Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[N:11]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[C:10]2=[O:27])[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:35]1[CH:36]=[N:37][CH:38]=[C:39]([CH2:41][N:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)[CH:40]=1>O1CCOCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[C:23]([C:20]1[CH:19]=[CH:18][C:17]([N:11]2[C:12](=[O:16])[C:13]([CH3:15])([CH3:14])[N:9]([CH2:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:35]4[CH:36]=[N:37][CH:38]=[C:39]([CH2:41][N:42]5[CH2:43][CH2:44][CH2:45][CH2:46]5)[CH:40]=4)[CH:7]=3)[C:10]2=[O:27])=[CH:22][CH:21]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: Brc1cncc(CN2CCCC2)c1
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(N)c3)C(C)(C)C2=O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(Nc4cncc(CN5CCCC5)c4)c3)C(C)(C)C2=O)cc1
Yield: 12.5 %

Procedure:
To a solution of 500 mg of 1-[(2-aminopyridin-4-yl)methyl]-3-(4-tert-butylphenyl)-5,5-dimethylimidazolidine-2,4-dione obtained in stage c) of Example 7 in 15 mL of dioxane are successively added, under argon, 46 mg of palladium diacetate, 95 mg of (9,9-dimethyl-9H-xanthene-3,6-diyl)bis(diphenylphosphine)(Xantphos), 1.8 g of caesium carbonate and 0.39 g of 3-Bromo-5-pyrrolidin-1-ylmethylpyridine obtained in stage a) below. The reaction mixture is refluxed for 4 hours and then filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol (96/4 by volume) to give 90 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[2-(5-pyrrolidin-1-ylmethylpyridin-3-ylamino)pyridin-4-ylmethyl]imidazolidine-2,4-dione, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].C(Cl)(=O)C(Cl)=O.[CH:31](O)([CH3:33])[CH3:32].N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH:31]([CH3:33])[CH3:32])=[O:13])(=[O:6])=[O:7]
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)O
Reactant: CC(C)O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)OC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Yield: 76.3 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoic acid (11) (0.73 g, 1.9 mmol) dissolved in 20 mL of anhydrous dichloromethane (DCM) was reacted with 1.1 mL (2.2 mmol) of oxalyl chloride (2.0 M in DCM). After completion of the reaction, a solution of 2 mL (1.57 g, 26.1 mmol) of isopropanol (iPrOH) and 0.16 mL of pyridine (0.15 g, 1.9 mmol) in 10 mL of anhydrous dichloromethane (DCM) was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 0.61 g (75% yield) of the title compound (25a) as a colorless oil. Rf=0.67 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3): δ=1.06 (s, 3H), 1.08 (s, 3H), 1.30-1.32 (m, 3H), 2.25-2.32 (m, 2H), 3.65 (t, J=5.6 Hz, 2H), 3.81 (s, 1H), 3.98 (d, J=9.2 Hz, 1H), 4.23 (d, J=9.2 Hz, 1H), 4.35 (d, J=11.2 Hz, 1H), 4.62 (d, J=11.2 Hz, 1H), 5.14 (m, 1H), 7.33-7.36 (m, 5H) ppm. MS (ESI) m/z 420.94 (M+H)+, 442.95 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [C:1](=O)=O.CC(C)=O.C([Li])CCC.CCCCCC.[CH2:19]([C@@H:26]1[C@@H:34]([O:35][CH2:36][CH2:37][C:38](=O)[CH3:39])[C@H:33]([CH3:41])[O:32][C:31](=[O:42])[C@@H:30]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:29][O:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:19]([C@@H:26]1[C@@H:34]([O:35][CH2:36][CH2:37][C:38]([CH3:1])=[CH2:39])[C@H:33]([CH3:41])[O:32][C:31](=[O:42])[C@@H:30]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:47])([CH3:49])[CH3:48])[CH2:29][O:28][CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C=O
Reactant: CC(=O)CCO[C@@H]1[C@@H](Cc2ccccc2)COC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CCCCCC
Product: C=C(C)CCO[C@@H]1[C@@H](Cc2ccccc2)COC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1C
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 22 %

Procedure:
To a suspension of methyltriphenylphosphonium bromide (346 mg, 0.969 mmol, 1.40 equiv) in anhydrous THF (7 mL) at −78° C. (dry ice/acetone) was added a 2.5 M solution of n-butyllithium in hexane (n-BuLi; 332 μL, 0.830 mmol, 1.20 equiv). The flask was removed from the cold bath for 25 min and then re-cooled to −78° C. In a separate vessel, tert-butyl ((3S,7S,8R,9S)-7-benzyl-9-methyl-2-oxo-8-(3-oxobutoxy)-1,5-dioxonan-3-yl)carbamate (311 mg, 0.692 mmol, 1.00 equiv) was dissolved in anhydrous THF (7 mL), cooled to −78° C., and transferred via cannula to the phosphonium ylide solution prepared above. The resulting light yellow suspension was stirred at −78° C. for 50 min and then transferred to a −50° C. bath (deficient dry ice/acetone) and stirred for 45 min. The suspension was slowly warmed to −20° C. over 1 h and then warmed to 0° C. (ice water bath) and stirred for 20 min. The reaction was quenched with ½ sat'd aq. ammonium chloride (NH4Cl; 20 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated to give a colorless oil. Purification by automated silica gel column chromatography (2-25% acetone in hexanes) provided tert-butyl ((3S,7S,8R,9S)-7-benzyl-9-methyl-8-((3-methylbut-3-en-1-yl)oxy)-2-oxo-1,5-dioxonan-3-yl)carbamate (68 mg, 22%) as a sticky oil: IR (ATR) 2977, 2933, 2875, 1750, 1712, 1497, 1454, 1367, 1326, 1250, 1202, 1163, 1080, 1042, 1023 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.38-7.23 (m, 2H), 7.23-7.10 (m, 3H), 5.16 (d, J=8.2 Hz, 1H), 4.95 (dq, J=9.2, 6.4 Hz, 1H), 4.80 (s, 1H), 4.77-4.69 (m, 1H), 4.59 (q, J=7.4 Hz, 1H), 3.88 (dd, J=11.5, 7.3 Hz, 1H), 3.83-3.71 (m, 1H), 1.57-1.46 (m, 3H), 3.65 (dt, J=8.7, 7.0 Hz, 1H), 3.50-3.31 (m, 2H), 3.25 (dd, J=11.4, 7.3 Hz, 1H), 3.20-3.02 (m, 2H), 2.32 (t, J=6.9 Hz, 3H), 1.91 (s, 1H), 1.49 (d, J=6.4 Hz, 3H), 1.41 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 172.27, 154.98, 142.31, 139.91, 129.15, 128.43, 126.12, 111.99, 85.31, 80.06, 75.48, 72.79, 72.30, 71.29, 52.93, 47.28, 38.33, 35.19, 28.28, 22.88, 18.80; HRMS-ESI (m/z) [M+Na]+ calc'd for C25H37NO6Na, 470.2513. found, 470.2522.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]2[C:13](=O)[CH:12]3[CH2:15][CH2:16][N:9]2[CH2:10][CH2:11]3)[CH:2]=1.[CH2:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH2:17]=[C:13]1[CH:12]2[CH2:15][CH2:16][N:9]([CH2:10][CH2:11]2)[CH:8]1[CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1C2CCN(CC2)C1Cc1cccnc1
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: C=C1C2CCN(CC2)C1Cc1cccnc1

Procedure:
The saturated ketone intermediates, such as 2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one, also present opportunities for derivatization. One example is the reaction with phosphorus ylids (Wittig and Horner-Emmons reagents) to give alkenes. These alkenes can subsequently be reduced to alkanes by catalytic hydrogenation, providing a means of producing 2-((heteroaryl)alkyl)-1-azabicycles with alkyl and substituted alkyl substituents at the 3-position of the azabicycle. Thus, by way of example, 2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one reacts with methylenetriphenylphosphorane to give 3-methylene-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane. Hydrogenation of this alkene, for example, over palladium on carbon catalyst, yields 3-methyl-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane as predominantly the cis diastereomer.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[N+:14]([C:17]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=2[C:37]#[N:38])=[CH:22][C:18]=1[C:19](Cl)=[O:20])([O-:16])=[O:15]>C1(C)C=CC=CC=1>[N+:14]([C:17]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][C:28]=2[C:37]#[N:38])=[CH:22][C:18]=1[C:19]([O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)=[O:20])([O-:16])=[O:15]
Reactant: OC1CCOC1
Reactant: N#Cc1cc(C(F)(F)F)ccc1Oc1ccc([N+](=O)[O-])c(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: N#Cc1cc(C(F)(F)F)ccc1Oc1ccc([N+](=O)[O-])c(C(=O)OC2CCOC2)c1
Reaction time: 8 h

Procedure:
3-Hydroxytetrahydrofuran (0.04 mole), toluene (50 ml) and triethylamine (0.04 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and addition funnel. A solution of 2-nitro-5-(2-cyano-4-trifluoromethylphenoxy)benzoyl chloride (0.04 mole) in toluene (20 ml) is slowly added at room temperature with stirring. After the addition is completed, stirring is continued for a period of about eight hours. After this time, the reaction mixture is washed with water and dried over anhydrous magnesium sulfate. The dried solution is then stripped of solvent under reduced pressure leaving a residue. This residue is purified by silica gel chromatography using toluene and ethyl acetate/toluene mixture as the eluant to yield the desired product 3-tetrahydrofuryl 2-nitro-5-(2-cyano-4-trifluoromethylphenoxy)benzoate.
Reaction SMILES: C([C:3]1([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[Cl:22])[CH2:9][CH2:8][CH2:7][CH2:6][C:5](=[CH:10]N(C)C)[C:4]1=O)C.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([NH:45][C:46]([NH2:48])=[NH:47])[CH:36]=[CH:37][C:38]=1[N:39]1[CH:43]=[C:42]([CH3:44])[N:41]=[CH:40]1>>[Cl:22][C:16]1[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=1[CH:3]1[C:4]2[N:48]=[C:46]([NH:45][C:35]3[CH:36]=[CH:37][C:38]([N:39]4[CH:43]=[C:42]([CH3:44])[N:41]=[CH:40]4)=[C:33]([O:32][CH3:31])[CH:34]=3)[N:47]=[CH:10][C:5]=2[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CCC1(c2cc(Cl)ccc2Cl)CCCCC(=CN(C)C)C1=O
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)C(c2cc(Cl)ccc2Cl)CCCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from crude ethyl 2-(2,5-dichloro-phenyl)-7-[1-dimethylamino-methylidene]-cycloheptanone (197 mg, ca. 0.61 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (169 mg, 0.45 mmol) using in analogous manner the procedure described in example 45b). Obtained as a pale-yellow solid (163 mg, 73%). MS ISP (m/e): 494.0 [(M+H)+]. mp 218-220° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:13](OC)=[O:14].[BH4-].[Li+].Cl.C(Cl)(Cl)Cl>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:13][OH:14]
Reactant: COC(=O)c1ccc2c(nc(C)n2C)c1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: Cc1nc2c(Cl)c(CO)ccc2n1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
To a solution of methyl 4-chloro-1,2-dimethyl-1H-benzimidazole-5-carboxylate (1.07 g) in anhydrous tetrahydrofuran (11 ml) was added portionwise lithium borohydride (198 mg) at room temperature and the mixture was stirred for 2 hr and heated to 60° C. Thereafter, lithium borohydride (99 mg) was added 3 times at 1 hr intervals. The reaction mixture was ice-cooled and adjusted to pH 2 with 1N hydrochloric acid. The mixture was stirred at room temperature for 30 min, and chloroform was added to the mixture. The precipitated crystals were collected by filtration to give 4-chloro-5-hydroxymethyl-1,2-dimethyl-1H-benzimidazole as colorless crystals (487 mg). The filtrate was extracted 6 times with chloroform:methanol=5:1. The organic layer was dried over anhydrous magnesium sulfate, filtrated and concentrated. The residue was crystallized from isopropyl ether to give the objective product as colorless crystals (417 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)=[N:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[OH:24]>>[Br:1][C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)=[N:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[OH:24])=[O:9]
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: Cc1nc(OCC2CC2)c(Br)cc1C(=O)O
Product: Cc1nc(OCC2CC2)c(Br)cc1C(=O)N[C@@H]1CCCC[C@H]1O

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 31b, using 5-bromo-6-cyclopropylmethoxy-2-methyl-nicotinic acid and (1R,2R)-2-amino-1-cyclohexanol as starting materials, MS (ISP): 383.1, 385.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:20])[N:11]([CH2:18][OH:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[P:21](Cl)(=[O:38])([O:30][CH2:31]C1C=CC=CC=1)[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[P:21]([O:30][CH3:31])([O:19][CH2:18][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)/[C:9](=[CH:8]/[C:3]2[NH:4][C:5]([CH3:7])=[CH:6][C:2]=2[CH3:1])/[C:10]1=[O:20])([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:38]
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(CO)c3ccccc32)[nH]1
Reactant: O=P(Cl)(OCc1ccccc1)OCc1ccccc1
Product: COP(=O)(OCc1ccccc1)OCN1C(=O)/C(=C\c2[nH]c(C)cc2C)c2ccccc21

Procedure:
The title compound was prepared from (3Z)-3-[(3,5-Dimethyl-1H-pyrrol-2-yl)-methylidene]-1-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one (1) and benzyl methyl phosphorochloridate (modification of procedure used to prepare {3(Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)-methylidene]-2-oxo-2,3-dihydro-1H-indol-1-yl}methyl acetate (2)).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]2[C:21]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[NH:15][C:14]=2[CH:22]=O)[CH2:6][CH2:5]1.OC1CCN(CCCC2C3CCCCC=3NC=2C=O)CC1.[CH2:45]([S:47]([C:50]1[CH:51]=[C:52]2[C:56](=[CH:57][CH:58]=1)[NH:55][C:54](=[O:59])[CH2:53]2)(=[O:49])=[O:48])[CH3:46]>>[CH2:45]([S:47]([C:50]1[CH:51]=[C:52]2[C:56](=[CH:57][CH:58]=1)[NH:55][C:54](=[O:59])/[C:53]/2=[CH:22]\[C:14]1[NH:15][C:16]2[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=2[C:13]=1[CH2:12][CH2:11][CH2:10][N:7]1[CH2:6][CH2:5][N:4]([CH2:3][CH2:2][OH:1])[CH2:9][CH2:8]1)(=[O:48])=[O:49])[CH3:46]
Reactant: O=Cc1[nH]c2c(c1CCCN1CCN(CCO)CC1)CCCC2
Reactant: CCS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Agent: O=Cc1[nH]c2c(c1CCCN1CCC(O)CC1)CCCC2
Product: CCS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCCN1CCN(CCO)CC1)CCCC3)C(=O)N2
Yield: 59.8 %

Procedure:
3-{3-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]- propyl}-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (64 mg, 0.2 mmol), prepared by following the procedure described for 3-[3-(4-hydroxy-piperidin-1-yl)- propyl]-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (example 20), was condensed with 5-ethylsulfonyloxindole (Example 5) (69 mg, 0.2 mmol, 65%pure). The reaction solution was purified by flash chromatography, eluting with dichloromethane/methanol (20/1, 15/1 then 10/1) to provide 63 mg of the desired compound.
Reaction SMILES: [CH:1]([C@@H:4]1[N:8]([C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[N:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:25]=5)=[CH:20][CH:19]=4)=[C:11]3[N:10]=2)[C:7](=[O:37])[NH:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:41][CH:42]1[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]1>CN(C=O)C>[CH:1]([C@H:4]1[CH2:5][N:6]([CH2:41][CH:42]2[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])[CH2:44][CH2:43]2)[C:7](=[O:37])[N:8]1[C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[CH:16][C:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[N:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:35])[CH3:36])[N:25]=4)=[CH:20][CH:19]=3)=[C:11]2[N:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@H]1CNC(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)[C@H]1CN(CC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
To a stirred solution of (S)-5-isopropyl-1-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-2-one (Example 25, Step 4; 80 mg, 0.15 mmol) in DMF (1 mL) was added NaH (60% dispersion in mineral oil, 12 mg, 0.31 mmol) at 0° C. under N2. After stirring at ambient temperature for 30 minutes, a solution of tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (77 mg, 0.28 mmol) in DMF (0.5 mL) was added dropwise. The reaction mixture was heated at 80° C. for 1 hour. After cooling, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (hexane:EtOAc, 1:4) to give (S)-tert-butyl 4-((4-isopropyl-2-oxo-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-1-yl)methyl)piperidine-1-carboxylate (99 mg, 90%).
Reaction SMILES: C([N:8]([CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[C:35]([C:40](=[O:42])[NH2:41])[CH:34]=1)[CH2:9][CH:10]([OH:29])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]([CH3:28])[C:21]([CH3:27])=[C:22]([C:24](=[O:26])[CH3:25])[N:23]=2)=[CH:15][CH:14]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:40]([C:35]1[CH:34]=[C:33]([CH:38]=[CH:37][C:36]=1[OH:39])[O:32][CH2:31][CH2:30][NH:8][CH2:9][CH:10]([OH:29])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]([CH3:28])[C:21]([CH3:27])=[C:22]([C:24](=[O:26])[CH3:25])[N:23]=2)=[CH:15][CH:14]=1)(=[O:42])[NH2:41]
Reactant: [H][H]
Reactant: CC(=O)c1nc(-c2ccc(OCC(O)CN(CCOc3ccc(O)c(C(N)=O)c3)Cc3ccccc3)cc2)n(C)c1C
Agent: [Pd]
Solvent: CO
Product: CC(=O)c1nc(-c2ccc(OCC(O)CNCCOc3ccc(O)c(C(N)=O)c3)cc2)n(C)c1C

Procedure:
A solution of 13.2 g of crude 1-[N-benzyl-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]]-3-[4-(4-acetyl-1,5-dimethyl-1H-imidazol-2-yl)-phenoxy]-2-propanol in 140 ml of methanol is hydrogenated with the addition of 1.3 g of palladium-on-carbon catalyst until 1 molar equivalent of hydrogen has been absorbed. After filtration and evaporation of the solvent, an oil is obtained which, after recrystallising twice from ethanol, yields 1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(4-acetyl-1,5-dimethyl-1H-imidazol-2-yl)-phenoxy]-2-propanol having a melting point of 128°-130°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:16]=[C:15]([N:17]([CH3:19])[CH3:18])[S:14][C:13]=2[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[CH2:32][N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)[C:26](Cl)=[O:27].[OH-].[Na+]>ClC1C=CC=CC=1.[Cl-].[Na+].O>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C:26]([C:16]2[C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:20][C:13]=3[S:14][C:15]=2[N:17]([CH3:18])[CH3:19])=[O:27])[CH:29]=[CH:30][C:31]=1[CH2:32][N:33]1[CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: CN(C)c1cc2ccc(OCc3ccccc3)cc2s1
Reactant: COc1cc(C(=O)Cl)ccc1CN1CCCC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Solvent: O
Product: COc1cc(C(=O)c2c(N(C)C)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Yield: 84 %

Procedure:
A solution of 6-benzyloxy-2-(dimethylamino)benzo[b]thiophene (2.5 g, 8.8 mmol) and 3-methoxy-4-[(1-pyrrolidinyl)methyl]benzoyl chloride (3.0 g, 1.3 equiv) in chlorobenzene (30 mL) was heated at 135° C. under nitrogen for 2 h. The cooled reaction mixture was diluted with brine (100 mL), neutralized with NaOH solution (5.0 M), and extracted with dichloromethane (100 mL×3). The combined organic layers were dried with sodium sulfate and concentrated under reduced pressure. Chromatography with Et3N:EtOAc (5:95) afforded the product as a brown oil (3.7 g, 84%).
Reaction SMILES: [CH3:1][S:2][C:3]1[O:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.Cl[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH:22][CH3:23])=[O:21])[CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:1][S:2][C:3]1[O:4][C:5]2[CH:11]=[C:10]([O:12][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH:22][CH3:23])=[O:21])[CH:15]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CSc1nc2ccc(O)cc2o1
Reactant: CNC(=O)c1cc(Cl)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc3nc(SC)oc3c2)ccn1
Temperature: 75 °C
Reaction time: 6 h

Procedure:
To a solution of 2-(methylthio)benzo[d]oxazol-6-ol (8.5 g, 46.7 mmol, 1 eq) in 80 mL of N,N-dimethylformamide was added 4-chloro-N-methylpyridine-2-carboxamide (16.0 g, 93.4 mmol, 2.0 eq) and cesium carbonate (45.7 g, 140.1 mmol, 3.0 eq). The reaction mixture was stirred at 75° C. for 6 hours. After the mixture was cooled to room temperature, the mixture was added 120 mL of water. After filtration, the solid was purified by silica gel column eluted with ethyl acetate and hexane to give the titled compound. MH+=316.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:11]([Br:12])=[CH:10][N:9]=[C:8]([NH:13][C:14]2[CH:15]=[C:16]([NH:20][C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[CH:17]=[CH:18][CH:19]=2)[N:7]=1.CCN(C(C)C)C(C)C.[CH2:37]([S:40](Cl)(=[O:42])=[O:41])[CH2:38][CH3:39]>ClCCl.CN(C1C=CN=CC=1)C>[Br:12][C:11]1[C:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][S:40]([CH2:37][CH2:38][CH3:39])(=[O:42])=[O:41])=[N:7][C:8]([NH:13][C:14]2[CH:15]=[C:16]([NH:20][C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[CH:17]=[CH:18][CH:19]=2)=[N:9][CH:10]=1
Reactant: NCCCNc1nc(Nc2cccc(NC(=O)N3CCCC3)c2)ncc1Br
Reactant: CCCS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCS(=O)(=O)NCCCNc1nc(Nc2cccc(NC(=O)N3CCCC3)c2)ncc1Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
To a solution of N-(3-((4-((3-aminopropyl)amino)-5-bromo-2-pyrimidinyl)amino)phenyl)-1-pyrrolidinecarboxamide (150 mg, 0.30 mmol) in dichloromethane (4 mL) was added DIEA (0.16 mL, 0.92 mmol) and DMAP (1.4 mg, 0.011 mmol) at 0° C., then a solution of 1-propanesulfonyl chloride (51 mg, 0.36 mmol) in dichloromethane (5 mL) was added. The resulting reaction mixture was stirred at 0° C. for 1 h and at room temperature overnight. The reaction mixture was concentrated. Purification by HPLC using acetonitrile/water gave the title compound (67 mg).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([CH3:22])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:4][CH2:3]1.[C:23]([O:27][C:28](=[O:31])[CH2:29]Br)([CH3:26])([CH3:25])[CH3:24].[OH-].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[C:23]([O:27][C:28](=[O:31])[CH2:29][O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([CH3:22])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:4][CH2:3]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CN([C@H]1CC[C@H](O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN([C@H]1CC[C@H](OCC(=O)OC(C)(C)C)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
To a suspension of 1 g (2.96 mmol) of trans-N-(4-hydroxy-cyclohexyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide in 12 mL of toluene were added 0.9 ml (6.04 mmol, 2 eq) of bromo-acetic acid tert-butyl ester, 100 mg (0.3mmol, 0.1 eq) of tetra-N-butylammonium hydrogensulfate and 12 mL of 50% aqueous NaOH. The mixture was stirred at 500 for 1 h. The organic phase was dissolved in EtOAc, dried over Na2SO4, and the solvent evaporated. Column chromatography on silica gel gave 1.3 g (97%) of trans-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-acetic acid tert-butyl ester as an off-white solid, MS: 469 (M+NH4+).