Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]=[CH:8][N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].Cl>C(Cl)(Cl)Cl.CC(O)C>[C:1]1([CH2:7][CH2:8][N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])C=Cc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])CCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75 %

Procedure:
2-Phenylnitroethene (5.12 g, 34.3 mmol, from step 15a) was dissolved in CHCl3 /i-PrOH (410:85 mL) and SiO2 (51.4 g) was added. NaBH4 (5.2 g, 137 mmol) was added in portions, and the mixture was stirred for 90 minutes at room temperature. HCl (0.5N, 100, mL) was added, and the mixture was stirred for 30 minutes. The layers were separated, and the aqueous phase was extracted with methylene chloride. The organic layers were combine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel (eluting with ether:hexanes 1:30) to give the title compound as an oil (3.89 g, 75%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][N:17]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7].I[Si](C)(C)C.CO>C(Cl)(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][N:17]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7]
Reactant: COc1cc(C(=O)Nc2ccccc2)ccn1
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccccc1)c1ccnc(O)c1
Temperature: 25 °C
Yield: 37.3 %

Procedure:
To a solution of 2-methoxy-N-phenylisonicotinamide (1.00 g, 4.38 mmol) in anhydrous chloroform (60 mL) was added iodotrimethylsilane (17.50 g, 87.50 mmol). The reaction mixture was stirred at reflux for 16 hours. After cooling to ambient temperature, methanol (10 mL) was added dropwise to quench the reaction. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed with saturated aqueous sodium bicarbonate solution (2×100 mL) and brine (150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrate in vacuo. The brown crude product was recrystallised from ethyl acetate and methanol to afford the title compound as a colourless solid (0.35 g, 19%): 1H NMR (300 MHz, DMSO-d6) δ 11.88 (br s, 1H), 10.31 (s, 1H), 7.73-7.68 (m, 2H), 7.47 (d, J=6.8 Hz, 1H), 7.31 (t, J=7.9 Hz, 2H), 7.10-7.05 (m, 1H), 6.81 (s, 1H), 6.49 (dd, J=6.8, 1.7 Hz, 1H); MS (ES+) m/z 215.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:20]=[C:19]([CH2:21][NH:22][CH3:23])[S:18][CH:17]=2)=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2].[CH:24]1([CH2:29][C:30](Cl)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([CH2:29][C:30]([CH2:23][NH:22][CH2:21][C:19]2[S:18][CH:17]=[C:16]([C:13]3[CH:14]=[CH:15][C:10]([CH2:9][C@H:4]([O:3][CH2:1][CH3:2])[C:5]([O:7][CH3:8])=[O:6])=[CH:11][CH:12]=3)[CH:20]=2)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CCO[C@@H](Cc1ccc(-c2csc(CNC)c2)cc1)C(=O)OC
Reactant: O=C(Cl)CC1CCCC1
Product: CCO[C@@H](Cc1ccc(-c2csc(CNCC(=O)CC3CCCC3)c2)cc1)C(=O)OC
Yield: 87.9 %

Procedure:
In a manner similar to that of Example 16(e), starting with 0.35 g (1 mmol) of methyl 2(S)-ethoxy-3-[4-(5-methylaminomethylthiophen-3-yl)phenyl]propanoate and 170 μl (1.15 mmol) of 2-cyclopentylacetyl chloride, 0.39 g (85%) of methyl 3-[4-(5-{[(2-cyclopentylacetyl)methylamino]methyl}thiophen-3-yl)phenyl]-2(S)-ethoxypropanoate is obtained.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11])([CH3:4])([CH3:3])[CH3:2].C(O[CH:17](N(C)C)[N:18]([CH3:20])[CH3:19])(C)(C)C>>[C:1]([CH:5]1[CH2:10][CH2:9][CH2:8]/[C:7](=[CH:17]\[N:18]([CH3:20])[CH3:19])/[C:6]1=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCCCC1=O
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)/C=C1\CCCC(C(C)(C)C)C1=O

Procedure:
2-tert-Butylcyclohexanone (93 mg, 0.60 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (105 mg) as a yellow oil which was used directly in the next step. MS ISP (m/e): 210.2 (100) [(M+H)+].
Reaction SMILES: [F:1][C:2]1[C:9]([I:10])=[C:8]([CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:12][OH:13]>C(O)C>[F:1][C:2]1[C:9]([I:10])=[C:8]([CH3:11])[CH:7]=[CH:6][C:3]=1/[CH:4]=[N:12]/[OH:13]
Reactant: NO
Reactant: Cc1ccc(C=O)c(F)c1I
Solvent: CCO
Product: Cc1ccc(/C=N/O)c(F)c1I
Reaction time: 3 h

Procedure:
A solution of 2-fluoro-3-iodo-4-methylbenzaldehyde (1.26 g, 4.77 mmol) in ethanol (5 mL) at RT was treated with hydroxylamine (5 mL) (50% wt. in water) and the reaction stirred for 3 h. The volatiles were removed and the residue was treated with water (5 mL), extracted with ethyl acetate (3×15 mL). The combined ethyl acetate layers were dried and concentrated. Purification on a 40 g ISCO column (eluted with 10-50% ethyl acetate in hexanes) provided the title compound as an off-white crystalline solid. MS (ESI, pos. ion) m/z: 280.0 (M+1).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH2:16][CH2:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:28][CH2:29][C:30](Cl)=[O:31]>ClCCl>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([C:30](=[O:31])[CH2:29][Cl:28])[CH2:16][CH2:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC(Oc2ccc3c(c2)CCN3)CC1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(c2)CCN3C(=O)CCl)CC1
Reaction time: 4 h

Procedure:
A solution of 5-(4-tert-butyl-cyclohexyloxy)-2,3-dihydro-1H-indole (0.55 g, 2 mmol), triethylamine (0.56 mL, 4 mmol) in dichloromethane (8 mL) was added chloroacetyl chloride (0.2 mL, 2.6 mmol) at 0° C. The solution was stirred from 0° C. to room temperature for 4 hrs. The solution was diluted with dichloromethane and washed with 5% aqueous citric acid, aqueous sodium biocarbonate, and water, dried over MgSO4, and concentrated. The residue was purified with silica gel column eluted with ethyl acetate in hexane to give product (0.37 g, yield: 52%). ESI-MS: 350.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:55][CH2:56][CH3:57])[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[N:35](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:7]=1[C:8]([O:10][CH2:11][O:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])=[O:9])[CH3:2].C(O)(=O)C>CO>[CH2:1]([C:3]1[N:4]=[C:5]([CH2:55][CH2:56][CH3:57])[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:32][N:33]=[N:34][N:35]=3)=[CH:21][CH:20]=2)[C:7]=1[C:8]([O:10][CH2:11][O:12][C:13](=[O:17])[CH:14]([CH3:15])[CH3:16])=[O:9])[CH3:2]
Reactant: CCCc1nc(CC)c(C(=O)OCOC(=O)C(C)C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CC(=O)O
Product: CCCc1nc(CC)c(C(=O)OCOC(=O)C(C)C)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.8 %

Procedure:
To a solution of 0.46 g isobutyryloxymethyl 4-ethyl-2-propyl-1-[[2'-(N-triphenylmethyl(tetrazol-5-yl))biphenyl-4-yl]methyl]imidazole-5-carboxylate in 10 mL MeOH was added 1 5 mL glacial acetic acid and the mixture stirred 2 days at room temperature. The reaction was evaporated to near dryness and the residue purified by flash chromatography using a 0% to 5% MeOH/CHCl3 gradient. There was obtained 0.250 g of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:17]=[C:18]4/[C:19](=[O:24])[NH:20][C:21](=[O:23])[S:22]/4)=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[C:5]([C:27]([F:30])([F:29])[F:28])[CH:4]=1)#[N:2].Cl.[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][CH2:36]Cl>>[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][CH2:36][N:20]1[C:19](=[O:24])/[C:18](=[CH:17]/[C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][C:6]2[CH:25]=[CH:26][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[C:27]([F:29])([F:30])[F:28])[CH:9]=[CH:10]3)/[S:22][C:21]1=[O:23]
Reactant: CN(C)CCCCl
Reactant: N#Cc1ccc(Cn2ccc3cc(/C=C4\SC(=O)NC4=O)ccc32)c(C(F)(F)F)c1
Agent: Cl
Product: CN(C)CCCN1C(=O)S/C(=C\c2ccc3c(ccn3Cc3ccc(C#N)cc3C(F)(F)F)c2)C1=O

Procedure:
4-({5-[(Z)-{3-[3-(Dimethylamino)propyl]-2,4-dioxo-1,3-thiazolidin-5-ylidene}methyl]-1H-indol-1-yl}methyl)-3-(trifluoromethyl)benzonitrile was prepared from [(5Z)-5-({1-[4-cyano-2-(trifluoromethyl)benzyl]-1H-indol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 246) and 3-(dimethylamino)propyl chloride hydrochloride following General Procedure H.
Reaction SMILES: [Si]([O:8][C@@H:9]([CH3:41])[C@@H:10]([NH:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[C:33]([Cl:39])[C:32]=1[CH3:40])[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][Si](C(C)(C)C)(C)C)[CH:17]=2)=[N:14][N:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[Cl:39][C:33]1[C:32]([CH3:40])=[C:31]([NH:30][C@@H:10]([C:11]2[O:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)=[N:14][N:15]=2)[C@@H:9]([OH:8])[CH3:41])[CH:38]=[CH:37][C:34]=1[C:35]#[N:36]
Reactant: Cc1c(N[C@@H](c2nnc(-c3cccc(O[Si](C)(C)C(C)(C)C)c3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3cccc(O)c3)o2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.6 %

Procedure:
To a 25 mL round bottom flask equipped with a magnetic stirrer and a septum was added 4-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(5-(3-(tert-butyldimethyl-silyloxy)phenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-chloro-3-methylbenzonitrile (intermediate 7c) (62 mg, 0.1 mmol), which was then dissolved in anhydrous THF (3 mL) under an atmosphere of nitrogen. To this was added the tetrabutylammonium fluoride as a 1M solution in THF (0.4 mL, 0.4 mmol) producing an instant color change to yellow. This was allowed to stir at room temperature for a period of 4 h. The so/vent was then removed under reduced pressure to yield a black residue. This residue was taken up in EtOAc (20 mL) and washed with water (2×10 mL), brine (1×10 mL) and dried over Na2SO4. The solution was then filtered and concentrated under reduced pressure using rotary evaporation to reveal a yellow solid. This was purified via silica gel chromatography eluted with 70% EtOAc/hexanes to provide the title compound as a white solid (31 mg, 81%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 8.88 (br s, 1H), 7.48 (m, 3H), 7.38 (m, 1H), 7.06 (m, 1H), 6.86 (d, J=8.8 Hz, 1H), 5.68 (d, J=8.5 Hz, 1H), 5.10 (dd, J=3.6, 8.5 Hz, 1H), 4.83 (br s, 1H), 4.62 (m, 1H), 2.40 (s, 3H), 1.41 (d, J=6.3 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F-].[Cs+]>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: [Pd]
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: Clc1ccc2c(-c3ccccc3)ccnc2c1

Procedure:
A mixture of 4,7-dichloroquinoline (12.5 g, 63.1 mmol), phenylboronic acid (9.63 g, 79 mmol) and cesium fluoride (24 g, 158 mmol) in 1,2-dimethoxyethane (300 mL) was degassed and purged three times with nitrogen gas before the addition of the tetrakis(triphenylphosphine) palladium(0) (3.64 g, 3.15 mmol). The resultant mixture was then stirred at reflux overnight. After cooling, the reaction was filtered over celite and washed with dichloromethane. After evaporation under reduced pressure, the residue was purified by column chromatography (eluting with hexane/EtOAc, 95:5) to yield the title compound. 1H NMR (400 MHz, acetone-d6): δ 9.0 (d, 1H), 8.15 (d, 1H), 7.95 (d, 1H), 7.65-7.55 (m, 6H), 7.5 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[Cl:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>>[Cl:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([NH:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:18]
Reactant: O=C(Cl)CCOCCCl
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNC(=O)CCOCCCl)cc1

Procedure:
Title compound was prepared starting from 4-methoxyphenylmethanamine and 3-(2-chloroethoxy)propanoyl chloride following the procedure outlined for Example 27A. 1H NMR (CDCl3): δ 2.38-2.41 (m, 2H), 2.60-2.63 (m, 2H), 3.54-3.60 (m, 2H), 3.66-3.69 (m, 2H), 3.80 (s, 3H), 4.45 (d, 2H, J=6.1 Hz), 6.12 (br t, 1H, D2O exchanged), 6.80-6.87 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:11]([Mg]Br)=[CH2:12]>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:12]=[CH:11][NH:8][C:7]=12
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: Clc1nccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 37 %

Procedure:
2-Chloro-3-nitropyridine (10 g, 63 mmol) in THF (200 mL) was cooled to −60° C. or lower. The solution was treated with vinyl magnesium bromide (200 mL, 1.0 M) at such a rate that the internal temperature was kept below −40° C. After the addition was complete, the solution was stirred for another 4-6 hours at −40° C. or less, and let warm up to room temperature gradually overnight. The reaction mixture was quenched with saturated NH4Cl. The organic layer was separated, and the aqueous layer was extracted with EtOAc three times. The combined organic layers were washed with H2O, brine, and dried over MgSO4. The solvents were removed under reduced pressure. The residue was suspended in CH2Cl2, loaded onto a silica gel column, and eluted with 1:4 EtOAc:hexanes to give 3.6 g (37%) of the desired product. MS (DCI) m/e 153 & 155 (M+H)+, 1H NMR (300 MHz, DMSO-d6): □ 12.0 (br s, 1H), 7.89 (d, J=5.4 Hz, 1H), 7.67 (m, 1H), 7.57 (d, J=5.4 Hz, 1H), 6.64 (m, 1H).
Reaction SMILES: N1N=C[N:4]([C:6]2[CH:11]=[CH:10][C:9](NN)=[CH:8][CH:7]=2)[CH:5]=1.[CH3:14]OC(OC)CCCCN1CCN(C(OC(C)(C)C)=O)CC1.C([O-])([O-])=O.[K+].[K+]>S(=O)(=O)(O)O>[NH:4]1[C:6]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:14]=[CH:5]1
Reactant: NNc1ccc(-n2cnnc2)cc1
Reactant: COC(CCCCN1CCN(C(=O)OC(C)(C)C)CC1)OC
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: c1ccc2[nH]ccc2c1
Yield: 116.4 %

Procedure:
A mixture of 4-(1,2,4-triazol-4-yl)phenylhydrazine (5.0 g, 28.6 mmol) and 5-[4-(tert-butyloxycarbonyl)piperazin-1-yl]pentanal dimethyl acetal (9.03 g, 28.6 mmol) in 4% sulphuric acid (150 ml) was heated at reflux for 48 h. The solution was cooled in an ice-bath, basified with solid K2CO3 and extracted with butan-1-ol (×3). The solvent was removed under vacuum and azeotroped with hexane (×2). The crude product was purified by chromatography on silica gel eluting with CH2Cl2 /MeOH/NH3 (30:8:1) to give the title-indole (3.9 g, 44%). δ(360 MHz, oxalate salt in D2O) 2.12-2.24 (2H, m, CH2); 2.93 (2H, t, J=7 Hz, CH2); 3.46-3.76 (8H, m, 4 of CH2) 7.37 (1H, dd, J=1.9 and 8.7 Hz, Ar-H); 7.39 (1H, s, Ar-H); 7.66 (1H, d, J=8.7, Ar-H); 7.82 (1H, d, J=1.9 Hz, Ar-H); 9.13 (2H, s, Triazole-H).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[N-:5]=[N+:6]=[N-:7].[Na+].[N-]=[N+]=[N-].[Al+3].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[C:19]1([CH:25]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[N:37]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[C:36]4[CH:44]=[CH:45][C:46]([C:48]#[N:49])=[CH:47][C:35]=4[N:34]=3)=[CH:29][CH:28]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:50]1([CH:25]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[N:37]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[C:36]4[CH:44]=[CH:45][C:46]([C:48]5[NH:49][N:7]=[N:6][N:5]=5)=[CH:47][C:35]=4[N:34]=3)=[CH:29][CH:28]=2)[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc2c(c1)nc(-c1ccc(OC(c3ccccc3)c3ccccc3)cc1)n2C1CCCCC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Product: c1ccc(C(Oc2ccc(-c3nc4cc(-c5nnn[nH]5)ccc4n3C3CCCCC3)cc2)c2ccccc2)cc1
Temperature: 0 °C
Yield: 20.6 %

Procedure:
Aluminum trichloride (33 mg, 0.247 mmol) was added to ice cold THF (4 mL). Sodium azide (48 mg, 0.744 mmol) was added and the resulting mixture was stirred under reflux for 30 min to complete the formation of the aluminum azide. Compound 8 (100 mg, 0.206 mmol) was added and the mixture stirred under reflux for 18 h. The reaction mixture was poured into ice cold dilute HCl to precipitate a solid. The solid was dissolved in DMF (2 mL) and the solution applied to a Shimadzu Prep HPLC. The product containing fractions were combined. Removal of the methanol resulted in the precipitation of 9 as a colorless solid (22.3 mg, 20.6% yield). ESI-MS m/e 527 (M=1). 1H NMR (DMSO) δ 8.33 (s, 1H), 8.20 (d, 1H, J=8.6 Hz), 8.0 (1H, d, J=7.41 Hz), 7.63 (d, 2H, J=8.7 Hz), 7.55 (d, 4H, J=7.2 Hz), 7.41-7.37 (m, 4H), 7.34-7.26 (m, 4). 6.72 (s, 1H), 4.34-4.27 (m, 1H), 2.36-2.23 (m, 2H), 1.97-1.83 (m, 4H), 1.66-1.62 (m, 1H), 1.43-1.21 (m. 3H).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[O:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][N:23]4[CH:27]=[CH:26][N:25]=[CH:24]4)=[CH:16][CH:15]=3)[N:11]=2)=[CH:4][CH:3]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[N:23]1([CH2:22][CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:10]3[N:11]=[C:7]([C:5]4[O:6][C:2]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:3][CH:4]=4)[O:8][CH:9]=3)=[CH:15][CH:16]=2)[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)o1
Product: c1ccc(-c2ccc(-c3nc(COc4ccc(CCCn5ccnc5)cc4)co3)o2)cc1
Yield: 92 %

Procedure:
In substantially the same manner as in Working Example 135, 2-(5-bromo-2-furyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole was allowed to react with phenylboronic acid to give 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(5-phenyl-2-furyl)oxazole. The yield was 92%. Recrystallization from ethyl acetate-isopropyl ether gave colorless needles, mp 130-131° C.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].[F:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:17](OC)=[O:18].Cl>O1CCCC1.COCCOC>[F:13][C:14]1[CH:15]=[C:16]([C:17](=[O:18])[CH2:3][S:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH:21]=[CH:22][C:23]=1[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC)cc1F
Reactant: CS(=O)(=O)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)CS(=O)(=O)c2ccccc2)cc1F

Procedure:
A solution of 864 mg. of sodium hydride and 5.3 g. of methylphenylsulfone in 20 ml. of 1,2-dimethoxyethane is stirred at 60° C. for one hour under an atmosphere of argon. To this solution is then added a solution of 5.0 g. of methyl 3-fluoro-4-(hexadecylamino)benzoate and 50 ml. of tetrahydrofuran and the reaction mixture is stirred at 60° C. for 1.5 hours. The mixture is cooled, poured onto ice, acidified with dilute hydrochloric acid to pH 3 and then extracted with chloroform. The organic layer is separated, washed three times with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated to dryness. The crude solid is chromatographed on silica gel, eluting with methylene chloride to yield 3'-fluoro-4'-(hexadecylamino)-2-(phenylsulfonyl)acetophenone.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:14])[NH:8][N:9]2[CH:13]=[CH:12][S:11][C:10]=12)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:22][CH3:23]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:14][CH2:22][CH3:23])=[N:8][N:9]2[CH:13]=[CH:12][S:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(=O)[nH]n2ccsc12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OCC)nn2ccsc12
Temperature: 25 °C
Yield: 72.6 %

Procedure:
To a DMF (119 mL) solution of 6-oxo-5,6-dihydro-pyrazolo[5,1-b][1,3]thiazole-7-carboxylic acid ethyl ester (8.5 g, 40.2 mmol), cesium carbonate (26.1 g, 80.2 mmol) and iodoethane (8.3 mL, 80.2 mmol) were added while stirring at room temperature. The mixture was stirred at room temperature for one hour, was extracted with diethyl ether, washed with brine, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by medium pressure amino silica gel column chromatography (n-heptane/ethyl acetate: 10% then 40%) to obtain the title compound (7.01 g, 29.2 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.Cl[CH2:12][C:13](=[O:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:12][C:13](=[O:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)CN[C@@H](C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-1-(4-fluorophenyl)ethylamine (5.0 g), chloroacetone (4.78 mL), cesium carbonate (13.9 g), and DMF (50 mL) was stirred at room temperature overnight. The reaction solution was diluted with water and ethyl acetate, and then the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography using a silica gel (hexane:ethyl acetate=5:1 to 0:100) to obtain 5.1 g of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]#[N:12])=[CH:2]1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+].O>CO>[CH2:13]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]#[N:12])=[CH:2]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: N#CCc1c[nH]c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#CCc1cn(Cc2ccccc2)c2ccccc12
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A mixture of 3-indolylacetonitrile (5 g, 32 mmol), triton B (40% in MeOH, 0.5 g), benzyl bromide (7.8 mL, 2 eq.) and aqueous NaOH (50%, 12.6 mL) was stirred for 2 hours at 20° C. Water was added. Solid was collected by filtration and washed with water and hexane and dried under high vacuum to give [1-benzyl-1H-indol-3-yl]acetonitrile (6.97 g). MS (ES): 247 (MH+).
Reaction SMILES: C[Si](I)(C)C.[CH3:6][C@H:7]([O:11][C:12]1[CH:13]=[C:14]([CH:25]=[C:26]([O:28][C:29]2[CH:41]=[CH:40][C:32]3[C:33](=[O:39])[N:34]([CH3:38])[CH2:35][CH2:36][O:37][C:31]=3[CH:30]=2)[CH:27]=1)[C:15]([NH:17][C:18]1[CH:23]=[N:22][C:21]([CH3:24])=[CH:20][N:19]=1)=[O:16])[CH2:8][O:9]C.C(=O)([O-])O.[Na+]>C(#N)C>[OH:9][CH2:8][C@@H:7]([O:11][C:12]1[CH:13]=[C:14]([CH:25]=[C:26]([O:28][C:29]2[CH:41]=[CH:40][C:32]3[C:33](=[O:39])[N:34]([CH3:38])[CH2:35][CH2:36][O:37][C:31]=3[CH:30]=2)[CH:27]=1)[C:15]([NH:17][C:18]1[CH:23]=[N:22][C:21]([CH3:24])=[CH:20][N:19]=1)=[O:16])[CH3:6]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCCN(C)C3=O)cc(C(=O)Nc2cnc(C)cn2)c1
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc4c(c3)OCCN(C)C4=O)cc(O[C@@H](C)CO)c2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.6 %

Procedure:
Trimethylsilyl iodide (0.35 mL, 2.4 mmol) was added to a solution of 3-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-5-[(4-methyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin-8-yl)oxy]-N-(5-methylpyrazin-2-yl)benzamide (236 mg, 0.48 mmol) in acetonitrile (10 mL) under an atmosphere of argon and the mixture stirred at RT for 18 hours. The mixture was poured onto a saturated sodium hydrogen carbonate solution (25 mL), the acetonitrile removed in vacuo, and the aqueous layer extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with sodium thiosulphate solution, brine, dried (MgSO4) and evaporated in vacuo to a residue which was chromatographed on silica, eluting with 1% methanol in ethyl acetate, to give the desired compound (107 mg).