Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)[CH:5]=[N:4][CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[N:18]1[CH:23]=[CH:22][C:21]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[NH:14][CH:13]=[CH:12]4)[CH:5]=[N:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: Clc1cncc(Nc2ccc3[nH]ccc3c2)n1
Reactant: OB(O)c1ccncc1
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: O
Solvent: COCCOC
Product: c1cc(-c2cncc(Nc3ccc4[nH]ccc4c3)n2)ccn1
Yield: 31.1 %

Procedure:
A mixture of N-(6-chloro-pyrazin-2-yl)-1H-indol-5-amine (0.030 g, 0.123 mmol), pyridine-4-boronic acid (0.018 g, 0.147 mmol), sodium carbonate (0.067 g, 0.615 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.007 g, 0.006 mmol) in DME:water (3:2, 5 mL) was heated at reflux for 20 h. The reaction mixture was concentrated under reduced pressure and the residue obtained was extracted with dichloromethane. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (5% methanol in CH2Cl2 as eluent) to yield N-(6-pyridin-4-ylpyrazin-2-yl)-1H-indol-5-amine (0.011 g, 31%) as a yellow solid. 1H NMR (CD3OD) δ 8.70-8.68 (d, J=6.17 Hz, 2H), 8.47 (s, 1H), 8.15 (s, 1H), 8.14 (d, J=1.50 Hz, 2H) 7.96 (d, J=1.70 Hz, 1H), 7.45-7.43 (d, J=8.64 Hz, 1H), 7.37-7.35 (dd, J=10.46, 1.83 Hz, 1H), 7.29-7.28 (d, J=3.06 Hz, 1H), 6.49-6.48 (d, J=3.02 Hz, 1H); MS (API-ES/Positive); m/z: 288 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)=[CH:7][N:6]=1)(=[O:3])[CH3:2].[C:20]1([C:26]2[N:27]=[C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:1]([NH:4][C:5]1[N:6]=[CH:7][C:8]([NH:11][C:12]([N:34]2[CH2:35][CH2:36][N:31]([C:28]3[S:29][CH:30]=[C:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:27]=3)[CH2:32][CH2:33]2)=[O:19])=[CH:9][N:10]=1)(=[O:3])[CH3:2]
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: CC(=O)Nc1ncc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ncc(NC(=O)N2CCN(c3nc(-c4ccccc4)cs3)CC2)cn1
Yield: 40 %

Procedure:
A solution of 2,2,2-trichloroethyl [2-(acetylamino)pyrimidin-5-yl]carbamate (60.0 mg, 0.187 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (44.9 mg, 0.183 mmol), diisopropylethylamine (0.0319 ml, 0.183 mmol) and dimethylsulfoxide (2 ml) was stirred at 80° C. for 4 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of tetrahydrofuran, ethyl acetate and hexane to obtain the desired product (31.0 mg, 40.0%) as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3(O)[CH2:20][C:19]4([CH3:22])[O:21][C:16]([CH3:23])([CH2:17][CH2:18]4)[CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:25][C:26]([C:28]2[NH:29][CH:30]=[C:31]([C:33]#[N:34])[N:32]=2)=[O:27])=[CH:4][CH2:3]1.[Si]([C:40]#[N:41])(C)(C)C.Cl[Sn](Cl)(Cl)Cl.CO>C(Cl)Cl.C(Cl)(Cl)Cl.O>[C:40]([C:14]1([C:12]2[CH:11]=[CH:10][C:9]([NH:25][C:26]([C:28]3[NH:29][CH:30]=[C:31]([C:33]#[N:34])[N:32]=3)=[O:27])=[C:8]([C:5]3[CH2:6][CH2:7][C:2]([CH3:35])([CH3:1])[CH2:3][CH:4]=3)[CH:13]=2)[CH2:20][C:19]2([CH3:22])[O:21][C:16]([CH3:23])([CH2:17][CH2:18]2)[CH2:15]1)#[N:41]
Reactant: C[Si](C)(C)C#N
Reactant: CC1(C)CC=C(c2cc(C3(O)CC4(C)CCC(C)(C3)O4)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(C3(C#N)CC4(C)CCC(C)(C3)O4)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 28.2 %

Procedure:
To a slurry of 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(3-hydroxy-1,5-dimethyl-8-oxa-bicyclo[3.2.1]oct-3-yl)-phenyl]-amide (21 mg, 0.044 mmol, as prepared in Example 93) in 1 mL of DCM at 0° C. was added TMSCN (25 μL, 0.19 mmol) followed by SnCl4 (4 mg, 0.01 mmol) dissolved in 0.08 mL of DCM. The reaction was warmed to room temperature and again treated with 25 μL of TMSCN and then SnCl4 (8 mg, 0.02 mmol) in 0.2 mL of DCM. After the reaction became homogeneous 1 mL of MeOH was added followed by 2 mL of water. The mixture was stirred for 5 min, CHCl3 (5 mL) was added and the layers were separated. The organic layer was dried (Na2SO4) and concentrated in vacuo. Purification of the residue twice by preparative TLC (5% MeOH—CHCl3, then 50% EtOAc-hexanes) afforded the title compound (6 mg, 28%). 1H-NMR (CD3OD; 400 MHz): δ 8.09 (d, 1H, J=8.3 Hz), 7.70 (s, 1H), 7.27-7.23 (m, 1H), 7.16-7.12 (m, 1H), 5.66-5.64 (m, 1H), 2.80-2.56 (m, 4H), 2.22-2.14 (m, 2H), 2.02-1.97 (m, 2H), 1.81-1.77 (m, 4H), 1.51-1.46 (m, 2H), 1.25 (s, 3H), 1.25 (s, 1H), 0.98 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C29H33N5O2 484.2 (M+1). found 484.0.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C@@H:22]([NH:28][C@@H:29]2[C:35](=[O:36])[N:34]([CH2:37][C:38]([O:40]C(C)(C)C)=[O:39])[C:33]3[CH:45]=[CH:46][CH:47]=[CH:48][C:32]=3[O:31][CH2:30]2)[C:23]([O:25]CC)=[O:24])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.Br.C(O)(=O)C>C(O)(=O)C.C(OCC)C>[C:23]([C@H:22]([NH:28][C@@H:29]1[C:35](=[O:36])[N:34]([CH2:37][C:38]([OH:40])=[O:39])[C:33]2[CH:45]=[CH:46][CH:47]=[CH:48][C:32]=2[O:31][CH2:30]1)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)([OH:25])=[O:24]
Reactant: CCOC(=O)[C@@H](CCCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)[C@@H](N[C@H](CCCCCC2CCNCC2)C(=O)O)COc2ccccc21
Reaction time: 1 h
Yield: 55.3 %

Procedure:
To a solution of tert-butyl 3(S)-[6-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylhexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.35 g) in acetic acid (1 ml) is added 30% hydrogen bromide-acetic acid solution (2 ml). The resulting mixture is allowed to stand for 1 hour at room temperature and then diluted with ethyl ether (100 ml). The supernatant layer is removed by decantation and the precipitate is dissolved in 1N sodium hydroxide solution (10 ml). The solution is allowed to stand for 60 minutes at room temperature. After addition of acetic acid (1 ml), the mixture is chromatographed on MCI gel using water-methanol (1:2) as an eluent. The eluate is concentrated in vacuo and lyophilized to give 3(S)-[1(R)-carboxy-6-(4-piperidyl)hexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid (0.13 g) as colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].CN(C=O)C.C(Cl)(=O)C([Cl:22])=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([Cl:22])=[O:6]
Reactant: COc1cccc(C(=O)O)c1OC
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)Cl)c1OC
Yield: 86.3 %

Procedure:
To a solution of 2,3-dimethoxybenzoic acid (10.9781 mmol, 2.0 g) in CH2Cl2 (20 mL) with a drop of DMF, was added oxalyl chloride (10.9781 mmol, 957.702:1) dropwise at RT After 2 hrs the reaction mixture was concentrated in vacuo to afford 2,3-dimethoxybenzoyl chloride (1.9 g, 90%):
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[C:14]([C:15]([F:18])([F:17])[F:16])=[C:13]([F:19])[C:12]([F:20])=[CH:11][C:7]=1[C:8](O)=[O:9]>CN(C)C=O.C1C=CC=CC=1>[F:5][C:6]1[C:14]([C:15]([F:18])([F:17])[F:16])=[C:13]([F:19])[C:12]([F:20])=[CH:11][C:7]=1[C:8]([Cl:3])=[O:9]
Reactant: O=C(O)c1cc(F)c(F)c(C(F)(F)F)c1F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=C(Cl)c1cc(F)c(F)c(C(F)(F)F)c1F

Procedure:
30 ml of benzene, 17 ml of thionyl chloride and several drops of N,N-dimethylformamide were added to 8.5 g (0.0348 mole) of 2,4,5-trifluoro-3-trifluoromethylbenzoic acid (VII), and the mixture was refluxed under heating for 3 hours. After the reaction, benzene and excess thionyl chloride were removed by evaporation under reduced pressure to obtain 2,4,5-trifluoro-3-trifluoromethylbenzoic acid chloride (VIII).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:12][CH:13]([CH3:31])[CH2:14][CH2:15][NH:16][C:17]([C:19]1[N:20]=[N:21][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:23][CH:24]=1)=[O:18]>>[CH3:12][CH:13]([CH3:31])[CH2:14][CH2:15][NH:16][C:17]([C:19]1[N:20]=[N:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:4](=[O:5])[C:3]3[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=3[Cl:1])[CH2:27][CH2:26]2)=[CH:23][CH:24]=1)=[O:18]
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3ccc(Cl)cc3Cl)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 2,4-dichlorobenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white solid (90% yield). 5H NMR (500 MHz, CS(C13) δ 8.07, 7.85, 7.47, 7.35, 7.28, 7.01, 4.02-4.09, 3.75-3.93, 3.33-3.52, 1.65-1.75, 1.52, 0.94. MS (ES+) m/z 450 (M).
Reaction SMILES: C(O)C.C(O[CH2:12][C:13]1([CH3:39])[CH2:17][C:16]2[C:18]([CH3:38])=[C:19]([N:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)[C:20]([CH3:23])=[C:21]([CH3:22])[C:15]=2[O:14]1)C1C=CC=CC=1.[CH:40]([OH:42])=[O:41]>[C].[Pd]>[CH:40]([O:42][CH2:12][C:13]1([CH3:39])[CH2:17][C:16]2[C:18]([CH3:38])=[C:19]([N:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=4)[CH2:26][CH2:25]3)[C:20]([CH3:23])=[C:21]([CH3:22])[C:15]=2[O:14]1)=[O:41]
Reactant: O=CO
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(COCc3ccccc3)O4)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(COC=O)O4)CC2)cc1
Temperature: 100 °C
Reaction time: 15 h
Yield: 49 %

Procedure:
To a solution of ethanol (7.0 mL) containing 1-{2-[(benzyloxy)methyl]-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl}-4-(4-methoxyphenyl)piperazine (30 mg, 0.0628 mmol) synthesized in Example 134, 10% palladium carbon (500 mg) and formic acid (7.0 mL) were serially added, and the mixture was stirred at 100° C. for 15 hours. After cooled to room temperature, palladium carbon was removed by filtration, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 97:3-80:20) and crystallized from ethyl acetate-hexane to obtain 290 mg of the title compound (yield: 49%). Melting point was 120 to 124° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([CH3:17])([CH3:16])[CH2:11][CH:10]1[C:5]2=[CH:6][C:7](=[O:18])[CH2:8][CH2:9]1>[Pd](Cl)Cl.[Pd].C(O)(C)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([CH3:16])([CH3:17])[CH2:11][C:10]1[CH:9]=[CH:8][C:7]([OH:18])=[CH:6][C:5]2=1
Reactant: CC1(C)CC2CCC(=O)C=C2c2cc(Br)ccc21
Agent: Cl[Pd]Cl
Agent: [Pd]
Solvent: CC(C)(C)O
Product: CC1(C)Cc2ccc(O)cc2-c2cc(Br)ccc21
Reaction time: 4 h
Yield: 90.6 %

Procedure:
6-Bromo-9,9-dimethyl-3-oxo-1,2,3,9,10,10a-hexahydrophenanthrene (0.250 g, 0.819 mmol)), palladium(II) dichloride (0.190 g, 10.7 mmol) and tert-butanol (5 ml) were mixed in a sealed tube and heater to 125-135° C. for 4 hours. The reaction is finished when all the palladium has precipitated on the glass wall and a yellow and transparent reaction mixture is observed. Water was then added and the aqueous phase was extracted with ethyl acetate. The organic extracts were dried with anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (ethyl acetate/hexane 5:95 to 10:90) to give the title material (0.225 g, 91%).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH:6]2[CH2:7][CH2:8][CH:3]1[C:4](=O)[C:5]2=O.COP(=O)OC.O.[NH2:19][NH2:20]>>[C:2]([C:3]1[CH:4]=[C:5]2[C:4]([CH:3]3[C:2]([CH3:11])([CH3:1])[CH:6]2[CH2:7][CH2:8]3)=[N:20][N:19]=1)([CH3:11])([CH3:6])[CH3:1]
Reactant: NN
Reactant: CC1(C)C2CCC1C(=O)C2=O
Agent: CO[PH](=O)OC
Solvent: O
Product: CC(C)(C)c1cc2c(nn1)C1CCC2C1(C)C

Procedure:
white solid MS (ESI): 231 (MH+). Prepared from 7,7-dimethyl-bicyclo[2.2.1]heptane-2,3-dione (Childs, Ronald F.; Rogerson, Carol V.; J. Am. Chem. Soc.; EN; 102; 12; 1980; 4159), 3,3-dimethyl-2-oxo-butyl)-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([SH:11])[CH:3]=1.CC(O[CH2:16][C:17]1[CH2:26][S:25][C@@H:20]2[C@H:21]([NH2:24])[C:22](=[O:23])[N:19]2[C:18]=1[C:27]([OH:29])=[O:28])=O>B(F)(F)F.C(#N)C>[NH2:24][C@@H:21]1[C:22](=[O:23])[N:19]2[C@@H:20]1[S:25][CH2:26][C:17]([CH2:16][S:11][C:4]1[CH:3]=[C:2]([CH3:1])[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=1)=[C:18]2[C:27]([OH:29])=[O:28]
Reactant: Cc1cc(S)nc2ccnn12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: FB(F)F
Solvent: CC#N
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)nc2ccnn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.70 g of 7-methylpyrazolo[1,5-a]pyrimidine-5-thiol and 1.15 g of (7R)-7-amino-cephalosporanic acid were dissolved in 10 ml of a 20 percent solution of boron trifluoride in acetonitrile and stirred at room temperature for 1 hour. The reaction mixture was concentrated and taken up in 10 ml of water. The solid was filtered off under suction. There was obtained (6R,7R)-7-amino-3-[[(7-methylpyrazolo[1,5-a]pyrimidin-5-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a reddish powder.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH2:25][CH3:26])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[S:27]1(=[O:34])(=[O:33])[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]1>>[O:33]=[S:27]1(=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH2:25][CH3:26])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Reactant: O=S1(=O)CCCCN1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCCS4(=O)=O)cc3C#N)CC2)c(C)c1
Yield: 86.6 %

Procedure:
Using 5-bromo-2-[4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (827 mg) described in Preparation Example 246 and [1,2]thiazinane 1,1-dioxide (351 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (810 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:28])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[C:16]([N+:22]([O-:24])=[O:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30].C(N(CC)CC)C>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:26])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C:29](=[O:31])[CH3:30])=[C:16]([N+:22]([O-:24])=[O:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)NCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
To a solution of 1-{4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-2-nitrophenyl}methanamine (0.3 g) and acetic anhydride (0.1 g) in dichloromethane (50 mL), a solution of triethylamine (0.1 g) in dichloromethane (5 mL) was added dropwise under ice cooling, and the mixture was then stirred for one hour at room temperature. The reaction solution was diluted with water, and the organic layer was then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was then purified by silica gel chromatogaphy to yield N-{4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-2-nitrobenzyl}acetamide (0.2 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13]3[N:21]=[C:20]4[C:16]([N:17]=[CH:18][N:19]4COCC[Si](C)(C)C)=[C:15]([O:30][C:31]4[CH:32]=[C:33]([NH:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:34]=[CH:35][CH:36]=4)[N:14]=3)[CH:9]=[N:8]2)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13]3[N:21]=[C:20]4[C:16]([N:17]=[CH:18][NH:19]4)=[C:15]([O:30][C:31]4[CH:32]=[C:33]([NH:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:34]=[CH:35][CH:36]=4)[N:14]=3)[CH:9]=[N:8]2)[CH2:3]1
Reactant: C=CC(=O)Nc1cccc(Oc2nc(Nc3cnn(C4CCN(C)C4)c3)nc3c2ncn3COCC[Si](C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC(=O)Nc1cccc(Oc2nc(Nc3cnn(C4CCN(C)C4)c3)nc3[nH]cnc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a mixture of N-{3-[(2-{[1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl]amino}-9-{[2-(trimethylsilyl)ethoxy]methyl}-9H-purin-6-yl)oxy]phenyl}prop-2-enamide (271 mg, 0.471 mmol) in DCM (5.89 mL) was added TFA (1.81 mL, 23.6 mmol). The resulting solution was stirred at rt overnight, then concentrated and dried under vacuum. The resulting residue was taken up in water and neutralized with NaHCO3 to get a slightly sticky suspension. The solid was filtered off, washed with water, dried, and collected to give the crude product, which was purified by SFC to afford the title compound (21 mg, 10 yield) as a lyophilized solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.80 (br. s., 1H) 10.37 (br. s., 1H) 9.20 (br. s., 1H) 8.01-8.11 (m, 1H) 7.61-7.78 (m, 1H) 7.48 (br. s., 1H) 7.37 (d, J=6.32 Hz, 1H) 7.03 (d, J=7.33 Hz, 2H) 6.36-6.59 (m, 1H) 6.20-6.34 (m, 1H) 5.77 (dd, J=10.23, 1.89 Hz, 1H) 4.57 (br. s., 1H) 3.99-4.27 (m, 1H) 3.65-3.94 (m, 3H) 3.00 (br. s., 2H) 2.79 (m, J=15.66 Hz, 1H) 2.00 (br. s., 1H) 1.23 (s, 1H). m/z (APCI+) for C22H23N9O2 446.05 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]1[CH2:21][C:20](=[O:22])[N:19]2[C@H:7]([CH2:8][C:9]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[NH:11][C:10]=3[C@@H:18]2[C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=2)[C:6]1=[O:32])[CH2:2][CH2:3][CH3:4].Cl[Sn]Cl.O.[OH-].[Na+]>CO>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([C@H:18]2[C:10]3[NH:11][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:9]=3[CH2:8][C@@H:7]3[C:6](=[O:32])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:21][C:20](=[O:22])[N:19]23)=[CH:24][CH:25]=1
Reactant: CCCCN1CC(=O)N2[C@@H](c3ccc([N+](=O)[O-])cc3)c3[nH]c4ccccc4c3C[C@@H]2C1=O
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCN1CC(=O)N2[C@@H](c3ccc(N)cc3)c3[nH]c4ccccc4c3C[C@@H]2C1=O
Temperature: 25 °C
Yield: 39.4 %

Procedure:
To a solution of Example 75 (1.5 g) in methanol (100 mL) was added SnCl2.H2O (3.06) and the resulting mixture was heated at reflux for 8 hours. The mixture was cooled to ambient temperature, poured into ice and was adjusted to pH5 with 1N NaOH. The methanol was evaporated off and the residue was basified to pH11 with 1N NaOH and extracted with EtOAc (2×150 mL). After drying over Na2SO4 and evaporation of EtOAc, the resulting yellow powder was purified by radial chromatography eluting with CH2Cl2 to give the title compound as a white powder (550 mg) m.p.:192° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4]Br.[F:7][C:8]([F:18])([F:17])[O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:6])[CH2:4][O:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:8]([F:7])([F:17])[F:18])=[CH:11][CH:12]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Bromoacetic acid methyl ester (8 ml, 84.2 mmol) was added to a mixture of 4-(trifluoromethoxy)phenol (10 g, 56.1 mmol) and potassium carbonate (11.6 g, 84.2 mmol) in N,N-Dimethylformamide (50 ml) and stirred at room temperature overnight. The reaction mixture was poured into water and neutralized with a 1 N hydrochloric acid aqueous solution, followed by extraction with diethylether. The result was concentrated and used for the subsequent reaction.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O[CH2:49][CH2:50][CH2:51][O:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[CH3:60])(=O)=O)=CC=1>>[CH3:37][O:36][CH2:35][CH2:34][CH2:33][N:30]1[C:31]2[C:26](=[CH:25][CH:24]=[C:23]([CH2:22][O:21][CH:9]3[CH:8]([C:5]4[CH:6]=[CH:7][C:2]([O:1][CH2:49][CH2:50][CH2:51][O:52][CH2:53][C:54]5[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=5[CH3:60])=[CH:3][CH:4]=4)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10]3)[CH:32]=2)[CH2:27][CH2:28][C:29]1=[O:38]
Reactant: Cc1ccc(S(=O)(=O)OCCCOCc2ccccc2C)cc1
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(O)cc3)cc21
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4C)cc3)cc21

Procedure:
Analogously to Method I, 0.150 g of tert-butyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 44d) and 0.808 g of 3-(2-methylbenzyloxy)propyl toluene-4-sulphonate are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.47 (2:1 EtOAc-heptane); Rt=6.04.
Reaction SMILES: [OH:1][C@@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C(Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[OH:1][C@@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3][C:4]([O:6][CH2:7][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:5]
Reactant: CCCCCCCCCCCCC[C@H](O)CC(=O)OC
Reactant: BrCc1ccccc1
Product: CCCCCCCCCCCCC[C@H](O)CC(=O)OCc1ccccc1

Procedure:
(S)-Methyl 3-hydroxyhexadecanoate and benzyl bromide were reacted according to a similar manner to that of Preparation 1 to give (S)-benzyl 3-hydroxyhexadecanoate.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C([O:12][C:13]([C@@H:15]1[CH2:19][C:18]([C:20]2[CH:25]=[CH:24][C:23](C)=[CH:22][N:21]=2)=[C:17]([CH3:27])[C@H:16]1[O:28][Si:29]([CH2:34][CH3:35])([CH2:32][CH3:33])[CH2:30][CH3:31])=O)C>C1(C)C=CC=CC=1>[CH3:27][C:17]1[C@@H:16]([O:28][Si:29]([CH2:30][CH3:31])([CH2:34][CH3:35])[CH2:32][CH3:33])[C@H:15]([CH:13]=[O:12])[CH2:19][C:18]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: CCOC(=O)[C@@H]1CC(c2ccc(C)cn2)=C(C)[C@H]1O[Si](CC)(CC)CC
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CC[Si](CC)(CC)O[C@@H]1C(C)=C(c2ccccn2)C[C@H]1C=O
Reaction time: 1 h

Procedure:
A solution of DIBAL-H (0.44 ml, 1.0 M in hexane, 0.44 mmol, 1.1 equiv) was added dropwise to a solution of silyl ether 29b (150 mg, 0.4 mmol) in toluene (2 ml) at −78° C. The reaction mixture was stirred at that temperature for 1 hr and quenched by dropwise addition of saturated NH4Cl solution (0.2 ml). The reaction mixture was allowed to reach room temperature and a saturated solution of Rochelle salt (1 ml) and brine (0.4 ml) were added. The mixture was extracted with ethyl acetate (3×2 ml) and the combined organic extracts were dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to give crude aldehyde 30b as a yellow liquid which was used in the next step without further purification.