Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C@:3]12[CH2:8][C@H:7]1[CH2:6][NH:5][CH2:4]2.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][CH2:19][Cl:20].O>CC(C)=O>[Cl:20][CH2:19][CH2:18][CH2:17][N:5]1[CH2:6][C@H:7]2[C@:3]([N:2]([CH3:9])[CH3:1])([CH2:8]2)[CH2:4]1
Reactant: CN(C)[C@@]12CNC[C@@H]1C2
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CN(C)[C@]12C[C@H]1CN(CCCCl)C2
Temperature: 65 °C
Yield: 40 %

Procedure:
To a solution of (1R,5S)-3-benzyl-N,N-dimethyl-3-azabicyclo[3.1.0]hexan-1-amine (0.28 g, 1.29 mmol) in MeOH (20 mL) was added 20% Pd(OH)2 (30 mg). The mixture was stirred at rt under H2 overnight and filtered. The filtrate was concentrated in vacuo to give the crude product (1R,5S)—N,N-dimethyl-3-azabicyclo[3.1.0]hexan-1-amine (0.16 g), which was used for the next step without further purification. To a solution of (1R,5S)—N,N-dimethyl-3-azabicyclo[3.1.0]hexan-1-amine in acetone (5 mL) was added anhydrous K2CO3 (0.35 g, 2.54 mmol, 2.0 eq) and 1-bromo-3-chloropropane (0.20 mL, 1.91 mmol, 1.5 eq) in turn. The reaction mixture was heated at 65° C. for 4 h, and then cooled to rt. To the reaction mixture was added water (5 mL) and the mixture was extracted with EtOAc (10 mL×3). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (30:1 (v/v) CHCl3/CH3OH) to give the title compound as colorless oil (103 mg, 40%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 203.2 (M+1).
Reaction SMILES: [CH:1]1([NH:9][C:10]([NH:12][NH:13][C:14](=O)[CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[CH2:19][CH2:18]2)=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(OCC)(=O)C>[OH-].[Na+]>[CH:1]1([N:9]2[C:14]([CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])[CH2:19][CH2:18]3)=[N:13][NH:12][C:10]2=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccccc1N1CCN(CCC(=O)NNC(=O)NC2CCCCCCC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1ccccc1N1CCN(CCc2n[nH]c(=O)n2C2CCCCCCC2)CC1
Temperature: 25 °C
Yield: 46.8 %

Procedure:
A suspension of N-cyclooctyl-2-{3-[4-(2-methoxyphenyl)piperazino]propanoyl}-1-hydrazinecarboxamide D3 (0.40 g, 0.93 mmol) in 2M NaOH aqueous solution (10 mL) was heated at reflux for 18 hrs. The solution was cooled to room temperature and the pH was adjusted to 8 by the drop-wise addition of HCl 28%. The resulting precipitate was filtered to afford a white solid, which was twice boiled with ethyl acetate and filtered while hot. The filtrates were combined and evaporated under reduced pressure to afford 0.18 g (47%) 4-cyclooctyl-5-{2-[4-(2-methoxyphenyl)piperazino]ethyl}-2,4-dihydro-3H-1,2,4-triazol-3-one E10.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[C:10]([NH:13][CH3:14])=[N:11][O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:12])[C:9]=1[C:10](=[NH:11])[NH:13][CH3:14])[CH3:2]
Reactant: CCOc1cccc2onc(NC)c12
Agent: [Pd]
Solvent: CO
Product: CCOc1cccc(O)c1C(=N)NC
Reaction time: 16 h

Procedure:
2.75 g [14.31 mmol] of 4-ethoxy-N-methyl-1,2-benzisoxazol-3-amine are hydrogenated in 30 ml of methanol and in the presence of 0.28 g of palladium (loading: 10, support: activated carbon) at room temperature and pressure 1 bar for 16 hours, analogously to the method from WO 2007/030582. The reaction mixture is filtered through silica gel, and rinsed through repeatedly with methanol. The combined filtrates are concentrated under reduced pressure. This leaves 1.1 g of product as a grey solid; the purity is >95% according to 1H NMR.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:5]=[C:6]([CH:14]=[C:15]([NH2:17])[CH:16]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].N1C=CC=CC=1.[Cl:25][CH2:26][CH2:27][CH2:28][S:29](Cl)(=[O:31])=[O:30]>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:5]=[C:6]([CH:14]=[C:15]([NH:17][S:29]([CH2:28][CH2:27][CH2:26][Cl:25])(=[O:31])=[O:30])[CH:16]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:8]
Reactant: COC(=O)c1cc(N)cc(C(=O)OC(C)(C)C)c1
Reactant: O=S(=O)(Cl)CCCCl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(NS(=O)(=O)CCCCl)cc(C(=O)OC(C)(C)C)c1
Reaction time: 16 h
Yield: 99.5 %

Procedure:
To a solution of 5-amino-isophthalic acid 1-tert-butyl ester 3-methyl ester (D79) (5.0 g, 20 mmol, 1 equiv), DMAP (0.3 g, 2.46 mmol, 0.12 equiv) and pyridine (1.64 g, 20 mmol, 1 equiv) in CH2Cl2 (80 ml) was added 3-chloropropanesulfonyl chloride (2.4 ml, 20 mmol, 1 equiv) dropwise. The resulting mixture was stirred for 16 h then diluted with AcOEt (150 ml). The organic phase was washed with 2N aqueous HCl solution and saturated aqueous NaHCO3 solution, dried over MgSO4 and concentrated in vacuo to give 5-(3-chloro-propane-1-sulfonylamino)-isophthalic acid 1-tert-butyl ester 3-methyl ester (D81) (7.8 g, 99%) as a pale orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.C(O)C.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:12])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[CH:5]=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cncc(Br)c1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)Nc2cncc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round-bottom flask charged with 5-bromopyridin-3-amine (0.400 g, 2.3 mmol) in ethanol (10 ml, 171 mmol), was added 4-methylbenzene-1-sulfonyl chloride (0.880 g, 4.6 mmol) into the mixture. The mixture was allowed to stir at ambient temperature overnight, while under inert atmosphere. The progress of the reaction was monitored by LC/MS, which showed mostly desired product. The mixture was diluted with DCM and saturated sodium bicarbonate solution, then extracted the organic layer with DCM (3×25 ml). The organics were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by ISCO silica-gel chromatography, in a gradient of 10-30% EtOAc/DCM. The fractions with desired product were combined and concentrated. This gave N-(5-bromopyridin-3-yl)-4-methylbenzenesulfonamide (0.350 g, 46% yield) as a light-yellow crystalline solid. MS (ESI pos. ion) m/z: 328 (MH+). Calc'd exact mass for Cl2H, BrN2O2S: 327. 1H NMR (400 MHz, chloroform-d): 2.43 (d, J=18.57 Hz, 3H), 7.35 (d, J=6.53 Hz, 2H), 7.69 (d, J=6.02 Hz, 2H), 7.80 (d, J=5.02 Hz, 2H), 8.13-8.20 (m, 1H), 8.42 (s, 1H).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]1[N:13]2[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=3)[CH:16]=[C:12]2[C:11](=[O:28])[NH:10][CH2:9]1)(=O)=O.[N-:29]=[N+:30]=[N-:31].[Na+].O.C([O-])(O)=O.[Na+]>C(#N)C.CN(C=O)C>[N:29]([CH2:6][CH2:7][CH:8]1[N:13]2[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=3)[CH:16]=[C:12]2[C:11](=[O:28])[NH:10][CH2:9]1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCCC1CNC(=O)c2cc(-c3cccc(OC(F)(F)F)c3)cn21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: [N-]=[N+]=NCCC1CNC(=O)c2cc(-c3cccc(OC(F)(F)F)c3)cn21
Yield: 79.1 %

Procedure:
2-{1-oxo-7-[3-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl}ethyl methanesulfonate (150 mg, 0.36 mmol) were reacted with sodium azide (60 mg 0.924 mmol) in acetonitrile/DMF 10 ml/2 ml at 80° C. for 18 hours. The reaction was worked up with water, saturated NaHCO3 and extracted with ethyl acetate. The organic phase, dried on Na2SO4, was filtered and evaporated. The crude was dissolved with diethyl ether and after a while, a solid precipitated, which was filtered to give 104 mg (80%) of 4-(2-azidoethyl)-7-[3-(trifluoromethoxy)phenyl]-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one.
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([O:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:5]=2[S:4][CH:3]=1.[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([C:2]2[C:6]3[N:7]=[CH:8][N:9]=[C:10]([O:11][CH:12]4[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]4)[C:5]=3[S:4][CH:3]=2)=[CH:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3c(Br)csc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3c(-c4ccc(S(C)(=O)=O)cc4)csc23)CC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 21.2 %

Procedure:
Tert-butyl 4-(7-bromothieno[3,2-d]pyrimidin-4-yloxy)piperidine-1-carboxylate (100 mg), 4-methanesulfonyl-phenylboronic acid (72 mg), Pd(PPh3)4 (17 mg) and 2N Na2CO3 (0.72 mL) were added to 1,4-dioxane (2 mL), and stirred at 100° C. for 12 hours in a hermetically sealed reactor. The reaction mixture was cooled to room temperature, extracted with ethyl acetate and distilled water, and the organic layer thus obtained was washed with water and a saline solution. Subsequently, the washed organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (25 mg).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[O:12]=[S:13]1(=[O:41])[CH2:18][CH2:17][CH:16]([CH2:19][S:20]([C:23]2[CH:24]=[C:25]([CH:29]([OH:40])[CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:26]=[CH:27][CH:28]=2)(=[O:22])=[O:21])[CH2:15][CH2:14]1>C(Cl)Cl>[O:41]=[S:13]1(=[O:12])[CH2:18][CH2:17][CH:16]([CH2:19][S:20]([C:23]2[CH:24]=[C:25]([C:29](=[O:40])[CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])[CH:26]=[CH:27][CH:28]=2)(=[O:21])=[O:22])[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccc(S(=O)(=O)CC2CCS(=O)(=O)CC2)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)c1cccc(S(=O)(=O)CC2CCS(=O)(=O)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Pyridinium chlorochromate (218 mg, 1.01 mmol) and molecular sieves were added to a solution of tert-butyl (3-(3-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)sulfonyl)phenyl)-3-hydroxypropyl)carbamate (650 mg, 1.40 mmol) in CH2Cl2 (20 mL) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was filtered through a Celite, the filtrate was diluted with EtOAc, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (60% EtOAc-hexanes gradient) gave tert-butyl (3-(3-(((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl)sulfonyl)phenyl)-3-oxopropyl)carbamate as a colorless liquid. Yield (0.438 g, 67%); 1H NMR (400 MHz, DMSO-d6): δ 8.36 (s, 1H), 8.28 (d, J=7.6 Hz, 1H), 8.16 (d, J=7.6 Hz, 1H), 7.83 (t, J=8.0 Hz, 1H), 6.87 (s, 1H), 3.51 (d, J=6.4 Hz, 2H), 3.32-3.28 (m, 4H), 3.28-3.23 (m, 2H), 3.20-3.13 (m, 1H), 3.04-3.01 (m, 1H), 2.32 (bs, 1H), 2.17-2.14 (m, 2H), 1.85-1.76 (m, 2H), 1.35 (s, 9H); MS: m/z 460.23 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])=[O:4].[OH2:13]>C(#N)C>[OH:13][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])=[O:4]
Reactant: O
Reactant: N#Cc1cccc(C(=O)CBr)c1
Solvent: CC#N
Product: N#Cc1cccc(C(=O)CO)c1

Procedure:
A solution of 776 mg of 3-(2-bromoacetyl)benzonitrile in acetonitrile (5 mL) and water (10 mL) is treated under microwave irradiation (125° C., 50 min) The same experiment is realized a second time with 976 mg. All the vials are collected, extracted with ethyl ether, dried over magnesium sulfate and concentrated under vacuum to give the desired compound.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N+:15]([O-:17])=[O:16])=[CH:6][C:7]([N+:12]([O-])=O)=[C:8]([CH:11]=2)[CH:9]=O)[CH2:3][CH2:2]1.ClC1C=CC([N:25]2[C:33](C(NC)=O)=[C:32]3[C:27](C=[C:29]([NH:41]S(C)(=O)=O)[C:30](C4CC4)=[CH:31]3)=N2)=CC=1.CC1C=CC(N)=NC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCO.C(Cl)Cl>[CH:1]1([C:4]2[C:5]([N+:15]([O-:17])=[O:16])=[CH:6][C:7]3[C:8](=[CH:9][N:41]([C:29]4[CH:30]=[CH:31][C:32]([CH3:27])=[CH:33][N:25]=4)[N:12]=3)[CH:11]=2)[CH2:3][CH2:2]1
Reactant: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(Cl)cc1
Reactant: O=Cc1cc(C2CC2)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cc1ccc(N)nc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCO
Product: Cc1ccc(-n2cc3cc(C4CC4)c([N+](=O)[O-])cc3n2)nc1
Temperature: 100 °C
Yield: 43 %

Procedure:
To a stirred solution of 5-cyclopropyl-2,4-dinitrobenzaldehyde (prepared according to the synthesis of Compound (1)) (50 mg, 0.212 mmol) in EtOH (750 mL) was added 5-methylpyridin-2-amine (25 mg, 0.23 mmol) and the resultant solution stirred at RT for 2d after which time a solid had precipitated from solution. Triphenylphosphine (167 mg, 0.64 mmol) was added in a single portion and the reaction then heated at 100° C. in a sealed tube for 4 h. Upon cooling to RT, the reaction was diluted with DCM (2 mL) and the organics were washed with aq. 30% hydrogen peroxide solution (2 mL). The organics were separated and filtered through a plug of MgSO4 and then purified by automated column chromatography (Biotage SP4, Grace 4 g silica cartridge) eluting with EtOAc:n-heptane (gradient elution, 0% equil. (2 CV), 0% (1CV), 0 to 100% (35 CV), 100% (5 CV)) to give (ii) (27 mg, 43%). ESI-MS: calculated [M+H]+ 295.1. observed [M+H]+ 295.2.
Reaction SMILES: CN(C)C1C=CC=CC=1.[Br:10][CH2:11][C:12](Br)=[O:13].[CH2:15]([O:22][C:23]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[C:26]([NH2:27])=[C:25]([C:34]([F:37])([F:36])[F:35])[CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([C:34]([F:36])([F:37])[F:35])[C:26]([NH:27][C:12](=[O:13])[CH2:11][Br:10])=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Br)CBr
Reactant: Nc1c(C(F)(F)F)cc(OCc2ccccc2)cc1C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: O=C(CBr)Nc1c(C(F)(F)F)cc(OCc2ccccc2)cc1C(F)(F)F
Reaction time: 1 h
Yield: 64.7 %

Procedure:
Under an argon atmosphere, N,N-dimethylaniline (2.78 mL, 21.9 mmol) and bromoacetyl bromide (1.91 mL, 21.9 mmol) were added dropwise to a solution of 4-benzyloxy-2,6-bis(trifluoromethyl)aniline (4.90 g, 14.6 mmol) in anhydrous toluene (150 mL) under ice cooling. Immediately after the dropwise addition, the mixture was heated under reflux and then stirred for 1 hour. After cooling, the reaction mixture was filtered through Celite and the insoluble matter was washed with toluene. The residue obtained by distilling the filtrate under reduced pressure was purified by chromatography on a silica gel column (developing solvent; hexane:acetone=10:1→6:1→5:1). The crude product thus obtained was recrystallized from hexane-acetone, whereby 4.31 g (yield: 64.7%) of N-[4-benzyloxy-2,6-bis(trifluoromethyl)phenyl]-2-bromoacetamide was obtained as colorless needle-like crystals.
Reaction SMILES: [O:1]1[C:5]2([CH2:15][CH2:14][C:8]3([CH2:12][CH2:11][NH:10][C:9]3=[O:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[F:16][C:17]([F:28])([F:27])[CH:18]([C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1)[OH:19].CNCCNC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C>[F:16][C:17]([F:27])([F:28])[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([N:10]2[CH2:11][CH2:12][C:8]3([CH2:14][CH2:15][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:6][CH2:7]3)[C:9]2=[O:13])=[CH:22][CH:21]=1)[OH:19]
Reactant: O=C1NCCC12CCC1(CC2)OCCO1
Reactant: OC(c1ccc(I)cc1)C(F)(F)F
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1N(c2ccc(C(O)C(F)(F)F)cc2)CCC12CCC1(CC2)OCCO1
Temperature: 80 °C
Yield: 62 %

Procedure:
1,4-Dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (352 mg, obtained in example 133, step 3) was dissolved in DMF (22 mL) at r.t. Then, 2,2,2-trifluoro-1-(4-iodophenyl)ethanol (755 mg, [CAS Reg. No. 857521-44-9; for synthesis see: Beyer et al., PCT Int. Appl. (2005), WO 2005061497 A1], N,N′-dimethylethylenediamine (sym) (294 mg), cuprous iodide (476 mg) and K3PO4 (1.06 g) were added to the reaction mixture. The mixture was heated to 80° C. for 4.5 hours. The reaction mixture was cooled down to 30° C. and more 2,2,2-trifluoro-1-(4-iodophenyl)ethanol (252 mg) was added. The mixture was re-heated to 80° C. for 2 hours. The reaction mixture was cooled, poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a colorless solid (415 mg, 62%). MS (m/e): 386.4 [MH+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([CH3:21])[CH:15]=3)=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[NH3:22].O1CCOCC1>O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH2:22])[N:7]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:15][C:16]=1[CH3:21]
Reactant: N
Reactant: Cc1cc(-c2ncccc2-c2ccnc(Cl)n2)ccc1F
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2ncccc2-c2ccnc(N)n2)ccc1F
Temperature: 60 °C
Reaction time: 12 h

Procedure:
4-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)pyrimidin-2-amine (Compound 919) was prepared as follows: A screw capped vial was charged with 2-chloro-4-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)pyrimidine (125 mg), 28% aq. Ammonia (3 mL), 1,4-dioxane (3 mL) and a stir bar. The vial was capped tightly, heated and stirred at 60° C. for 12 h. The heterogeneous solution was cooled to room temperature, diluted with water, filtered. The solid (90 mg) was suspended in 50% EtOAc/hexanes, stirred and heated at 80° C. for 30 min. Upon cooling to room temperature, the suspension was filtered and the solid was suction dried to provide 4-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)pyrimidin-2-amine as a white solid (73 mg). 1H NMR (300 MHz, DMSO-d6): δ 8.69 (dd, J=4.7, 1.7 Hz, 1H), 8.07 (d, J=5.0 Hz, 1H), 7.93 (dd, J=7.8, 1.7 Hz, 1H), 7.47 (dd, J=7.8, 4.8 Hz, 1H), 7.38 (dd, J=7.4, 1.6 Hz, 1H), 7.18-6.95 (m, 2H), 6.70 (s, 2H), 6.20 (d, J=5.0 Hz, 1H), 2.19 (s, 3H). 19F NMR (282 MHz, DMSO-d6): δ −118.16 (q, J=7.7 Hz).LCMS: rt 4.40 min (A), purity 99%, MS (m/e) 281 MH+.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si](C(C)(C)C)(C)C)[CH:12]=[CH:11][C:10]=1[C@H:23]1[CH2:28][CH2:27][C@H:26]([NH:29][C:30](=[O:40])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[CH:32]=2)[CH2:25][CH2:24]1)(C(C)(C)C)(C)C.ClC(Cl)C.O.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[C@H:23]1[CH2:24][CH2:25][C@H:26]([NH:29][C:30](=[O:40])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-:39])=[O:38])[CH:32]=2)[CH2:27][CH2:28]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](NC(=O)c3cccc([N+](=O)[O-])c3)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Solvent: CC(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(N[C@H]1CC[C@H](c2ccc(O)cc2O)CC1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
To a round bottomed flask was added trans-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]-3-nitrobenzamide (52 mg), dichloroethane (9 ml), water (3 ml), and trifluoroacetic acid (3 ml). The reaction mixture was heated under reflux for 15 hr, cooled to room temperature, and toluene (15 ml) was added. The reaction mixture was concentrated in vacuo, methanol (15 ml) was added, and further concentrated to remove residual trifluoroacetic acid. Purification via flash chromatography (SiO2, ethyl acetate/petroleum ether, gradient elution using 1:3, then 1:1, v/v) furnished the title compound (20 mg, 63%) as a white solid. δH ((CD3)2CO): 1.52-1.68 (4H, m), 1.87-1.95 (2H, m), 2.09-2.17 (2H, m), 2.87 (1 H, tt), 3.97-4.08 (1 H, m), 6.30 (1 H, dd), 6.38 (1 H, d), 6.99 (1 H, d), 7.77 (1H, t), 7.90 (1H, s), 7.96 (1 H, d), 8.05 (1 H, s), 8.33 (1 H, dd), 8.37 (1 H, dd), 8.68 (1 H, t); m/z (ES+) 357 )M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].I[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29].O>CS(C)=O>[CH2:3]([C:11]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]([F:32])([F:33])[C:28]([F:29])([F:30])[F:31])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCCCCCC(C(=O)OCC)C(=O)OCC
Reactant: FC(F)(F)C(F)(F)CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCCCC(CCCCC(F)(F)C(F)(F)F)(C(=O)OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
Sodium hydride (60%, 326 mg, 8.14 mmol) was added to dimethyl sulfoxide (5 ml) under argon atmosphere and cooled to 0° C. To this mixture, diethyl 2-(7-octeny)malonate (2 g, 7.40 mmol) dissolved in dimethyl sulfoxide (5 ml) was slowly added, followed by stirring for 1 hour. After cooling to 0° C., 1-iodo-5,5,6,6,6-pentafluorohexane (2.68 g, 8.88 mmol) dissolved in dimethyl sulfoxide (5 ml) was slowly added to the reaction mixture, followed by stirring for 2 hours at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/20) to give diethyl 2-(7-octenyl)-2-(5,5,6,6,6-pentafluorohexyl)malonate (2.3 g, Yield 70%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C1(S([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=3)=[CH:19]2)(=O)=O)C=CC=CC=1>>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:29]1[N:28]=[C:27]([C:20]2[C:21]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[NH:18][CH:19]=2)[CH:32]=[CH:31][N:30]=1
Reactant: Nc1ccccc1Cl
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: Clc1ccccc1Nc1nccc(-c2c[nH]c3ncccc23)n1
Yield: 19.6 %

Procedure:
Using the procedure of example 1, 2-chloro-aniline (103 mg) was reacted with compound 1f (100 mg) to provide compound 12 (17 mg, 20%). 1H NMR (400 MHz, CD3OD) δ 8.75 (d, J=7.6 Hz, 1H), 8.39 (d, J=8.4 Hz, 1H), 8.36 (d, J=5.2 Hz, 1H), 8.30 (d, J=4.8 Hz, 1H), 8.20 (s, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.25 (d, J=5.2 Hz, 1H), 7.22 (dd, J=7.6 Hz, 4.8 Hz, 1H), 7.12 (t, J=7.6 Hz, 1H). MS (ESI) m/z 322: (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH:7]=[O:8].Br[C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[N:13]([CH3:15])[CH3:14]>>[CH3:14][N:13]([CH3:15])[C:12]1[CH:11]=[C:10]([CH:7]([C:6]2[S:5][CH:4]=[N:3][C:2]=2[CH3:1])[OH:8])[CH:18]=[CH:17][CH:16]=1
Reactant: CN(C)c1cccc(Br)c1
Reactant: Cc1ncsc1C=O
Product: Cc1ncsc1C(O)c1cccc(N(C)C)c1

Procedure:
The title compound was prepared from 4-methyl-5-thiazolecarbaldehyde and 3-bromo-N,N-dimethylaniline using the method of Example 32. M.p. 135°-138° C.
Reaction SMILES: [CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2].Br[CH2:15][CH2:16][CH2:17][F:18]>>[F:18][CH2:17][CH2:16][CH2:15][N:5]1[C:6]([CH3:9])=[C:7]([CH3:8])[C:3]([CH:1]=[O:2])=[C:4]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: FCCCBr
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Product: COC(=O)c1c(C=O)c(C)c(C)n1CCCF

Procedure:
The title compound was prepared as pale yellow crystals in 90.89% yeild in a similar procedure to that described in Referential Example 9 by using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 1-bromo-3-fluoropropane.