24][C:23]=2[CH:22]=1)[CH2:33][CH2:32][CH2:31]4>>[CH3:19][O:20][C:21]1[CH:37]=[CH:36][C:35]2[C@H:27]3[CH2:28][CH2:29][C@H:30]4[C@H:34]([C@@H:26]3[CH2:25][CH2:24][C:23]=2[CH:22]=1)[CH2:33][CH2:32][C:31]4=[O:1]
Reactant: COc1ccc2c(c1)CC[C@H]1[C@@H]3CCC[C@H]3CC[C@H]21
Reactant: Oc1ccc2c(c1)CC[C@H]1[C@@H]3CCC[C@H]3CC[C@H]21
Product: COc1ccc2c(c1)CC[C@H]1[C@@H]3CCC(=O)[C@H]3CC[C@H]21

Procedure:
The 7α-substituted gon-4-en-3-one thus obtained can be aromatized to the 3-hydroxygona-1,3,5(10)-triene [Yuan, S.-S. et al, Steroids 39, 279 (1982)] which then can be methylated to the 3-methoxy derivative. Conversion to a 3-methoxygona-1,3,5(10)-triene can also be achieved directly [Brito, M. et al, Synth. Commun. 26, 623 (1996)]. When R6 is (17α-H,17β-OR7), the 17-hydroxy group is deprotected and oxidized to produce a 3-methoxygona-1,3,5(10)-trien-17-one derivative [for oxidation reactions, see: Hudlicky, M., Oxidations in Organic Chemistry, ACS Monograph 186, Washington, D.C., 1990]. When R6 is (17α-C≡CH,17β-OR7), the 17-hydroxy group is again deprotected and the 17α-ethynyl-17β-hydroxy derivative is converted to the 17-ketone e.g. by reaction with silver carbonate on celite [Rao, P. N. et al, Steroids 59, 621 (1994)] or other methods known in the art. In both cases, conversion to the 17-ketone can also be accomplished prior to aromatization. The 3-methoxygona-1,3,5(10)-trien-17-one derivative thus obtained can be brominated directly, for instance by reaction with copper(II) bromide in benzene/methanol [Segaloff, A. et al, Steroids 2, 99 (1973)]. The 3-methoxygona-1,3,5(10)-tren-17-one derivative can also be converted to the enol acetate and then treated with bromine [Johnson, W. S. et al, J. Am. Chem. Soc. 79, 2005 (1957)], or to the enol silyl ether followed by reaction with e.g. N-bromosuccinimide [Heathcock, C. H. et al, J. Amer. Chem. Soc. 104, 6081 (1982)]. Dehydrobromination of the 16α-bromoketone, e.g. by reaction with LiBr/Li2CO3/DMF [Bull, J. R. et al, J. Chem. Soc., Perkin Trans. I, 241 (1990)], usually results in a mixture of (14β)-3-methoxygona-1,3,5(10),15-tetraen-17-one and 3-methoxygona-1,3,5(10),14-tetraen-17-one derivatives. They can be separated whereafter the latter is reduced to the corresponding (17β)-3-methoxygona-1,3,5(10),14-tetraen-17-ol derivative by use of sodium borohydride, lithium aluminium hydride or other reducing agents.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10](O)[CH:11]=1)[O:8][C:7]([CH3:14])([CH3:13])[CH2:6][C:5]2([CH3:16])[CH3:15].C(N(CC)CC)C.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26].C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[CH:11]=1)[O:8][C:7]([CH3:14])([CH3:13])[CH2:6][C:5]2([CH3:16])[CH3:15]
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CC(C)(C)c2cc(Br)cc(O)c2O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC1(C)CC(C)(C)c2cc(Br)cc(C#C[Si](C)(C)C)c2O1
Yield: 84.2 %

Procedure:
Following General Procedure D and using 6-bromo-8-hydroxy-2,2,4,4-tetramethyl chroman (Intermediate 17, 1.0 g, 3.51 mmol), triethyl amine (5 mL), copper(I)iodide (0.066 g, 0.351 mmol), trimethylsilyl acetylene (2.5 mL, 17.6 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.246 g, 0.351 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 0.5% ethyl acetate in hexane as the eluent, the title compound (1.08 g, ˜100%) was obtained as a brown oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:2]1.[CH:16](N(CC)C(C)C)(C)C.Cl.[CH3:26][N:27](C)[OH:28].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C>[CH3:26][N:27]([O:28][CH3:16])[C:13](=[O:15])[CH2:12][CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)O
Reactant: O=C(O)CCCc1c[nH]c2ccccc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: CON(C)C(=O)CCCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
To a slurry of 1.75 g (8.61 mmol) of 3-indolebutyric acid (Aldrich Chemical Co.) in acetonitrile at room temperature was added 7.0 mL (40.2 mmol) of N,N-diisopropylethylamine, 1.0 g (10.3 mmol) of N,N-dimethylhydroxylamine hydrochloride and 4.19 g (9.5 mmol) of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) and the resulting mixture was allowed to stir at room temperature overnight and was then concentrated to dryness. The residue was dissolved into ethyl acetate and washed with water, 0.5N HCl, saturated NaHCO3 and brine and then dried over MgSO4 and concentrated. Flash chromatography (elution with a gradient of 2-10% ether in methylene chloride) provided 2.0 g of the amide 139. 1H NMR consistent with structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][N:10]=[C:11]3[CH:16]=[CH:15][C:14]([C:17]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)([C:19]4[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=4)[OH:18])=[CH:13][C:12]=23)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+]>O.C1COCC1>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)([OH:18])[C:19]2[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=2)=[CH:13][C:12]=1[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:9]
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2noc(-c3cccc(Cl)c3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc(N)c(C(=O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 49 %

Procedure:
TiCl3/15% in H2O (200 ml) was added at room temperature to a solution of intermediate (6-c) (38 g) in THF (300 ml). The mixture was stirred at room temperature for 90 minutes. The mixture was poured out on ice, basified with K2CO3, filtered over celite, washed with ethyl acetate and decanted. The organic layer was dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.1 and 95/5/0.1), yielding 18.7 g (49%) of (±)-[2-amino-5-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]phenyl](3-chlorophenyl)methanone (interm. 6-d).
Reaction SMILES: [C@@H:1]1([NH:10][C:11]2[N:16]=[CH:15][N:14]=[C:13]([NH:17][C@H:18]3[C@@H:22]4[O:23][C:24]([CH3:27])([CH3:26])[O:25][C@@H:21]4[C@@H:20]([CH2:28][OH:29])[CH2:19]3)[CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CCN(CC)CC.Cl[S:38]([NH2:41])(=[O:40])=[O:39].C(#N)C>C(Cl)Cl>[S:38](=[O:40])(=[O:39])([O:29][CH2:28][C@@H:20]1[C@@H:21]2[C@@H:22]([O:23][C:24]([CH3:26])([CH3:27])[O:25]2)[C@H:18]([NH:17][C:13]2[CH:12]=[C:11]([NH:10][C@@H:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]3)[N:16]=[CH:15][N:14]=2)[CH2:19]1)[NH2:41]
Reactant: NS(=O)(=O)Cl
Reactant: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](Nc3cc(N[C@H]4CCc5ccccc54)ncn3)[C@@H]2O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1(C)O[C@@H]2[C@@H](COS(N)(=O)=O)C[C@@H](Nc3cc(N[C@H]4CCc5ccccc54)ncn3)[C@@H]2O1
Reaction time: 2 h
Yield: 54 %

Procedure:
To a solution of [(3aR,4R,6R,6aS)-6-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-methanol (100. mg, 0.252 mmol) and Et3N (0.0527 mL, 0.378 mmol) in DCM (2.50 mL) was added dropwise a 2.00 M solution of chlorosulfonamide in ACN (0.190 mL, 0.380 mmol) at 0° C. and the mixture was stirred for 2 h. The reaction was diluted with DCM, quenched with H2O and the organic layer was separated, then concentrated in vacuo. The residue was purified via silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM to afford the title compound (65.0 mg, 54%). LC/MS: Rt=1.58 min, ES+ 476 (AA standard).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].S(O[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42])(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[C:1]1(=[O:11])[N:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42])[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: COC(=O)CCCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCCCCCCCCCCCN1C(=O)c2ccccc2C1=O
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of potassium phthalimide (2.96 g, 16.0 mmoles) and 100 ml of dried N,N-dimethylformamide was heated at 110° C. To this mixture was added dropwise 80 ml of a solution of methyl 18 tosyloxyoctadecanoate (5.0 g, 10.7 mmoles) in 80 ml of N,N-dimethylformamide, and the mixture was heated with stirring at 110° C. for 2 hours. The reaction mixture was poured into ice water to a total volume of 1.2 1, and stirred for 30 minutes. Thereafter, the precipitates that formed were collected by filtration and dissolved in chloroform. The obtained solution was washed with water and then with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and isolated and purified by silica 9el column chromatography [eluent: mixture of benzene and methylene chloride (volume ratio: 2:1)], to give methyl 18-phtahlimideocatadecanoate (4.15 g, 88%) having the following properties.
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.C(O)(=O)/C=C/C(O)=O.[CH3:17][N:18]1[C:22]2([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:21]([NH2:28])[CH2:20][CH2:19]1.C([O-])(O)=O.[Na+].Cl[C:35]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:36]=1[C:37](Cl)=[O:38].C(Cl)(Cl)[Cl:46]>>[CH3:17][N:18]1[C:22]2([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[CH:21]([NH:28][C:37](=[O:38])[C:36]2[CH:40]=[CH:41][C:42]([Cl:44])=[C:43]([Cl:46])[CH:35]=2)[CH2:20][CH2:19]1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CN1CCC(N)C12CCCCC2
Reactant: ClC(Cl)Cl
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: CN1CCC(NC(=O)c2ccc(Cl)c(Cl)c2)C12CCCCC2
Temperature: 25 °C

Procedure:
To a stirring suspension of 3.0 g (0.017 mole) of 1-methyl-4-amino-azaspiro[4.5]decane of Example 2 and 5.0 g of NaHCO3 in 50 ml of CHCl3 was added dropwise 3.8 g (0.018 mole) of 2,4-dichlorobenzoyl chloride in 25 ml of CHCl3. The reaction was refluxed for 3 hours, cooled to room temperature, filtered, and the solvent evaporated to give an oil. The residue was triturated with boiling hexane and decanted; the hexane solution afforded 3.1 g of 1-methyl-4-(3,4-dichlorobenzamido)-1-azaspiro[4.5]decane on standing. The solid was dissolved in ether and a solution of ethereal HCl was added. The resulting solid was collected and recrystallized three times from ethanol to give 2.4 g (37.5%) m.p. 227°-229° C. of 1-methyl-4-(2,4-dichlorobenzamido)-1-azaspiro[4.5]decane hydrochloride.