Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:14]=[CH:13][N:12](C(=O)C(C)(C)C)[CH:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[Mn]([O-])(=O)(=O)=[O:22].[K+].[OH2:27]>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:22])=[O:27]
Reactant: O
Reactant: Cc1ccc(C2C=CN(C(=O)C(C)(C)C)C=C2)cc1F
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: O=C(O)c1ccc(-c2ccncc2)cc1F
Temperature: 100 °C

Procedure:
The product of part (a) (75.0 g) in 2 L water was heated on a steam bath, and 200 g potassium permanganate was added portion-wise. The reaction mixture was heated at 100° C. for three days and then filtered to remove manganese oxide. The filtrate was concentrated in vacuo and the residue dried to give 36.1 g of 2-fluoro-4-(4pyridinyl)benzoic acid.
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C=C.[C:28]([O:32][CH3:33])(=[O:31])[CH:29]=[CH2:30]>[Br-].C([N+](CC)(CC)CC)C>[C:28]([O:32][CH3:33])(=[O:31])/[CH:29]=[CH:30]/[CH:1]=[CH:2]/[CH3:3]
Reactant: C=CC(=O)OC
Reactant: C=CCCl
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C=CCO
Product: C/C=C/C=C/C(=O)OC
Temperature: 120 °C

Procedure:
Quantities of 1.9 grams alyl allyl chloride dimer, 2.75 grams tetraethyl ammonium bromide, 5.25 grams of triphenyl phosphine, 45 cc allyl alcohol, and 60 cc methyl acrylate are introduced into a reaction chamber and heated to 120°C for 20 hours. Methyl sorbate is produced to the extent of 10% by weight of the final reaction solution.
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[S:10][C:9]=1[C:16]([O:18]C)=O)[CH3:5].O>C1COCC1>[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[S:10][C:9]=1[C:16]([NH2:2])=[O:18])[CH3:5]
Reactant: [NH4+]
Reactant: COC(=O)c1sc([N+](=O)[O-])cc1N=NN(C)C
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)N=Nc1cc([N+](=O)[O-])sc1C(N)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 26 %

Procedure:
To an ice cold (0-5° C.) solution of ammonium hydroxide (35 mL) was added a solution of methyl 3-[(dimethylamino)diazenyl]-5-nitrothiophene-2-carboxylate (400 mg) in THF (10 mL) for 5 min and stirred at rt for 20 h. The solution was poured into ice cooled water and extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-ethyl acetate (50:50) as eluents to give the product as a yellow color solid (90 mg, 26%), mp 240-246° C. 1H NMR (400 MHz, DMSO-d6): δ 8.22 (1H, s), 8.05 (1H, s), 7.91 (1H, s), 3.63 (3H, s), 3.26 (3H, s); LC-MS (positive ion mode): m/z 266 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH2:12][C:13]1[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[NH:15][CH:14]=1)[C:5]([O:7]C(C)(C)C)=[O:6].[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30].C(Cl)Cl>>[CH3:1][O:2][C:3](=[O:28])[C:4]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH2:12][C:13]1[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[NH:15][CH:14]=1)[C:5]([OH:7])=[O:6].[F:32][C:31]([F:34])([F:33])[C:29]([O-:35])=[O:30]
Reactant: COC(=O)C(Cc1c[nH]c2cccnc12)(C(=O)OC(C)(C)C)c1ccccc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(Cc1c[nH]c2cccnc12)(C(=O)O)c1ccccc1
Product: O=C([O-])C(F)(F)F

Procedure:
A RT solution of 2-[phenyl-(1H-pyrrolo[3,2-b]pyridin-3-yl-methyl)-malonic acid tert-butyl ester methyl ester (320 mg) in a mixture TFA/DCM (2/1, 9 mL) was stirred for 1.5 h, and concentrated to give 2-[Phenyl-(1H-pyrrolo[3,2-b]pyridin-3-yl-methyl)-malonic acid mono-methyl ester as a trifluoroacetate salt.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23]([O:25]CC)=O)[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][NH:33][CH3:34]>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([N:33]([CH2:32][CH2:31][N:30]([CH3:35])[CH3:29])[CH3:34])=[O:25])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: CNCCN(C)C
Solvent: CCO
Product: CN(C)CCN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 85 °C
Yield: 154.1 %

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (560 mg, 1.42 mmol) in ethanol (2 ml) was treated with N,N,N′-trimethylethylenediamine (900 □1,0.91 mmol) and the resulting mixture was heated at 85° C. in a sealed tube for 4.5 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with a system of 95:5:0.5 (dichloromethane:methanol:ammonia) to afford the title compound as a colourless oil (632 mg).
Reaction SMILES: [CH:1]([Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[F:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([C@@H:22]3[CH2:26][CH2:25][CH2:24][N:23]3[CH2:27][CH2:28][CH2:29][OH:30])=[N:20][N:21]=2)[CH:18]=1.CCN(CC)CC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([C@@H:22]3[CH2:26][CH2:25][CH2:24][N:23]3[CH2:27][CH2:28][CH2:29][O:30][Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])=[N:20][N:21]=2)[CH:18]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: OCCCN1CCC[C@H]1c1nnc2ccc(F)cn12
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[Si](OCCCN1CCC[C@H]1c1nnc2ccc(F)cn12)(C(C)C)C(C)C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
Triisopropylsilyl chloride (266μ□L, 1.24 mmol) was added to a solution of Intermediate 84e (218 mg, 0.82 mmol) and Et3N (26μ□L, 1.24 mmol) in DCM (8.00 mL). The reaction was stirred overnight then 4-(dimethylamino)pyridine (10.0 mg, 0.082 mmol) added. The reaction was stirred for 3 h then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-7.5% [2M NH3 in MeOH] in DCM, to give the title compound (317 mg, 92%). 1H NMR (300 MHz, CDCl3): 0.92 (21H, s), 1.56-1.68 (2H, m), 1.89-2.10 (3H, m), 2.21-2.40 (3H, m), 2.56 (1H, dt, J 12.1, 7.9), 3.40 (1H, m), 3.46-3.64 (2H, m), 4.22 (1H, t, J 8.4), 7.16 (1H, ddd, J 9.9, 7.5, 2.3), 7.71 (1H, ddd, J 10.0, 4.9, 0.6), 8.64 (1H, m).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[NH:9][C:5]=2[C:4]=1[N:13]1[CH2:17][CH:16]([CH2:18][NH2:19])[O:15][C:14]1=[O:20])[CH3:2].[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[CH2:1]([C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[NH:9][C:5]=2[C:4]=1[N:13]1[CH2:17][CH:16]([CH2:18][NH:19][C:21](=[O:23])[CH3:22])[O:15][C:14]1=[O:20])[CH3:2]
Reactant: CCc1ccc2nc(C)[nH]c2c1N1CC(CN)OC1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCc1ccc2nc(C)[nH]c2c1N1CC(CNC(C)=O)OC1=O
Reaction time: 2 h

Procedure:
A mixture of (±)-3-(5'-1-Ethyl-2-methylbenzimidazolyl)-5-(aminomethyl)oxazolidin-2-one (XL, EXAMPLE 71, 0.100 g) in pyridine (2 ml) and acetic anhydride (1 ml) is stirred under nitrogen for 2 hrs. The mixture is then concentrated under reduced pressure to give the title compuond, no further purification is necessary by analysis, mp 217°-218°. NMR (CDCl3 /DMF-d7, 300 MHz) 7.74, 7.52, 4.80, 4.27, 3.93, 3.58, 2.61 and 1.38 δ; CMR (DMF-d7, 75.47 MHz) 13.06, 14.67, 22.2, 38.65, 42.2, 72.01, 101.7, 109.34, 109.96, 114.57, 132.5, 134.2, 143.3, 153.5, 155.7 and 171.7 δ.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[C:24]([CH:29]=O)[CH:23]=[CH:22]4)=[N:16][CH:17]=2)=[CH:10][CH:9]=[N:8]1.[CH2:33]1[C@@H:37]2[CH2:38][NH:39][CH2:40][CH2:41][N:36]2[C:35](=[O:42])[O:34]1.N1NC(C2C=CC(OC3C=C4C(=CC=3)N=C(CN3CCC(N5CCOC5=O)CC3)C=C4)=NC=2)=CC=1>>[N:8]1[NH:7][C:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[C:24]([CH2:29][N:39]3[CH2:40][CH2:41][N:36]5[C:35](=[O:42])[O:34][CH2:33][C@@H:37]5[CH2:38]3)[CH:23]=[CH:22]4)=[N:16][CH:17]=2)=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)CCOCn1nccc1-c1ccc(Oc2ccc3nc(C=O)ccc3c2)nc1
Reactant: O=C1OC[C@@H]2CNCCN12
Agent: O=C1OCCN1C1CCN(Cc2ccc3cc(Oc4ccc(-c5ccn[nH]5)cn4)ccc3n2)CC1
Product: O=C1OC[C@@H]2CN(Cc3ccc4cc(Oc5ccc(-c6ccn[nH]6)cn5)ccc4n3)CCN12

Procedure:
The title compound 16 is synthesized from intermediate D (0.100 g, 0.220 mmol) and (S)-hexahydro-oxazolo[3,4-a]pyrazin-3-one (48.0 mg, 0.269 mmol) according to the procedure described for the synthesis of compound 11.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:9](Cl)(=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].CO>N1C=CC=CC=1>[OH:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N:6][CH:7]=1
Reactant: CCCCCC(=O)Cl
Reactant: Nc1ncc(O)cn1
Solvent: CO
Solvent: c1ccncc1
Product: CCCCCC(=O)Nc1ncc(O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
5-Hydroxypyrimidin-2-amine (40 g, 360 mmol) was dissolved in pyridine (200 mL), the solution was added with hexanoyl chloride (121 g, 899 mmol), and the mixture was stirred at room temperature for 0.5 hour. The reaction mixture was added with methanol (100 mL), the mixture was concentrated under reduced pressure, and the resulting residue was diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the resulting residue was dissolved in methanol (200 mL). The solution was added with saturated ammonia solution in methanol (250 mL) under ice cooling and stirring, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:acetone=2:1) to obtain N-(5-hydroxypyrimidin-2-yl)hexanamide (39.5 g, 52%) as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([NH:9][NH2:10])=[O:8].[N:13]([CH2:16][CH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O)=[N+:14]=[N-:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[N:13]([CH2:16][CH2:17][CH2:18][C:19](=[N:10][NH:9][C:7](=[O:8])[C:6]1[CH:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[CH3:12])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[N+:14]=[N-:15]
Reactant: Cc1ccc(Cl)cc1C(=O)NN
Reactant: [N-]=[N+]=NCCCC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(Cl)cc1C(=O)NN=C(CCCN=[N+]=[N-])c1ccccc1
Reaction time: 16 h
Yield: 59.4 %

Procedure:
To a solution of 5-chloro-2-methylbenzohydrazide (2.70 g, 14.62 mmol) prepared as in Example 1, Step B, in toluene (100 mL) was added 4-azido-1-phenylbutan-1-one (3.04 g, 16.1 mmol) prepared as in Example 70, Step A, followed by p-toluenesulfonic acid monohydrate (0.28 g, 1.46 mmol). The reaction was heated to reflux and stirred under a Dean-Stark trap for 16 hours. The cooled mixture was diluted with EtOAc (300 mL) and washed with NaHCO3 (100 mL). The aqueous layer was extracted with EtOAc (100 mL) and the combined organics were washed with brine (100 mL), dried over Na2SO4 and concentrated. The residue was triturated with ether and filtered to afford the product (3.09 g, 59%) as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH3:12])[N:7]([CH2:13][C:14]([OH:16])=O)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:17]#[N:18].[F:19][C:20]([F:32])([F:31])[C:21]1[N:26]=[CH:25][C:24]([C:27]([NH:29][NH2:30])=O)=[CH:23][CH:22]=1>>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH3:12])[N:7]([CH2:13][C:14]3[O:16][C:27]([C:24]4[CH:25]=[N:26][C:21]([C:20]([F:32])([F:19])[F:31])=[CH:22][CH:23]=4)=[N:29][N:30]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:17]#[N:18]
Reactant: CCc1nc2c(Cl)c(C#N)ccc2n1CC(=O)O
Reactant: NNC(=O)c1ccc(C(F)(F)F)nc1
Product: CCc1nc2c(Cl)c(C#N)ccc2n1Cc1nnc(-c2ccc(C(F)(F)F)nc2)o1

Procedure:
Synthesized as described in Example 200C from (4-chloro-5-cyano-2-ethyl-1H-benzimidazol-1-yl)acetic acid and 6-(trifluoromethyl)-3-pyridinecarbohydrazide: MS (APCl) m/z 433 (M+1).
Reaction SMILES: C(N[C@H](C(O)=O)CC(C)C)(=O)C.[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([C@H:24]([NH2:30])[CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH3:14].[C:31]([NH:34][C:35]1[CH:45]=[CH:44][CH:43]=[C:37]2[C:38]([O:40][C:41](=O)[C:36]=12)=[O:39])(=[O:33])[CH3:32].C(O)(=O)C.C=CCl>CCO>[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([CH:24]([N:30]2[C:41](=[O:40])[C:36]3[C:37](=[CH:43][CH:44]=[CH:45][C:35]=3[NH:34][C:31](=[O:33])[CH3:32])[C:38]2=[O:39])[CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH3:14]
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Reactant: CCOc1cc([C@H](N)CS(C)(=O)=O)ccc1OC
Agent: C=CCl
Agent: CC(=O)N[C@@H](CC(C)C)C(=O)O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Yield: 75 %

Procedure:
A 500 mL 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser. The reaction vessel was charged with (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-yl amine N-acetyl-L-leucine salt (25 g, 56 mmol, 98% ee), 3-acetamidophthalic anhydride (12.1 g 58.8 mmol), and glacial acetic acid (250 mL). The mixture was refluxed over night and then cooled to <50° C. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate. The resulting solution was washed with water (250 mL×2), saturated aqeous NaHCO3 (250 mL×2), brine (250 mL×2), and dried over sodium sulphate. The solvent was evaporated in vacuo, and the residue recrystallized from a binary solvent containing ethanol (150 mL) and acetone (75 mL). The solid was isolated by vacuum filtration and washed with ethanol (100 mL×2). The product was dried in vacuo at 60° C. to a constant weight, affording 19.4 g (75% yield) of (S)-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-inoisoindoline-1,3-dione with 98% ee. Chiral HPLC (15/85 EtOH/20 mM KH2PO4 @pH 0.5, Ultron Chiral ES-OVS from Agilent Technology, 150 mm×4.6 mm, 0.4 mL/min., @240 nm): 25.4 min (S-isomer, 98.7%), 29.5 min (R-isomer, 1.2%). 1H-NMR (CDCl3) δ: 1.47 (t, 3H), 2.26 (s, 3H), 2.87 (s, 3H), 3.68–3.75 (dd, 1H), 3.85 (s, 3H), 4.07–4.15 (q, 2H), 4.51–4.61 (dd, 1H), 5.84–5.90 (dd, 1H), 6.82–8.77 (m, 6H), 9.46 (s, 1H). 13C-NMR (DMSO-d6) δ: 14.66, 24.92, 41.61, 48.53, 54.46, 55.91, 64.51, 111.44, 112.40, 115.10, 118.20, 120.28, 124.94, 129.22, 131.02, 136.09, 137.60, 148.62, 149.74, 167.46, 169.14, 169.48.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH2:9])[CH:5]=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[F:19][C:20]([F:26])([F:25])[S:21](Cl)(=[O:23])=[O:22]>ClCCl.C(=O)(O)[O-].[Na+].[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][S:21]([C:20]([F:26])([F:25])[F:19])(=[O:23])=[O:22])[CH:5]=[N:6][CH:7]=1
Reactant: NCc1cncc(Br)c1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(NCc1cncc(Br)c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-bromo-3-pyridinemethanamine (CAS#135124-70-8, 170 mg, 0.65 mmol) in dichloromethane (5 mL) at 0° C. was added diisopropylethylamine (0.55 mL, 3.25 mmol) and trifluoromethanesulfonyl chloride (0.083 mL, 0.78 mmol). The reaction was stirred at 0° C. for 15 minutes and then warmed to room temperature and stirred for an additional 30 minutes. The reaction was then diluted with saturated aqueous sodium bicarbonate and brine, and then further diluted with dichloromethane. The layers were separated and the aqueous layer was extracted two additional times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to provide N-(5-bromo-pyridin-3-ylmethyl)-C,C,C-trifluoro-methanesulfonamide with out the need for further purification. MS: (ES+) m/z 318.9 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O:24][C:25](=[O:28])[CH2:26]Br)([CH3:23])([CH3:22])[CH3:21]>CN(C)C=O>[CH2:1]([O:8][C:9]([C:11]1[N:12]([CH2:26][C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:28])[C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(OCc1ccccc1)c1cc2ccccc2[nH]1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1c(C(=O)OCc2ccccc2)cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 18.80 g 1H-indole-2-carboxylic acid benzyl ester in 70 ml N,N-dimethylformamide 1.98 g sodium hydride were added at 0C. After stirring for 1 hour 15.91 ml bromo-acetic acid tert.-butyl ester were added to the mixture and the reaction mixture was stirred for 2 hours at room temperature. After removal of the solvent under reduced pressure the residue was partitioned between 300 ml water and 300 ml dichloromethane. The aqueous layer was washed twice with additional 200 ml dichloromethane. Subsequently the combined organic phases were washed with a saturated aqueous solution of sodium chloride. After filtration the solvent was removed under reduced pressure and the residue was crystallized from ethoxy-ethane/heptane. The product was obtained as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:25][CH:24]3[O:26][CH:21]([CH2:22][CH2:23]3)[CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:19]4[CH2:25][CH:24]5[O:26][CH:21]([CH2:22][CH2:23]5)[CH2:20]4)=[N:3][C:2]([C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])cc2)OC1(C)C
Reactant: CN1CCN(Cc2cc3nc(Cl)nc(N4CC5CCC(C4)O5)c3s2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CN1CCN(Cc2cc3nc(-c4ccc([N+](=O)[O-])cc4)nc(N4CC5CCC(C4)O5)c3s2)CC1

Procedure:
In a 100 mL microwave vial was placed 3-(2-chloro-6-((4-methylpiperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (168 mg, 0.426 mmol) and 4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborolane (127 mg, 0.512 mmol) in DME (5 ml) to give a yellow solution. Na2CO3 (2M solution in water) (0.853 ml, 1.706 mmol) was added. The mixture was degassed by bubbling N2 through the solution. Pd(PPh3)4 (49.3 mg, 0.043 mmol) was added. The mixture was heated under reflux (oil bath at 95 C). LC MS (RT 2.8, M+H=481) showed complete conversion after 7.5 h. The reaction mixture was diluted with ethyl acetate and washed with a sat. solution of NaHCO3. A precipitate remained that was insoluble in either organic or aqueous phase. LCMS showed that both the precipitate and the organic phase contained product.
Reaction SMILES: C([O:8]C(=O)CC(N1C=CC(C2C=CC=CC=2)=C1)C(NC1CC2=CN(C3C2=CC=CC=3)CCOCCNC1=O)=O)C1C=CC=CC=1.FC(F)(F)C(O)=O.[CH2:53]([O:56][C:57](=[O:73])[CH2:58][C@@H:59]([NH2:72])[C:60]([NH:62][C@H:63]([C:68](=[O:71])[NH:69][CH3:70])[C:64]([CH3:67])([CH3:66])[CH3:65])=[O:61])[CH:54]=[CH2:55].[C:74]([C:76]1[CH:81]=[CH:80][C:79]([C:82]#[C:83][CH:84]2[CH2:88][CH:87](OC)O[CH:85]2OC)=[CH:78][CH:77]=1)#[N:75].FC(F)(F)C(O)=O>CCCCCCC.CC(O)=O>[CH2:53]([O:56][C:57](=[O:73])[CH2:58][C@@H:59]([N:72]1[CH:87]=[CH:88][C:84]([C:83](=[O:8])[CH2:82][C:79]2[CH:80]=[CH:81][C:76]([C:74]#[N:75])=[CH:77][CH:78]=2)=[CH:85]1)[C:60]([NH:62][C@H:63]([C:68](=[O:71])[NH:69][CH3:70])[C:64]([CH3:65])([CH3:66])[CH3:67])=[O:61])[CH:54]=[CH2:55]
Reactant: O=C(CC(C(=O)NC1Cc2cn(c3ccccc23)CCOCCNC1=O)n1ccc(-c2ccccc2)c1)OCc1ccccc1
Reactant: COC1CC(C#Cc2ccc(C#N)cc2)C(OC)O1
Reactant: C=CCOC(=O)C[C@@H](N)C(=O)N[C@H](C(=O)NC)C(C)(C)C
Solvent: CCCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: C=CCOC(=O)C[C@H](C(=O)N[C@H](C(=O)NC)C(C)(C)C)n1ccc(C(=O)Cc2ccc(C#N)cc2)c1

Procedure:
As described in Example 1(c) for the preparation of N-(8-oxo-4-oxa-1,7-diaza-tricyclo[9.6.1.012,17 ]octadeca-11(18),12,14,16-tetraen-9-yl)-3-(3-phenyl-1H-pyrrol-1-yl)succinamic acid benzyl ester, 3(R)-amino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid allyl ester trifluoroacetate salt and 3-[2-(4-cyanophenyl)-ethynyl]-2,5-dimethoxy-tetrahydrofuran were heated with trifluoroacetic acid (1 equiv) at 70° C. for 4 hours. Flash column chromatography twice with 0.5% HOAc/15% EtOAc/CH2Cl2 as eluant and azeotrope with n-heptane afforded 800 mg (36%, 43% based on recovered furan) of 3(R)-[3-[(4-cyanophenyl)acetyl]-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]succinamic acid allyl ester as a brown oil. 1H NMR (CDCl3): δ 7.58 (d, 2H, J=8.1 Hz), 7.47 (dd, 1H, J=1.9, 1.9 Hz), 7.36 (d, 2H, J=8.1 Hz), 6.84 (d, 1H, J=9.0 Hz), 6.74 (dd, 1H, J=2.8, 2.8 Hz), 6.63 (dd, 1H, J=1.6, 2.8 Hz), 6.08 (dd, J=2.8, 6.8 Hz), 5.82 (ddt, 1H, J=5.9, 10.3, 17.1 Hz), 5.26 (ddd, 1H, J=1.2, 2.8, 17.1 Hz), 5.19 (q, 1H, J=7.2 Hz), 4.56 (dddd, 2H, J=1.6, 2.8, 4.4, 15.9 Hz), 4.18 (d, 1H, J=9.0 Hz), 4.05 (s, 2H), 3.34 (dd, 1H, J=7.2, 16.8 Hz), 2.99 (dd, 1H, J=7.2, 16.8 Hz), 2.72 (d, 3H, J=5.0 Hz), 0.90 (s, 9H). 13C NMR (CDCl3): δ 191.2, 170.2, 169.4, 168.0, 140.6, 132.2, 131.3, 130.3, 125.7, 125.7, 122.0, 119.0, 118.9, 110.5, 110.4, 66.0, 61.0, 59.4, 46.1, 37.5, 34.8, 31.9, 29.0, 26.5, 26.0. IR (KBr): 3320, 2965, 229, 1736, 1648, 1531, 1173 cm-1. HRFABMS: Calculated for C27H33N4O5 (M+H+): 493.2451. Found 493.2462. Anal. Calculated for C27H32N4O5.0.2 H2O.0.2 CH2Cl2 : C, 63.66; H, 6.44; N, 10.92. Found: C, 63.86; H, 6.56; N, 10.58.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][C:17]([O:23][CH2:24][C:25]4[CH:26]=[C:27]([CH:34]=[CH:35][CH:36]=4)[C:28]([O:30]CC=C)=[O:29])=[CH:18][CH:19]=3)[O:14][CH:13]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].N1CCOCC1>O1CCCC1>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][C:17]([O:23][CH2:24][C:25]4[CH:26]=[C:27]([CH:34]=[CH:35][CH:36]=4)[C:28]([OH:30])=[O:29])=[CH:18][CH:19]=3)[O:14][CH:13]=2)=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: C=CCOC(=O)c1cccc(COc2ccc3c(=O)c(-c4ccc(NS(C)(=O)=O)cc4)coc3c2)c1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CS(=O)(=O)Nc1ccc(-c2coc3cc(OCc4cccc(C(=O)O)c4)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of prop-2-enyl 3-[(3-{4-[(methylsulfonyl)amino]phenyl}-4-oxochromen-7-yloxy)methyl]benzoate (88.8 mg, 0.176 mmol), tetrakis(triphenyl-phosphine)palladium(0) (10 mg, 0.009 mmol) in dry tetrahydrofuran 2 ml) was added morpholine (77 mg, 0.88 mmol), and the mixture was stirred at room temperature under argon for 2 hours. Solvent was then removed reduced pressure, and the residue dissolved in acetone, mixed with silica gel, the solvent removed under reduced pressure, and the silica gel eluted with methylene chloride/methanol (95/5) containing 1% acetic acid, to provide 3-[(3-{4-[(methylsulfonyl)amino]phenyl}-4-oxochromen-7-yloxy)methyl]benzoic acid; 1H NMR (400 MHz, DMSO-d6) δ: 13.1 (br s, 1H), 9.84 (s, 1H), 8.47 (s, 1H), 8.08-8.06 (m, 2H), 7.94 (d, 1H, J=7.8 Hz), 7.76 (d, 1H, J=7.7 Hz), 7.58-7.45 (m, 3H), 7.30 (d, 1H, J=1.8 Hz), 7.27 (d, 2H, J=8.5 Hz), 7.20 (dd, 1H, J=1.8 Hz, J=8.9 Hz), 5.38 (s, 2H), 3.03 (s, 3H). (ESI) m/z 466 (M+H)+.