Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([CH:8]2[C:12](=[O:13])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)=[C:10]([NH2:24])[O:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25]N.CO>O>[C:2]1([CH:8]2[C:12](=[O:13])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=3)=[C:10]([NH:24][CH3:25])[O:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2ccccc2)O1
Reactant: CN
Agent: Cl
Solvent: O
Solvent: CO
Product: CNC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2ccccc2)O1
Reaction time: 48 h
Yield: 93 %

Procedure:
In this example, 2.5 ml of aqueous 2N hydrochloric acid was added at room temperature to a stirred slurry containing 10 g of 2-phenyl-3-oxo-4-(3-trifluoromethylphenyl)-5-amino-2,3-dihydrofuran in 60 ml of aqueous 40 wt % methyl amine followed by the addition of 50 ml of methanol. The resulting suspension was heated to reflux and refluxed for about 24 hours and then allowed to cool and stand at room temperature for about 2 days. The mixture was then added to a dilute acid solution containing 58 ml of aqueous 12N hydrochloric acid in 300 ml of water and then extracted twice with methylene chloride. The methylene chloride extracts were combined and successively washed once with water, once with saturated aqueous sodium bicarbonate and once with saturated aqueous sodium chloride. The washed solution was dried over magnesium sulfate and evaporated under vacuum affording 9.7 g of the title compound as a pale yellow foam (yield=93%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([C:24](=[O:26])[CH3:25])[CH:21]=[CH:22][CH:23]=3)=[CH:14][C:12]=2[CH:13]=1.[CH3:27][Mg]Br.CCOCC>O1CCCC1>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([C:24]([OH:26])([CH3:27])[CH3:25])[CH:21]=[CH:22][CH:23]=3)=[CH:14][C:12]=2[CH:13]=1
Reactant: CC(=O)c1cccc(-c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)c1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@@H]1CCCN1CCc1cc2cc(-c3cccc(C(C)(C)O)c3)ccc2o1
Reaction time: 8 h

Procedure:
The product from Example 136C (87 mg, 0.25 mmol) was dissolved into tetrahydrofuran (5 mL), treated with 3 M methylmagnesium bromide in ether (0.3 mL, 0.9 mmol), stirred overnight, quenched with 0.5 M aqueous dipotassium hydrogen phosphate, and diluted with EtOAc and a little CH2Cl2. The resulting emulsion was sonicated, and the aqueous phase was separated and extracted with EtOAc. The combined organic phases were washed consecutively with 0.5 M aqueous dipotassium hydrogen phosphate and brine, dried (Na2SO4), concentrated, and chromatographed on silica with a gradient of 2 to 10% MeOH/20% MeCN/CH2Cl2 followed by 10% MeOH/CH2Cl2 to provide the title compound as an orange resin (˜33% yield). 1HNMR (300 MHz, CD3OD) δ 1.20 (d, 3 H), 1.42-1.58 (m, 1 H), 1.58 (s, 6 H), 1.76-1.90 (m, 2 H), 1.96-2.12 (m, 1 H), 2.3-2.7 (m, 3 H), 2.97-3.13 (m, 2 H), 3.22-3.4 (m, 2 H), 6.62 (s, 1 H), 7.38 (dd, 1 H), 7.40-7.46 (m, 2 H), 7.46-7.48 (m, 2 H), 7.72 (dd, 1 H), 7.76 (dd, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31]([O:33]CC3C=CC=CC=3)=[O:32])[CH2:26][CH2:25]2)[CH:19]=1)[C:7]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[O:8])([O-])=O.C([O-])=O.[NH4+]>O1CCCC1.CN(C=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31]([OH:33])=[O:32])[CH2:26][CH2:25]2)[CH:19]=1)[C:7]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[O:8]
Reactant: COCCOC(=O)c1ccc(Nc2cccc(N3CCN(CC(=O)OCc4ccccc4)CC3)c2)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCOC(=O)c1ccc(Nc2cccc(N3CCN(CC(=O)O)CC3)c2)c(N)c1

Procedure:
To a solution of 2-methoxyethyl 3-nitro-4-(3-(4-(benzyloxy-carbonyl-methyl)-1-piperazinyl)-phenylamino)-benzoate (3d) (3.5 g; 6.4 mmol) in a mixture of tetrahydrofurane (50 ml) and DMF (5 ml) was added palladium catalyst (0.9 g; 5% Pd on activated carbon) and ammonium formiate (0.8 g; 12.6 mmol) and the mixture was heated to reflux for 2 hours. The cooled mixture was filtered through celite and the solvent was removed under reduced pressure to leave 2d, quantitatively.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH3:21][CH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][NH2:30])[CH2:24][CH2:23]1.[BH4-].[Na+]>CO>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:30][CH2:29][CH2:28][CH:25]2[CH2:26][CH2:27][CH:22]([CH3:21])[CH2:23][CH2:24]2)[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Reactant: CC1CCC(CCN)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCC2CCC(C)CC2)ccc1Oc1ccc(C(N)=O)cn1
Reaction time: 8 h

Procedure:
Place 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Ex 414, Part B) (0.100 g, 0.367 mmol), 2-(4-methylcyclohexyl)ethylamine (0.0571 g, 0.404 mmol) and 3 Å molecular-sieves in a vial. Add methanol (3.6 mL), cap and stir the mixture overnight. Add NaBH4 (ca. 3-5 eq in two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 5 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 10 g ISCO® column with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give 6-(2-methoxy-4-{[2-(4-methylcyclohexyl)ethylamino]methyl}phenoxy)nicotinamide. Dissolve the compound in dichloromethane (2.5 mL) and add 1 equivalent of 0.50 M methanesulfonic acid in dichloromethane. Stir the solution for a short time before concentrating to give the title compound: TOF MS ES+ 398.2 (M+H)+, HRMS calcd for C23H32N3O3 398.2444 (M+H)+, found 398.2440, time 0.52 min; Anal. Calcd for C23H31N3O3.0.5H2O: C, 57.35; H, 7.22; N, 8.36. Found: C, 57.33; H, 6.94; N, 8.34.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.Cl.CN>CN(C=O)C.O>[CH3:17][NH:18][C:10]([C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([CH2:15][CH3:16])[CH2:13][CH3:14])=[O:11]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCC(CC)(NC(=O)OC(C)(C)C)C(=O)O
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(CC)(NC(=O)OC(C)(C)C)C(=O)NC
Reaction time: 0.5 h
Yield: 45 %

Procedure:
A mixture of 2-(tert-butoxycarbonylamino)-2-ethylbutanoic acid (Example 23 a, 400 mg 2 mmol), HBTU (CAN 94790-37-1, 1.3 g, 3 mmol), Et3N (0.7 g, 7 mmol) in DMF (10 mL) was stirred for 30 min, then methanamine hydrochloride (CAN 593-51-1, 260 mg, 6 mmol) was added into the mixture and the solution was stirred overnight. After that, the solution was diluted with water (20 mL) and extracted with ethyl acetate (3×30 mL), the combined organic layer was washed with water (3×50 mL) and brine (60 mL), then evaporated to dryness. The crude product (0.18 g, 45%) obtained as a light yellow solid was used for the next step directly.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[C:3](=O)[CH2:4][CH3:5].P(Cl)(Cl)(Cl)=O.[NH2:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)[C:18]([N:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1)=[N:17]2.C>C(#N)C.O>[CH3:30][N:27]1[CH2:28][CH2:29][N:24]([C:19]2[C:18]([N:31]3[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]3)=[N:17][C:16]3[C:21](=[CH:22][CH:23]=[C:14]([N:13]=[C:3]([N:2]([CH3:7])[CH3:1])[CH2:4][CH3:5])[CH:15]=3)[N:20]=2)[CH2:25][CH2:26]1
Reactant: CN1CCN(c2nc3ccc(N)cc3nc2N2CCN(C)CC2)CC1
Reactant: CCC(=O)N(C)C
Solvent: CC#N
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCC(=Nc1ccc2nc(N3CCN(C)CC3)c(N3CCN(C)CC3)nc2c1)N(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 11.33 g. (0.112 mole) of N,N-dimethylpropionamide in 110 ml. of acetonitrile (dried over molecular sieves) is added 8.3 ml. of phosphorous oxychloride at 5°-10° C. The mixture is stirred at room temperature for 90 minutes. To the resulting yellow solution is added 13.7 g. (0.040 mole) of 6-amino-2,3-bis(4-methyl-1-piperazinyl)quinoxaline (prepared as in Example 1) in several portions with stirring. The mixture is placed in an oil bath at 65° C. and stirred for 16 hours. The reaction mixture is cooled and is poured into 400 ml. of ice plus water, stirred for 10 minutes and filtered. The filtrate is made alkaline to a pH greater than 13 with 5 N sodium hydroxide and extracted with five 100 ml. portions of chloroform. The combined extract is washed with two 100 ml. portions of water, dried over anhydrous potassium carbonate and anhydrous calcium sulfate and stripped of solvent by water pump evacuation to yield a residual oil which is crystallized on standing. The residue formed is recrystallized from 350 ml. of acetonitrile and is filtered and the solid collected is dried in vacuo at 78° C. over phosphorous pentoxide. The yellow solid obtained is dissolved in 160 ml. of hot acetonitrile, treated with activated charcoal, recrystallized by cooling at -10° C. and is filtered and dried as above to give 4.0 g. of yellow solid, m.p. 173°-175° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Cl:7][C:8]1[CH:13]=[C:12](Cl)[N:11]=[C:10]([CH3:15])[N:9]=1.CC([O-])(C)C.[K+].O>C1COCC1>[Cl:7][C:8]1[N:9]=[C:10]([CH3:15])[N:11]=[C:12]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH:13]=1
Reactant: Nc1nccs1
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc(Nc2nccs2)n1
Temperature: 0 °C
Yield: 51.5 %

Procedure:
To a cool (0° C.), stirring suspension of 2-aminothiazole (3.05 g, 0.0305 mol), 4,6-dichloro-2-methylpyrimidine (5.84 g, 0.0358 mol) in THF (50 mL) was added dropwise over 10 minutes via addition funnel a solution of t-BuOK (40 mL, 30% wt in THF, 0.1069 mol). The reaction was allowed to slowly warm to room temperature overnight. To the reaction was added water (40 mL) and the resulting clear solution was extracted with chloroform and then chloroform/methanol (4:1). The combined extracts were concentrated to near dryness to give a precipitate. The solid was collected by filtration to give the title material (3.559 g) as a solid. The filtrate was concentrated to dryness and the resulting solid was dissolved in boiling methanol and allowed to precipitate overnight aided with the addition of some water. The solid was collected by filtration, washed with water and air dried to give the title material (1.451 g) as a solid. The aqueous layer from the extraction was acidified with 10% HCl and a precipitate was formed. The solid was collected by filtration, washed with water to give the title material (1.559 g) as a solid. The solids were combined to give the title material (6.569 g, 95%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 2.53 (3H, s), 6.90 (1H, s), 7.21 (1H, d, J=3.5 Hz), 7.46 (1H, d, J=3.5 Hz), 11.87 (1H, s). LC/MS (M+H)+: 227, 229. HPLC ret. time (Condition E): 1.427 min.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([S:11][CH3:12])[CH:8]=[C:7]([NH2:13])[CH:6]=1.N1C=CC=CC=1.[Cl:21][CH2:22][CH2:23][CH2:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH3:2][O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([S:11][CH3:12])[CH:8]=[C:7]([NH:13][S:25]([CH2:24][CH2:23][CH2:22][Cl:21])(=[O:27])=[O:26])[CH:6]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COC(=O)c1cc(N)cc(SC)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1cc(NS(=O)(=O)CCCCl)cc(SC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.3 %

Procedure:
To a solution of 3-amino-5-methylsulfanyl-benzoic acid methyl ester hydrochloride (D62) (130 mg, 0.556 mmol, 1 equiv) in CH2Cl2 (2 ml) was added pyridine (142 ml, 1.75 mmol, 3 equiv), DMAP (6.8 mg, 0.056 mmol, 0.1 equiv) and then 3-chloropropane sulfonyl chloride (71 μl, 0.584 mmol, 1.05 equiv) dropwise over 2 min. The resulting mixture was stirred at room temperature for 2 h, diluted with AcOEt, washed sequentially with 2N aqueous HCl solution, saturated aqueous NaHCO3 solution and brine, dried over Na2SO4 and concentrated in vacuo to give 3-(3-chloropropane-1-sulfonylamino)-5-methylsulfanyl-benzoic acid methyl ester (D66) (196 mg, 104%) as light brown crystals. [M−H]−=336.0 RT=3.20 min
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][CH:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:13][C:7]=2[C:6]([N+:20]([O-])=O)=[CH:5][CH:4]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][CH:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[CH2:13][C:7]=2[C:6]([NH2:20])=[CH:5][CH:4]=1
Reactant: COc1ccc([N+](=O)[O-])c2c1CCCC(N1CCOCC1)C2
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)c2c1CCCC(N1CCOCC1)C2
Yield: 100.3 %

Procedure:
4-(1-Methoxy-4-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-morpholine (1.51 g, 4.94 mmol) was dissolved in ethanol (100 mL) and hydrogenated over 10% palladium on carbon (151 mg) at 50 psi using a Parr shaker for 4 hours. The palladium was removed by filtration and the ethanol was concentrated to afford a brown foam which was purified via ISCO chromatography (gradient elution: 2 to 10% methanol:dichloromethane) to afford 4-methoxy-8-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-ylamine (1.37 g, 99%) as a light brown solid.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C@H:7]1[CH2:30][O:29][C:10]2=[CH:11][CH:12]=[C:13]3[C:17]([N:16]([CH2:18][C@H:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH3:20])[N:15]=[CH:14]3)=[C:9]2[CH2:8]1)=[N+]=[N-].C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39].C(=O)(O)[O-].[Na+]>CO.[Pd]>[C:25]([Si:22]([CH3:24])([CH3:23])[O:21][C@H:19]([CH3:20])[CH2:18][N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]3[O:29][CH2:30][C@H:7]([O:6][CH2:5][CH2:4][NH:1][C:38](=[O:40])[CH3:39])[CH2:8][C:9]3=2)[CH:14]=[N:15]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: C[C@H](Cn1ncc2ccc3c(c21)C[C@@H](OCCN=[N+]=[N-])CO3)O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)NCCO[C@H]1COc2ccc3cnn(C[C@@H](C)O[Si](C)(C)C(C)(C)C)c3c2C1
Reaction time: 8 h
Yield: 54.2 %

Procedure:
A mixture of the product from step B (0.73 g, 1.69 mmol) and palladium-on-carbon (10%, 0.07 g) in methanol (50 mL) was placed under an atmosphere of hydrogen and stirred overnight. The mixture was filtered, evaporated to an oil (0.61 g, 88%) which was dissolved in dichloromethane (30 mL). To this solution was added triethylamine (0.304 g, 3.01 mmol) and acetyl chloride (0.142 g, 0.129 mL, 1.81 mmol), and the mixture was stirred for 1 h, mixed with a saturated solution of sodium bicarbonate (100 mL) and extracted with ethyl acetate. The dried extracts were evaporated to a residue which was purified by chromatography (silica, gradient, 30% to 90% ethyl acetate in hexane) to give an oil (0.41 g, 61%): LCMS (+ESI) m/z 448 (M+H).
Reaction SMILES: [Br:1][CH:2](Br)[C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:7]([C:16]#[N:17])[C:6]=1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=[O:4].C1COCC1.P([O-])(OCC)OCC>>[Br:1][CH2:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:7]([C:16]#[N:17])[C:6]=1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=[O:4]
Reactant: N#Cc1c(N2CCOCC2)sc(C(=O)C(Br)Br)c1-c1ccc(Cl)cc1Cl
Agent: CCOP([O-])OCC
Solvent: C1CCOC1
Product: N#Cc1c(N2CCOCC2)sc(C(=O)CBr)c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 30 %

Procedure:
To a mixture of 5-(dibromoacetyl)-4-(2,4-dichlorophenyl)-2-morpholin-4-ylthiophene-3-carbonitrile (46.9 mg, 0.0000870 mol) in THF (0.78 mL, 0.0096 mol) was added diethyl phosphite (13.7 uL, 0.000107 mol) and TEA (14.9 uL, 0.000107 mol) at 0° C. After addition, the mixture was warmed to rt after 20 min. The reaction mixture was evaporated and the residue was suspended in ice/water. The solid was filtered and purified by column chromatography to afford 5-(2-bromoacetyl)-4-(2,4-dichlorophenyl)-2-morpholinothiophene-3-carbonitrile (12 mg, 30%). LCMS: (FA) ES+ 460.88; 1H NMR (400 MHz, d1-chloroform) δ: 7.59 (d, 1H), 7.42 (dd, 1H), 7.33 (d, 1H), 3.90-3.85 (m, 4H), 3.75-3.69 (m, 5H), 3.62 (d, 1H).
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[O:5][C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:7][N:8]=1.C([Li])CCC.[CH2:19]([Sn:23](Cl)([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22]>C1COCC1.CCCCCC>[CH2:28]([Sn:23]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:24][CH2:25][CH2:26][CH3:27])[C:2]#[C:3][C:4]1[O:5][C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:7][N:8]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)(C)c1cnc(C=C(Br)Br)o1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](C#Cc1ncc(C(C)(C)C)o1)(CCCC)CCCC
Reaction time: 0.5 h
Yield: 109.3 %

Procedure:
To a stirred solution of 1,1-dibromo-2-(5-t-butyl-oxazol-2-yl)ethylene (6.0 g, 19 mmole) in anhydrous THF (80 mL) at −78 deg C. under argon atmosphere. was added with 1.6 M n-butyllithium (32 mL, 51 mmole) in hexane dropwise over 20 min., the reaction mixture, stirred at −78 deg C. for 30 min and treated with tributyltin chloride (5.5 mL, 20 mmole). The reaction mixture was stirred for 30 min, warmed to 0 deg C., stirred at 0 deg C. for 30 min, and then at room temperature for 45 min. The mixture was passed through a short column of silica gel (deactivated with 2% triethylamine in hexane), and eluted with 10% EtOAc in dichloromethane to obtain crude product of 1-tributylstannyl-2-(5-t-butyl-oxazol-2-yl)acetylene as a brown oil (9.10 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][I:10]>C(O)C>[I-:10].[CH3:9][N+:3]1[CH:4]=[CH:5][CH:6]=[C:7]([NH2:8])[C:2]=1[Cl:1]
Reactant: CI
Reactant: Nc1cccnc1Cl
Solvent: CCO
Product: C[n+]1cccc(N)c1Cl
Product: [I-]
Reaction time: 8 h
Yield: 57.6 %

Procedure:
A mixture of 2-chloro-3-aminopyridine (12.8 g) and methyl iodide (56.8 g) was allowed to stand overnight in dark place at room temperature. To the mixture was added ethanol (20 ml) and the precipitates were collected by filtration, washed with diisopropyl ether and dried to give 1-methyl-2-chloro-3-aminopyridinium iodide (15.5 g), mp. 165° to 167° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]2[C:17]([O:23][CH3:24])=[N:18][CH:19]=[CH:20][C:21]=2[I:22])=[C:10]([N+:25]([O-])=O)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O>P(OCC)(OCC)OCC>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:9]=[C:10]2[C:11]([CH:14]=[C:15]([C:16]3[C:17]([O:23][CH3:24])=[N:18][CH:19]=[CH:20][C:21]=3[I:22])[NH:25]2)=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1nccc(I)c1/C=C/c1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Agent: CCOP(OCC)OCC
Solvent: O
Product: COc1nccc(I)c1-c1cc2ccc(NC(=O)OC(C)(C)C)cc2[nH]1
Temperature: 25 °C
Yield: 33.4 %

Procedure:
A solution of {4-[(E)-2-(4-iodo-2-methoxy-pyridin-3-yl)-vinyl]-3-nitro-phenyl}-carbamic acid tert-butyl ester (800 mg, 1.61 mmol) in triethyl phosphite (16.0 ml) was refluxed for 3 h. The reaction mixture was cooled to 25° C. and poured into water and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (70/30 hexanes/ethyl acetate) afforded [2-(4-iodo-2-methoxy-pyridin-3-yl)-1H-indol-6-yl]-carbamic acid tert-butyl ester (250 mg, 33%) as a white solid. MH+ 465.9.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH3:30][NH:31][O:32][CH3:33].Cl>C(Cl)Cl>[CH3:33][O:32][N:31]([CH3:30])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([Si:2]([CH3:13])([CH3:12])[CH3:1])[CH:4]=1
Reactant: C[Si](C)(C)c1cccc(C(=O)O)c1
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1cccc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A solution of 3-trimethylsilylbenzoic acid in methylene chloride (12 ml) was cooled to -22° C. and N-methylmorpholine (2.0 ml) was added. To the mixture isobutylchloroformate (0.88 ml) was added. The mixture was stirred for 25 min. followed by the addition of N,O-dimethylhydroxylamine hydrochloride (0.9 g). The mixture was stirred at -22° C. for 1 hr., allowed to warm to room temperature and stirred for 1.5 hr. The reaction mixture was poured into dil HCl and the aqueous phase was extracted with diethyl ether (2×100 ml). The combined organic extracts were washed with dil NaHCO3 and dried over Na2 SO4. The solvent was removed in vacuo and the crude product purified by flash chromatography (10% EtOAc in hexane) to yield 600 mg of the desired product. HRMS calc. 238.1263. Found: 238.1268.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([S:34]([CH3:37])(=[O:36])=[O:35])[CH2:30][CH2:29]2)=[O:27])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[O:38]1[CH2:43][CH2:42][C:41](=O)[CH2:40][CH2:39]1>>[CH3:37][S:34]([N:31]1[CH2:30][CH2:29][N:28]([C:26]([C:21]2[NH:22][C:23]3[C:19]([CH:20]=2)=[CH:18][C:17]([C:15]([N:11]2[CH2:12][CH2:13][CH2:14][N:8]([CH:41]4[CH2:42][CH2:43][O:38][CH2:39][CH2:40]4)[CH2:9][CH2:10]2)=[O:16])=[CH:25][CH:24]=3)=[O:27])[CH2:33][CH2:32]1)(=[O:36])=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1
Reactant: O=C1CCOCC1
Product: CS(=O)(=O)N1CCN(C(=O)c2cc3cc(C(=O)N4CCCN(C5CCOCC5)CC4)ccc3[nH]2)CC1

Procedure:
The title compound was synthesized in analogy to example 47, from 4-[2-(4-methanesulfonyl-piperazine-1-carbonyl)-1H-indole-5-carbonyl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester and tetrahydro-4H-pyran-4-one. Yellow gum. MS (m/z): 518.3 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])=[N+]=[N-]>CCO.[OH-].[OH-].[Pd+2]>[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][P:15](=[O:22])([O:16][CH2:17][CH3:18])[O:19][CH2:20][CH3:21]
Reactant: CCOP(=O)(CCOCCOCCOCCN=[N+]=[N-])OCC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOP(=O)(CCOCCOCCOCCN)OCC
Reaction time: 4 h

Procedure:
To a solution of diethyl 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethylphosphonate (1 eq) in EtOH (0.1 M) was added Pd(OH)2 (0.05 eq). The reaction mixture was stirred under hydrogen (1 atm) for 4 hours. The mixture was filtered through Celite and washed with MeOH. The solvent was removed en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% MeOH/DCM with 0.5% NH3 to give the product as a colorless oil.