Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)Cl.[N:11]1[CH:12]=[CH:13][N:14]2[CH:19]=[C:18]([CH2:20][C:21]3[N:25]4[N:26]=[C:27]([C:30]5[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=5)[CH:28]=[CH:29][C:24]4=[N:23][CH:22]=3)[CH:17]=[CH:16][C:15]=12>O>[CH3:35][N:33]1[CH:34]=[C:30]([C:27]2[CH:28]=[CH:29][C:24]3[N:25]([C:21]([CH2:20][C:18]4[CH:17]=[CH:16][C:15]5[N:14]([C:13]([CH:4]=[O:5])=[CH:12][N:11]=5)[CH:19]=4)=[CH:22][N:23]=3)[N:26]=2)[CH:31]=[N:32]1
Reactant: CN(C)C=O
Reactant: Cn1cc(-c2ccc3ncc(Cc4ccc5nccn5c4)n3n2)cn1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1cc(-c2ccc3ncc(Cc4ccc5ncc(C=O)n5c4)n3n2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DMF (2 mL) was cooled down to 0° C. and then POCl3 (0.130 mL, 1.397 mmol) was added slowly. The solution was stirred for 10 min then it was warmed up to rt and the 3-(imidazo[1,2-a]pyridin-6-ylmethyl)-6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine (Example 10, 200 mg, 0.607 mmol) was introduced. The RM was warmed up to 120° C. and stirred for 2 h. It was cooled down to rt and water was added. It was extracted twice with EtOAc. Combined organic layers was washed with brine and dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, 0 to 20% MeOH in DCM) to afford after evaporation of the solvent the title compound as a yellow solid (tR 0.7 min (conditions 2), MH+=358).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[F:20][C:21]1([F:25])[CH2:24][NH:23][CH2:22]1>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([N:23]3[CH2:24][C:21]([F:25])([F:20])[CH2:22]3)=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: FC1(F)CNC1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Agent: Cl
Product: O=C(c1cc(OCC(F)(F)F)c(C2CC2)cn1)N1CC(F)(F)C1

Procedure:
The title compound was synthesized in analogy to Example 63b, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7) as starting materials and isolated (21 mg, 37%) as colorless oil; MS (ESI, m/z): 337.4 (M+H+).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][C:46]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][C:46]=3[Cl:52])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: Clc1ccc(CBr)c(Cl)c1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3ccc(Cl)cc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2,4-dichlorobenzene and isolated as white solid (5.3 mg, 29%). MS (m/e): 441.4 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[C:12]1[CH:11]=[CH:10][C:9]([C:18]#[N:19])=[CH:8][C:7]=1[NH:6][C:5]2=[O:20].BrC1C=CC(S(O[C@@H:32]2[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:34]([C:44]([O:46][CH3:47])=[O:45])[CH2:33]2)(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN1C(=O)CCC1.CCOC(C)=O>[Br:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:13]2[C:4](=[C:5]([O:20][C@H:32]3[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:34]([C:44]([O:46][CH3:47])=[O:45])[CH2:33]3)[N:6]=[C:7]3[C:12]=2[CH:11]=[CH:10][C:9]([C:18]#[N:19])=[CH:8]3)[CH:3]=1
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Reactant: COc1cc2c(cc1Br)c(=O)[nH]c1cc(C#N)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@@H]1C[C@@H](Oc2nc3cc(C#N)ccc3c3cc(OC)c(Br)cc23)CN1C(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
To a solution of 8-bromo-9-methoxy-6-oxo-5,6-dihydrophenanthridine-3-carbonitrile (C1), 8-bromo-9-methoxy-6-oxo-5,6-dihydrophenanthridine-3-carbonitrile (354 mg, 1.07 mmol) in NMP (10 mL) was added 1-tert-butyl 2-methyl (2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate (549 mg, 1.18 mmol) and Cs2CO3 (876 mg, 2.69 mmol). The mixture was then heated to 60° C. for 18 h, and worked up with water and EtOAc. The organic layer was washed with brine, dried over MgSO4, and the solvent was removed in vacuo. The crude material was purified on silica (gradient elution, 10-50% EtOAc/hex) to yield the title compound. LRMS ((M-Boc)+H)+=456.2.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][C:17]([C:21]([F:24])([F:23])[F:22])=[C:18](O)[N:19]=2)=[N:6]1.P(Cl)(Cl)(Cl)=O.[NH3:34]>C(#N)C>[F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][C:17]([C:21]([F:24])([F:23])[F:22])=[C:18]([NH2:34])[N:19]=2)=[N:6]1
Reactant: Oc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nnc1C(F)(F)F
Reactant: N
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nnc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
690 mg (1.768 mmol) of 3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6-(trifluoromethyl)-1,2,4-triazin-5-ol were admixed with 9 ml of phosphoryl chloride and stirred at RT overnight. The reaction mixture was diluted with 50 ml of dry acetonitrile and, with ice-cooling, stirred into 123 ml of concentrated aqueous ammonia solution (25% strength). Stirring was carried out for 48 h at RT and for 24 h at 50° C. After cooling, the acetonitrile was removed on a rotary evaporator, water was added, the precipitate was filtered off with suction and the filtercake was washed with a little water. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water with 0.1% TFA, gradient 30:70→95:5). This gave 125 mg (18% of theory) of the target compound.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C@@H:4]1[C@@H:6]([C:7](Cl)=[O:8])[C:5]1([CH3:11])[CH3:10].[CH3:13][C:14]1[CH:15]([OH:25])[CH2:16][C:17](=[CH2:24])[C:18]=1[CH2:19][C:20]([F:23])([F:22])[F:21].N1C=CC=CC=1.N>CN(C)C1C=CN=CC=1.O1CCCC1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[CH3:1][C:2]([CH3:12])=[CH:3][C@@H:4]1[C@@H:6]([C:7]([O:25][CH:15]2[CH2:16][C:17](=[CH2:24])[C:18]([CH2:19][C:20]([F:21])([F:22])[F:23])=[C:14]2[CH3:13])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: CC(C)=C[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Reactant: C=C1CC(O)C(C)=C1CC(F)(F)F
Agent: CN(C)c1ccncc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: N
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=C1CC(OC(=O)[C@@H]2[C@@H](C=C(C)C)C2(C)C)C(C)=C1CC(F)(F)F
Reaction time: 2 h
Yield: 52.4 %

Procedure:
Under ice-water cooling, 350 mg of (1R)-trans-3-(2-methyl-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid chloride was added dropwise to the mixed solution of 300 mg of (RS)-2-methyl-4-methylidene-3-(2,2,2-trifluoroethyl)cyclopent-2-en-1-ol, 5 mg of 2,6-di-tert-butyl-4-methylphenol, 185 mg of pyridine and 5 mg of 4-dimethylaminopyridine in 10 ml of dry terahydrofuran and then the resultant reaction mixture was allowed to react further 6 hours at room temperature. Then 10 ml of 10% aqueous ammonia solution was added to the solution and vigorously stirred for 2 hours. The reaction mixture was extracted three times with diethyl ether and the ether layers were combined. The combined layer was washed with brine and dried over anhydrous magnesium sulfate. After removal of the drying agent, the solvent was evaporated. The obtained residue was subjected to silica gel column chromatography to afford 280 mg of the desired (RS)-2-methyl-4-methylidene-3-(2,2,2-trifluoroethyl)cyclopent-2-en-1-yl (1R)-trans-3-(2-methyl-1-propenyl)-2,2-dimethylcyclopropanecarboxylate (Compound No.15). Yield 52% (Eluent: n-hexane/ethyl acetate=30/1, 2,6-di-tert-butyl-4-methylphenol 0.1% ) nD21 1.4805
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[CH:5]2.[CH3:17][N:18]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[C:21]2[CH:33]=[N:34][N:35]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:20]=2[C:19]1=[O:44]>>[CH:14]1([CH2:13][O:12][C:3]2[C:2]([C:22]3[C:21]4[CH:33]=[N:34][N:35]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:43])[CH3:42])[C:20]=4[C:19](=[O:44])[N:18]([CH3:17])[CH:23]=3)=[CH:10][CH:9]=[C:8]3[C:4]=2[CH:5]=[N:6][N:7]3[CH3:11])[CH2:16][CH2:15]1
Reactant: Cn1ncc2c(OCC3CC3)c(Br)ccc21
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2cnn(COCC[Si](C)(C)C)c2c1=O
Product: Cn1cc(-c2ccc3c(cnn3C)c2OCC2CC2)c2cnn(COCC[Si](C)(C)C)c2c1=O

Procedure:
This compound was synthesized according to the procedure of Example 10, Step 5, using 5-bromo-4-(cyclopropylmethoxy)-1-methyl-1H-indazole and 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one as the starting materials. LCMS calculated for C25H34N5O3Si (M+H)+: m/z=480.2. found: 480.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[C:4]([C:22]([F:25])([F:24])[F:23])[CH:3]=1.C(N(CC)CC)C.[OH:33][CH:34]([CH:38]1[CH2:42][O:41][C:40]([CH3:44])([CH3:43])[O:39]1)[CH2:35][NH:36][CH3:37]>O1CCCC1>[OH:33][CH:34]([CH:38]1[CH2:42][O:41][C:40]([CH3:44])([CH3:43])[O:39]1)[CH2:35][N:36]([CH3:37])[S:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([S:9](=[O:11])(=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[C:22]([F:25])([F:24])[F:23])[CH:13]=1)(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)c1cccc(S(=O)(=O)Nc2ccc(F)cc2C(F)(F)F)c1
Reactant: CNCC(O)C1COC(C)(C)O1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(CC(O)C1COC(C)(C)O1)S(=O)(=O)c1cccc(S(=O)(=O)Nc2ccc(F)cc2C(F)(F)F)c1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
8.36 g (20 mmol) of 3-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]-benzenesulfonic acid chloride is dissolved in 40 ml of tetrahydrofuran, 2.52 g (25 mmol) of triethylamine and 4.03 (25 mmol) of 2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-N-methylethylamine are added and stirred for 3 hours at 45° C. The reaction mixture is then concentrated by evaporation under reduced pressure, the residue is extracted with ethyl acetate and the extract is chromatographed on silica gel 60 (Merck) with ethyl acetate/hexane. 9.35 g (16.8 mmol)=84% of the theoretical yield is obtained as an amorphous solid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32])[CH2:19]P(=O)(OCC)OCC.[H-].[Na+].O>O1CCCC1>[F:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32])[CH:19]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(F)c1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=Cc2ccc([N+](=O)[O-])c(F)c2)CC1
Reaction time: 4 h
Yield: 64.8 %

Procedure:
tert-Butyl 4-oxopiperidine-1-carboxylate (126 mmol, 25.04 g) and diethyl 3-fluoro-4-nitrobenzylphosphonate (126 mmol, 36.6 g) in tetrahydrofuran (220 mL) were stirred and sodium hydride (163 mmol, 6.54 g, 60% in oil) was added. The reaction was stirred for 4 hours and then water was added. The reaction was extracted with dichloromethane and the organics were dried (magnesium sulfate), filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with dichloromethane to give a bright yellow solid. This solid was filtered, washed with heptane and vacuum dried to afford the title compound (27.47 g). 1H NMR (CDCl3, 400 MHz): δ 8.1 (t, 1H), 7.1 (s, 1H), 7.05 (s, 1H), 6.35 (s, 1H), 3.55 (m, 2H), 3.45 (m, 2H), 2.52 (m, 2H), 2.4 (m, 2H), 1.49 (s, 9H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].[H-].[Na+].Cl[CH:16](Cl)[CH2:17][O:18][CH2:19][CH:20](Cl)Cl>C1COCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:9]([O:11][CH3:12])=[O:10])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: COC(=O)Cc1ccccc1F
Reactant: ClC(Cl)COCC(Cl)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [H-]
Solvent: C1CCOC1
Product: COC(=O)C1(c2ccccc2F)CCOCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52.5 %

Procedure:
To an ice-bath cooled, stirred solution of methyl 2-(2-fluorophenyl)acetate (3.4 g, 20 mmol) in THF (100 mL) was added NaH (1.8 g, 44 mmol). The reaction was stirred at 0° C. for 10 minutes and then dichloroethyl ether (2.7 mL, 22 mmol) and tetrabutylammonium bromide (0.33 g, 1.0 mmol) were added sequentially. The yellow reaction mixture was stirred for 16 hours at room temperature and then quenched with a saturated ammonium chloride solution. The aqueous layer was extracted with EtOAc (3×60 mL), and the organic layers were combined, dried (Na2SO4), filtered and concentrated to afford a yellow oil. Purification by flash chromatography (100% DCM) provided a pale yellow oil (2.5 g). MS m/e=239.0 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([CH2:18]P(=O)(OCC)OCC)#[N:17].[H-].[Na+].O>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:18]/[C:16]#[N:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#C/C=C/C1CCN(Cc2ccccc2)CC1
Yield: 109.8 %

Procedure:
A solution of 1-benzyl-4-formylpiperidine (4.5 g) in tetrahydrofuran (20 ml) was added dropwise to a suspension of diethyl cyanomethylphosphonate (4.31 g) and sodium hydride (0.97 g, 60% suspension in oil) in tetrahydrofuran (30 ml) at 0° C. under stirring. After stirring for 1 hour at ambient temperature, the mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and brine and dried over magnesium sulfate, and evaporated in vacuo to give (E)-3-(1-benzylpiperidin-4-yl)-2-propenenitrile (5.5 g) as an oil.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5](/[CH:8]=[CH:9]/[C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[O:6][CH:7]=1.[CH3:18][S:19]([CH2:22][C:23]1[N:24]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)[CH:25]=[CH:26][N:27]=1)(=[O:21])=[O:20].[H-].[Na+]>>[F:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1/[CH:9]=[CH:8]/[C:5]1[O:6][CH:7]=[C:3]([CH2:2][O:38][C:35]2[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][N:24]3[CH:25]=[CH:26][N:27]=[C:23]3[CH2:22][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:37][CH:36]=2)[N:4]=1
Reactant: CS(=O)(=O)Cc1nccn1CCCCc1ccc(O)cc1
Reactant: Fc1cccc(F)c1/C=C/c1nc(CCl)co1
Agent: [H-]
Agent: [Na+]
Product: CS(=O)(=O)Cc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3c(F)cccc3F)n2)cc1
Yield: 65.5 %

Procedure:
Using 4-(chloromethyl)-2-[(E)-2-(2,6-difluorophenyl)ethenyl]-1,3-oxazole (228 mg), 4-[4-[2-[(methylsulfonyl)methyl]-1H-imidazol-1-yl]butyl]phenol (250 mg). and 65% sodium hydride (32.9 mg), the same reaction as Example 11-(i) was carried out to yield the titled compound (280 mg) as colorless needle crystals.
Reaction SMILES: C(#N)C.[Cl:4][CH2:5][CH2:6][CH:7]1[CH2:13][N:12]([CH3:14])[C:11](=O)[C:10]2[CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:19][C:9]=2[O:8]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:25]>C1(C)C=CC=CC=1>[Cl:4][CH2:5][CH2:6][CH:7]1[CH2:13][N:12]([CH3:14])[C:11](=[S:25])[C:10]2[CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:19][C:9]=2[O:8]1
Reactant: CN1CC(CCCl)Oc2ccc(C(F)(F)F)cc2C1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CN1CC(CCCl)Oc2ccc(C(F)(F)F)cc2C1=S

Procedure:
To 30 ml of acetonitrile was added 1.25 g (0.004 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methyl-7-(trifluoromethyl)-1,4-benzoxazepine-5(4H)-one and 0.92 g (0.002 mole) of phosphorus pentasulfide and the reaction mixture heated to reflux for 4 hr. After cooling, 30-40 ml of toluene was added and the mixture filtered. The filtrate was washed with 3×50 ml of saturated potassium carbonate, charcoaled, filtered, and concentrated by rotary evaporation. The residue was crystallized from isopropyl ether to give 0.65 g (50%) of yellow, analytically pure crystals, m.p., 146°-48° C.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]([C:18]3[N:19]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[N:22]=3)[OH:17])=[CH:8]2)=[CH:4][CH:3]=1.CCCCCC.C(OCC)(=O)C>ClCCl.O=[Mn]=O>[Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([C:18]3[N:19]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:35])[CH3:36])[CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[N:22]=3)=[O:17])=[CH:8]2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccccn2)nc1C(O)c1cn(Cc2ccc(Cl)cc2)c2ccccc12
Agent: O=[Mn]=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: C[Si](C)(C)CCOCn1cc(-c2ccccn2)nc1C(=O)c1cn(Cc2ccc(Cl)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
A mixture of [1-(4-chloro-benzyl)-1H-indol-3-yl]-[4-pyridin-2-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-methanol (10 mg, 18.4 mmol) and (10 mg, 18.4 mmol) and MnO2 (0.2 g, 2.3 mmol) in dichloromethane (5 mL) was stirred at room temperature for two hours. Flash silica gel chromatography (2:1 hexane/ethyl acetate) afforded the oxidized product [1-(4-chloro-benzyl)-1H-indol-3-yl]-[4-pyridin-2-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-methanone as a syrup (10 mg, 100%). 1H NMR (CDCl3) δ −0.02 (s, 9H), 0.99 (t, 2H, J=7), 3.68 (t, 2H, J=7), 5.40(s, 2H), 5.99 (s, 2H), 7.15–7.40 (m, 9H), 7.75 (t, 1H, J=4), 7.85 (d, 1H, J=6), 8.00 (s, 1H), 8.60(d, 1H, J=6), 9.00 (s, 1H)ppm; ESMS calcd for (C30H31ClN4O2Si): 542.2; found: 543.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C@@H:14]([CH:30]([CH3:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:11]([CH2:33][C@@H:34]([CH:44]([CH3:46])[CH3:45])[CH2:35][O:36]CC2C=CC=CC=2)[O:10][C:9]1([CH3:48])[CH3:47])=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C@@H:14]([CH:30]([CH3:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:11]([CH2:33][C@@H:34]([CH:44]([CH3:46])[CH3:45])[CH2:35][OH:36])[O:10][C:9]1([CH3:47])[CH3:48])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COCCCOc1cc(C[C@@H](C[C@H]2[C@H](C[C@H](COCc3ccccc3)C(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)C(C)C)ccc1OC
Agent: [Pd]
Solvent: C1CCOC1
Product: COCCCOc1cc(C[C@@H](C[C@H]2[C@H](C[C@H](CO)C(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)C(C)C)ccc1OC

Procedure:
3.7 g of 3-tert-butoxycarbonyl-5(S)-(3-benzyloxy-2(S)-isopropyl-propyl)-4(S)-{2(S)-iso-propyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine are hydrogenated in the presence of 1.0 g of 5% Pd/C in 50 ml of tetrahydrofuran for 15 minutes at room temperature and under normal pressure. The reaction mixture is filtered and concentrated by evaporation. The residue is purified by means of FC (140 g of silica gel, ethyl acetate/hexane=1:2). The title compound is obtained: Rf (ethyl acetate/hexane=1:2)=0.28.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([C:11]#[C:12][Si](C)(C)C)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>CO.O>[C:11]([C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=1)#[CH:12]
Reactant: C[Si](C)(C)C#Cc1ccc(N)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: C#Cc1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2-Nitro-4-(trimethylsilylethinyl)aniline (3.96 g; 16.9 mmol; 1 eq.) was dissolved in MeOH (50 ml) and CH2Cl2 (50 ml) and treated with K2CO3 (9.33 g; 67.6 mmol; 4 eq.). After stirring at room temperature for 5 h, the mixture was diluted with water. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3×100 ml). The combined organic layers were dried over Na2SO4, evaporated and the residue was purified by flash chromatography on silica using a CHCl3/MeOH gradient. Yield: 2.06 g (75.1%); MS m/z: 163.4 [M+H]+
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>[Ag].CN(C)C=O>[N:17]1([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:16])[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: c1c[nH]cn1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: [Ag]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCn1ccnc1

Procedure:
A mixture of 0.1 mole of 2-(4-bromobutyl)-1H-isoindole-1,3(2H)-dione and 0.1 mole of the silver salt of imidazole were heated in 300 ml. of dimethylformamide for 8 hours. The reaction mixture was concentrated to remove the solvent and the residue was boiled with 200 ml. of toluene and filtered to remove the insoluble material. The toluene layer was concentrated and the desired product was purified by HPLC using ethyl acetate and a silica gel column.
Reaction SMILES: Cl.Cl.Cl.[N:4]1[CH:9]=[CH:8][C:7]([CH2:10][C@H:11]([C:13]([N:15]2[CH2:20][CH2:19][CH:18]([CH:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[CH2:17][CH2:16]2)=[O:14])[NH2:12])=[CH:6][CH:5]=1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:37](O)=[O:38])[CH:35]=2)[CH:30]=[CH:29]1>>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:37]([NH:12][C@@H:11]([C:13]([N:15]3[CH2:16][CH2:17][CH:18]([CH:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)[CH2:19][CH2:20]3)=[O:14])[CH2:10][C:7]3[CH:6]=[CH:5][N:4]=[CH:9][CH:8]=3)=[O:38])[CH:35]=2)[CH:30]=[CH:29]1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: CN1CCC(C2CCN(C(=O)[C@H](N)Cc3ccncc3)CC2)CC1
Agent: Cl
Product: CN1CCC(C2CCN(C(=O)[C@@H](Cc3ccncc3)NC(=O)c3ccc4cc[nH]c4c3)CC2)CC1

Procedure:
Using methods substantially equivalent to those described in Method D-1, the titled compound was prepared from 1-[β-(4-pyridinyl)-D-alanyl]-4-(1-methylpiperidin-4-yl)piperidine trihydrochloride and indole-6-carboxylic acid (23%).