Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[C:19]([CH3:20])=[CH:18][S:17][CH:16]=2)[N:12]([S:21]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)(=[O:23])=[O:22])[CH:11]=1)C)(C)(C)C.[C:31](=[O:34])([O-:33])O.[Na+].F[C:37](F)(F)[C:38]([OH:40])=[O:39]>>[C:38]([OH:40])(=[O:39])/[CH:37]=[CH:1]/[C:31]([OH:33])=[O:34].[CH3:6][NH:7][CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[C:19]([CH3:20])=[CH:18][S:17][CH:16]=2)[N:12]([S:21]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)(=[O:22])=[O:23])[CH:11]=1
Reactant: Cc1cscc1-c1cc(CN(C)C(=O)OC(C)(C)C)cn1S(=O)(=O)c1cccnc1
Reactant: O=C([O-])O
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Product: CNCc1cc(-c2cscc2C)n(S(=O)(=O)c2cccnc2)c1
Product: O=C(O)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
By a similar reaction as in Example 59 and using tert-butyl {[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (943 mg), the title compound was obtained as colorless crystals (yield 553 mg, 57%). More specifically, tert-butyl{[5-(4-methyl-3-thienyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (943 mg) was dissolved in trifluoroacetic acid (3 mL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was basified with a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:9) to give a free salt of the title compound as a colorless oil (yield 631 mg). A solution of the obtained free salt in ethyl acetate (5 mL) was added to a solution of fumaric acid (211 mg) in methanol (2 mL), and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol-water to give the title compound as colorless crystals (yield 553 mg, 57%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)O1.I[C:28]1[CH:33]=[CH:32][N:31]([CH2:34][CH2:35][C@@:36]([CH3:51])([S:47]([CH3:50])(=[O:49])=[O:48])[C:37]([NH:39][O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)=[O:38])[C:30](=[O:52])[CH:29]=1>COCCOC.CO.C(OCC)(=O)C>[CH3:51][C@@:36]([S:47]([CH3:50])(=[O:48])=[O:49])([CH2:35][CH2:34][N:31]1[CH:32]=[CH:33][C:28]([C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:19][CH:20]=2)=[CH:29][C:30]1=[O:52])[C:37]([NH:39][O:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][O:42]1)=[O:38]
Reactant: C[C@@](CCn1ccc(I)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Reactant: CC1(C)OB(c2ccc(-n3cccn3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: C[C@@](CCn1ccc(-c2ccc(-n3cccn3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
Trisdibenzylidine dipalladium (29 mg, 0.049 mmol) was added to a mixture of potassium carbonate (343 mg, 2.46 mmol), 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1H-pyrazole (133 mg, 0.49 mmol) and (2R)-4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (245 mg, 0.49 mmol), which may be synthesized as described in Preparation 2B in 1,2-dimethoxyethane-methanol (5.0 mL, 1:1). The reaction was heated to 80° C. and allowed to stir overnight. The reaction was diluted with ethyl acetate (10 mL), filtered through a pad of Celite, and concentrated under reduced pressure. The crude material was purified by flash chromatography (1:0-9:1 ethyl acetate/methanol) to provide a colorless residue (58 mg, 23%). MS (LCMS) m/z 513.7 (M−1).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([CH2:15][CH2:16][OH:17])[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][OH:14])[CH:7]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:17][CH2:16][CH2:15][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][OH:14])[CH:7]=1)(=[O:4])=[O:3]
Reactant: OCCc1cccc(CCO)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1cccc(CCO)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.67 mL) in DCM (2 mL) was added dropwise to a stirred solution at 0° C. of 2,2′-(1,3-phenylene)diethanol (1.30 g) and triethylamine (1.36 mL) in DCM (30 mL). The reaction mixture was stirred for 1 hour at 0° C. and then washed with water. The aqueous layer was re-extracted with DCM and the combined organic phases were dried, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 3% methanol in dichloromethane as solvent. Fractions containing the product were evaporated to dryness to afford the titled compound. Yield 0.52 g.
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]#[N:11])[CH:5]=[CH:4]1.[Cl:18][C:19]([Cl:24])([Cl:23])[C:20](Cl)=[O:21].C(N(CC)CC)C>O1CCCC1>[Cl:18][C:19]([Cl:24])([Cl:23])[C:20]([O:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10]#[N:11])[CH:5]=[CH:4]1)=[O:21]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: N#CC(=C1C=CC(=NO)C=C1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CC(=C1C=CC(=NOC(=O)C(Cl)(Cl)Cl)C=C1)c1ccccc1
Temperature: 5 °C
Reaction time: 0.83 h

Procedure:
8 g (36 mmol) of (4-Hydroxyimino-cyclohexa-2,5-dienylidene)-phenyl-acetonitrile, prepared as described in example 1.1, are dissolved in 90 ml of tetrahydrofuran (THF) and cooled in an ice bath. After adding 7.2 g (39 mmol) of trichloroacetyl chloride to the solution, 5.4 g (54 mmol) of triethylamine are added dropwise, keeping the temperature below 5° C. While the reaction mixture is stirred at 5° C. for 50 min, a precipitate is formed. The precipitate is filtered off and washed with THF. The filtrate is concentrated by a rotary evaporator. The residue is diluted with 2-propanol (2-PrOH) and stirred at room temperature overnight. After cooling the mixture in an ice bath, the solid is isolated by filtration and washed with 2-PrOH. The product is obtained in the form of an orange solid,mp 147-148° C.(Dec). The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 6.97 (dd, 1H), 7.30 (dd, 1H), 7.38 (dd, 1H), 7.52 (s, 5H), 7.65 (dd, 1H). 1H-NMR reveals the presence of a single isomer.
Reaction SMILES: CN1C([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=2)=NC(CCC(O)=O)=N1.[CH3:30][N:31]([C:40](=[N:43][C:44](=[O:51])[CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])SC)[N:32]=[CH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:30][N:31]([C:40](=[N:43][C:44](=[O:51])[CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:13]=1)[N:32]=[CH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCOC(=O)CC(=O)N=C(SC)N(C)N=Cc1ccccc1
Reactant: Cn1nc(CCC(=O)O)nc1NCCCOc1cccc(CN2CCCCC2)c1
Product: CCOC(=O)CC(=O)N=C(NCCCOc1cccc(CN2CCCCC2)c1)N(C)N=Cc1ccccc1
Yield: 155.6 %

Procedure:
A mixture of 3-[3-(1-piperidinylmethyl)phenoxy]propanamine (A) (3.61 g) and ethyl 3-[[[1-methyl-2-(phenylmethylene)hydrazino](methylthio)methylene]amino]-3-oxopropanoate (4.7 g) was heated at 50° under water pump vacuum during 4 h. to gave the title compound as an orange gum (7.3 g). T.l.c. System D, Rf 0.65.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].CC(C)N=C=NC(C)C.[C:19]([O:23][C:24]([N:26]1[CH2:39][CH2:38][C:37]2[C:36]3[C:35]([Cl:40])=[C:34]([Cl:41])[CH:33]=[CH:32][C:31]=3[N:30]([CH2:42][C:43](O)=[O:44])[C:29]=2[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C1C=CN=CC=1)C.C1COCC1.CCOC(C)=O>[Cl:41][C:34]1[CH:33]=[CH:32][C:31]2[N:30]([CH2:42][C:43]([NH:4][C:3]3[CH:5]=[CH:6][CH:7]=[C:8]([CH3:9])[C:2]=3[CH3:1])=[O:44])[C:29]3[CH2:28][CH2:27][N:26]([C:24]([O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:25])[CH2:39][CH2:38][C:37]=3[C:36]=2[C:35]=1[Cl:40]
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3ccc(Cl)c(Cl)c23)CC1
Reactant: Cc1cccc(N)c1C
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)Cn2c3c(c4c(Cl)c(Cl)ccc42)CCN(C(=O)OC(C)(C)C)CC3)c1C
Reaction time: 4 h
Yield: 58.4 %

Procedure:
DMAP (89 mg, 0.73 mmol), 2,3-dimethylaniline (98 mg, 0.81 mmol) and DIC (0.13 mL, 0.81 mmol) were added to the solution of crude [3-(tert-butoxycarbonyl)-9,10-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl]acetic acid (0.30 g, 0.73 mmol) in dry THF (3.5 mL). After 4 h, additional 2,3-dimethylaniline (0.049 mL, 0.40 mmol) and THF (2 nL) was added. The reaction was diluted with EtOAc after 25 h followed by washing with 10% aqueous citric acid (75 mL), saturated aqueous NaHCO3 (40 mL), and brine (40 mL). A precipitate in the combined organic layers was filtered to yield 0.22 g (58%) white solid: mp 232.5-233.0° C.; 1H NMR (DMSO, 400 MHz) δ 9.77 (s, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.28 (d, J=8.7 Hz, 1H), 7.13 (d, J=6.8 Hz, 1H), 7.03 (m, 2H), 5.11 (s, 2H), 3.64 (m, 4H), 3.39 (m, 2H), 3.03 (m, 2H), 2.24 (s 3H), 2.09 (s, 3H), 1.41 (s, 9H); IR (diffuse reflectance) 2977, 1692, 1659, 1541, 1474, 1451, 1412, 1366, 1303, 1269, 1201, 1174, 1112, 791, 773 cm−1; MS (EI) m/z 515 (M+), 376, 226, 224, 212, 189, 149, 133, 119, 55, 52; HRMS (EI) calcd for C27H31Cl2N3O3 515.1743, found 515.1747.
Reaction SMILES: [Cl:1][C:2]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:12][C:11]2[C:3]=1[N:4]=[C:5]1[C:10]=2[CH:9]=[C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:7]=[CH:6]1.O(C)S([C:29](F)(F)F)(=O)=O>C1(C)C=CC=CC=1.C(OCC)C>[ClH:1].[Cl:1][C:2]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH+:12]([CH3:29])[C:11]2[C:3]=1[N:4]=[C:5]1[C:10]=2[CH:9]=[C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:7]=[CH:6]1
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: Clc1c2nc3ccc(-c4ccccc4)cc3c-2[nH]c2ccccc12
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C[NH+]1C2=c3cc(-c4ccccc4)ccc3=NC2=C(Cl)c2ccccc21
Product: Cl
Reaction time: 24 h
Yield: 279.1 %

Procedure:
To a solution of 11-chloro-7-phenylquindoline from Example 96 (0.250 g, 0.760 mmol) in toluene (10 ml, freshly distilled) stirring under nitrogen was added methyl triflate (0.130 mL, 0.114 mmol). The mixture stirred for 2 h at room temperature and was diluted with diethyl ether (40 mL) and filtered. The orange filter cake was placed under high vacuum for 24 h. The orange residue was suspended in chloroform and adsorbed onto neutral alumina. The adsorbent was chromatographed over basic alumina (eluting with chloroform until the eluant was free of impurities by TLC, then eluting with 0.2% methanol in chloroform). The violet fractions were collected and concentrated to a small volume (50 mL). The violet solution was acidified with ethereal 1 M HCl to a bright yellow endpoint. The mixture was cooled below room temperature and filtered. The filter cake was dried under high vacuum to yield 0.121 g (42%) of the title compound as a red solid; 1H NMR (DMSO-d6) δ 13.62 (s, 1H), 8.90-8.86 (m, 2H), 8.60 (d, J=8.4, 1H), 8.27-8.20 (m, 2H), 8.06 (t, J=7.6, 1H), 7.92-7.88 (m, 3H), 7.55 (t, J=7.6, 2H), 7.44 (t, J=7.6, 1H), 5.11 (s, 3H); 13C NMR (DMSO-d6) δ 145.21, 139.37, 138.58, 135.80, 134.31, 133.73, 132.84, 132.04, 129.10, 129.00, 128.39, 127.55, 127.28, 126.96, 126.62, 124.55, 123.80, 123.37, 118.82, 114.93, 113.91, 40.65; MS (FAB, m/z) 343 (M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH:12]2[CH2:17][CH2:16][C:15](=[C:18]3[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)=[CH:6][CH:5]=1.C1(C)C=CC(S(NN)(=O)=O)=CC=1>CN(C=O)C.C(OCC)(=O)C.O>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH:12]2[CH2:17][CH2:16][CH:15]([CH:18]3[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CNC2CCC(=C3CC3)CC2)cc1
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CNC2CCC(C3CC3)CC2)cc1
Temperature: 100 °C

Procedure:
4-[(4-Cyclopropylidenecyclohexylamino)methyl]benzoic acid methyl ester (1.1 g, 3.9 mmol) was dissolved in DMF (40 mL) and p-toluenesulfonic acid hydrazide (2.8 g, 15.4 mmol) was added. The reaction was heated to 100° C. for 16 hours. After cooling to room temperature the reaction mixture was diluted with ethyl acetate (75 mL) and water (40 mL) was added. The aqueous phase was extracted with ethyl acetate (25 mL) and the combined organic phases washed with aqueous saturated sodium hydrogen carbonate (2×30 mL) and water (5×30 mL). The organic phase was dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (25 g silica) using heptane and ethyl acetate (1:1) as eluent to give 4-[(4-cyclopropylcyclohexylamino)methyl]benzoic acid methyl ester.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1.[Br:29][CH2:30][CH2:31]Br.O>C(#N)C>[Br:29][CH2:30][CH2:31][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:14]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:11]2[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=2)=[CH:16][CH:17]=1
Reactant: Oc1ccc(N(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: Clc1ccc(N(c2ccc(Cl)cc2)c2ccc(OCCBr)cc2)cc1
Temperature: 25 °C

Procedure:
To a 250 mL rbf was added cesium carbonate (4.93 g, 15.14 mmol) and anhydrous acetonitrile (50 mL). A solution of 4-(bis(4-chlorophenyl)amino)phenol (69, 2.5 g, 7.57 mmol) in acetonitrile (25 mL) was added, and an immediate light purple colour was observed. 1,2-dibromoethane (7.11 g, 37.9 mmol) was added and the reaction was heated to reflux for 5 days. After cooling to RT, the reaction mixture was poured into water (250 mL), mixed well and separated. The aqueous portion was extracted with EtOAc (2×100 mL) and the combined organics were washed with water (2×250 mL), dried over MgSO4, filtered and solvent removed by rotary evaporation. Flash chromatography (2% EtOAc/hexanes) afforded 70 as a clear, colourless oil (1.42 g, 43%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[N:3]=1.[OH:17][CH2:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Si:10]([O:9][CH2:8][C:4]1[N:3]=[C:2]([O:17][CH2:18][C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][N:20]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:7]=[CH:6][CH:5]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1COc1cccc(CO[Si](C)(C)C(C)(C)C)n1
Temperature: 100 °C

Procedure:
2-Bromo-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridine (702 mg, 2.32 mmol, from Example 21a), tert-butyl (2S)-2-(hydroxymethyl)piperidine-1-carboxylate (500 mg, 2.32 mmol), Pd(OAc)2 (26 mg, 0.116 mmol), 2-(di-t-butylphosphino)biphenyl (42 mg, 0.139 mmol) and Cs2(CO3) (1.51 g, 4.64 mmol) were mixed in toluene (20 ml). The reaction was stirred under an N2 atmosphere and heated to 100° C. on an oil bath for 24 h. The solvent was evaporated in vacuo and the residue separated between EtOAc (250 ml) and water (250 ml). The organic phase washed with water (250 ml) and the combined aqueous phases were extracted with EtOAc (250 ml). The combined EtOAc phases were dried over Na2SO4 (s), filtered and evaporated in vacuo. Purification by silica gel flash chromatography using a 40+M Biotage column with a gradient of 5-20% EtOAc in heptane yielded the title compound as a colorless oil. Yield: 729 mg (72%). 1H NMR (400 MHz, CDCl3) δ 7.43 (t, 1H, J=7.8 Hz), 6.91 (d, 1H, J=7.3 Hz), 6.44 (d, 1H, J=8.2 Hz), 4.57 (s, 2H), 4.48 (m, 1H), 4.25 (d, 2H, J=7.4 Hz), 3.91 (d, 1H, J=11.6 Hz), 2.76 (dt, 1H, J=13.3 Hz, J=2.0 Hz), 1.69 (d, 1H, J=12.0 Hz), 1.57-1.37 (m, 5H), 1.27 (s, 9H), 0.84 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: [C:1]([C:4](=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)[C:5]([O:7]CCC#N)=[O:6])(=O)[CH3:2].[NH2:22]/[C:23](/[CH3:49])=[CH:24]\[C:25]([O:27][CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][C:34]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:33][CH2:32]1)=[O:26].C(O)(=O)C>CC(O)C>[C:43]1([C:34]2([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:33][CH2:32][N:31]([CH2:30][CH2:29][CH2:28][O:27][C:25]([C:24]3[CH:12]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=4)[C:4]([C:5]([OH:7])=[O:6])=[C:1]([CH3:2])[NH:22][C:23]=3[CH3:49])=[O:26])[CH2:36][CH2:35]2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCCC#N
Reactant: C/C(N)=C/C(=O)OCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC1=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCCCN2CCC(c3ccccc3)(c3ccccc3)CC2)=C(C)N1

Procedure:
8.1 g of 2-cyanoethyl 2-acetyl-3-(3-nitrophenyl)acrylate and 10.6 g of 3-(4,4-diphenylpiperid-1-yl)-propyl 3-aminocrotonate are heated at the boiling point under reflux in 120 ml of 2-propanol and 0.5 ml of glacial acetic acid for 4 hours. After most of the solvent has been distilled off and 2 portions of 50 ml of toluene each have been added, the residue is concentrated to dryness. The residue, which has foamed as a solid, is taken up in isopropanol, and diethyl ether is added to the clear solution until the resulting cloudiness first persists. After the mixture has been left to stand in a refrigerator, the starting compound crystallizes out in the form of fine platelets. m.p.: 158°-160° C.; yield: 14.3 g.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[OH-].[K+].[OH:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[NH:19][C:20]1[S:21][C:22]2[CH:28]=[C:27]([CH:29]=[O:30])[CH:26]=[CH:25][C:23]=2[N:24]=1.[CH3:31]O>CCOC(C)=O>[CH3:31][O:30][CH:29]([C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1)[C:27]1[CH:26]=[CH:25][C:23]2[N:24]=[C:20]([NH:19][C@@H:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C@H:13]3[OH:12])[S:21][C:22]=2[CH:28]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: CO
Reactant: O=Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COC(c1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 336 h
Yield: 5.4 %

Procedure:
To a solution of 1H-pyrrolo[2,3-b]pyridine (205 mg, 1.74 mmol) in MeOH (20 mL) were added potassium hydroxide (162 mg, 2.9 mmol) and 2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazole-6-carbaldehyde from Step 2 of this Example (400 mg, 1.45 mmol) sequentially at rt. The reaction mixture was stirred at rt for 14 d. The resulting mixture was diluted with EtOAc (80 mL) and washed with water, brine. The organic layer was dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by 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)-2-((6-(methoxy(1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol as a white solid (32 mg, 5.4%). 1H NMR (300 MHz, CDCl3) δ 9.70 (br s, 1H), 8.26 (dd, J=1.4, 4.8 Hz, 1H), 7.85 (dd, J=1.3, 7.7 Hz, 1H), 7.64 (d, J=1.3 Hz, 1H), 7.44-7.54 (m, 1H), 7.34 (d, J=8.3 Hz, 1H), 6.97-7.11 (m, 2H), 5.64 (br s, 1H), 5.56 (s, 1H), 3.44-3.67 (m, 3H), 3.42 (s, 3H), 2.06-2.27 (m, 2H), 1.65-1.87 (m, 2H), 1.14-1.53 (m, 4H). LCMS (ESI) m/z 409 (M+H)+.
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].[O-]CC.[Na+].C(O)C.[C:13]([C:16](=[CH:22]N(C)C)[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=O)[CH3:14]>>[CH3:3][C:2]1[N:5]=[C:13]([CH3:14])[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:22][N:4]=1
Reactant: CCOC(=O)C(=CN(C)C)C(C)=O
Reactant: CC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc(C)nc1C
Yield: 76 %

Procedure:
Acetamidine hydrochloride was added to a 10% sodium ethoxide-ethanol solution (410 mL, 0.53 mol) at room temperature. Then, ethyl 2-acetyl-3-(dimethylamino)acrylate (98 g, 0.53 mol) was added to the mixture, and the mixture was heated under reflux for 24 hrs. Ethanol was evaporated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and the solvent was evaporated. The residue was distilled under reduced pressure to give the title compound (73 g, yield 76%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)[C:9](=[O:19])[NH:8][C:7]1=[O:20].[F:21][C:22]([F:36])([F:35])[C:23]1[CH:28]=[CH:27][C:26]([C@:29]23[CH2:34][C@H:33]2[CH2:32][NH:31][CH2:30]3)=[CH:25][CH:24]=1>CCO>[ClH:1].[ClH:1].[CH3:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9](=[O:19])[NH:8][C:7](=[O:20])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:31]3[CH2:32][C@H:33]4[C@:29]([C:26]5[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:36])[F:35])=[CH:28][CH:27]=5)([CH2:34]4)[CH2:30]3)[CH:11]=2)[CH:17]=[CH:16][N:15]=1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Reactant: Cc1cc(-c2cn(CCCCCl)c(=O)[nH]c2=O)ccn1
Solvent: CCO
Product: Cc1cc(-c2cn(CCCCN3C[C@@H]4C[C@]4(c4ccc(C(F)(F)F)cc4)C3)c(=O)[nH]c2=O)ccn1
Product: Cl
Reaction time: 2 h
Yield: 43.1 %

Procedure:
A solution of 1-(4-Chloro-butyl)-5-(2-methyl-pyridin-4-yl)-1H-pyrimidine-2,4-dione (Prep46, 74 mg, 0.25 mmol), (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4, 57 mg, 0.25 mmol), and TEA (101 μl, 1 mmol) in absolute EtOH (3 mL) was refluxed for 48 hours. The reaction was then evaporated under vacuum and the residue was dissolved in 2N HClaq and washed with ethyl acetate. The aqueous phase was then basified with solid NaHCO3 and extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated; the residue was dissolved in DCM and treated with PS-isocyanate (250 mg) resin under stirring for 2 h. After filtration and evaporation of the solvent the crude was purified by LC-MS preparative and then loaded on SCX cartridge washing with MeOH and eluting with MeOH/NH3 95:5 to give 30 mg of the title compound as free base (33%, yield). 5-(2-methyl-4-pyridinyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2,4(1H,3H)-pyrimidinedione was dissolved in dioxane and then treated with a solution of 4N HCl in dioxane (2 eq) to give the title compound as a pale yellow solid. (33 mg, 23.5%)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[F:11][C:12]1[CH:26]=[CH:25][C:15]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([OH:27])[CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[C:20]([O:19][C:18]([NH:17][CH2:16][C:15]1[CH:25]=[CH:26][C:12]([F:11])=[CH:13][C:14]=1[O:27][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:24])([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)CCCCBr
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCCCOc1cc(F)ccc1CNC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
Ethyl 5-bromopentanoate (14.9 mmol) was added dropwise over 15 minutes to a mixture of tert-butyl 4-fluoro-2-hydroxybenzylcarbamate (Example 15; 12.4 mmol) and potassium carbonate (16.1 mmol) in DMA (37 ml). The reaction was heated at 60° C. for 4 hours, followed by the addition of another amount of ethyl 5-bromopentanoate (4.5 mmol) and potassium carbonate (4.8 mmol) and heating at 60° C. for 2 hours. The solvent was evaporated. The residue was taken up in AcOEt and filtered. The filtrate was washed with AcOEt (×3) and concentrated in vacuo. The residue was purified by column chromategraphy over SiO2 (Hexanes/AcOEt, 8/1, v/v) to afford the target compound (4.1 gr, 96% purity).