Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH:7]=1.[Cl:17][C:18]1[CH:31]=[CH:30][C:29]2[CH:28]3[CH2:32][C:21]([CH2:33][N:34]4[CH2:39][CH2:38][C:37](=[O:40])[CH2:36][CH2:35]4)([C:22]4[C:27]3=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:20]=2[CH:19]=1>>[Si:10]([O:9][CH2:8][C:6]1[CH:7]=[C:2]([C:37]2([OH:40])[CH2:38][CH2:39][N:34]([CH2:33][C:21]34[CH2:32][CH:28]([C:29]5[CH:30]=[CH:31][C:18]([Cl:17])=[CH:19][C:20]=53)[C:27]3[C:22]4=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:35][CH2:36]2)[CH:3]=[N:4][CH:5]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OCc1cncc(Br)c1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Product: CC(C)(C)[Si](C)(C)OCc1cncc(C2(O)CCN(CC34CC(c5ccccc53)c3ccc(Cl)cc34)CC2)c1
Yield: 51 %

Procedure:
Using a procedure similar to that described in example 1 except employing 3-bromo-5-(tert-butyldimethylsilyl)oxymethylpyridine (described in example 69b) and 1-(2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 1m), the title compound was formed in 51% yield as an oil. TLC analysis (Rf 0.20, 25% ethyl acetate in hexane). MS (CI, CH4) m/z 561 (M+1,100), 563 (40), 589 (M+29,20), 545 (26), 429 (26).
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:5]3[C:6]=1[CH2:7][NH:8][C:9](=[O:14])[C:10]=3[CH:11]=[CH:12][CH:13]=2.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+].[Li+].[Cl-]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:15]1([N:3]2[C:4]3[C:5]4[C:6]([CH2:7][NH:8][C:9](=[O:14])[C:10]=4[CH:11]=[CH:12][CH:13]=3)=[CH:2]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1NCc2c(Br)[nH]c3cccc1c23
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: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1NCc2cn(-c3ccccc3)c3cccc1c23
Yield: 93.1 %

Procedure:
To a suspension of 2 (0.1065 g, 0.424 mmol) in 20 mL toluene/10 mL EtOH was added phenylboronic acid (0.08 g, 0.636 mmol), Na2CO3 (0.113 g, 1.06 mmol) dissolved in a minimum amount of water, LiCl (0.054 g, 1.27 mmol), and tetrakis(triphenylphosphine)palladium(0) (24.5 mg, 21.0 μmol). The reaction mixture was refluxed for 16 h. The solvent was removed in vacuo, and the residue was taken up in EtOAc and washed with saturated aqueous NaHCO3, H2O, and brine. The organic layer was dried over Na2SO4 and concentrated to give a yellow solid, which was purified by flash column chromatography eluting with a gradient of 20% of EtOAc in hexanes to give 0.098 g of a mixture of 3 as a yellow solid. mp 215-218° C. (dec); 1H NMR (DMSO-d6) δ 5.04 (s, 2H), 7.17 (t, 1H, J=7.5 Hz), 7.34 (d, 1H, J=6.6 Hz), 7.35 (d, 1H, J=7.4 Hz), 7.50 (m, 4H), 7.66 (d, 1H, J=7.7 Hz), 7.84 (s, 1H), 11.64 (s, 1H); HRMS (M+H) 249.1023.
Reaction SMILES: [CH:1]1([O:7][N:8]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.NN.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH:1]1([O:7][NH:8][S:29]([C:26]2[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:28][CH:27]=2)(=[O:31])=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1c2ccccc2C(=O)N1OC1CCCCC1
Agent: NN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)NOC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.6 %

Procedure:
2-(cyclohexyloxy)-1H-isoindole-1,3(2H)-dione (11.8 mmol, 2.89 g) was combined with hydrazine (13.0 mmol, 0.41 mL) in anhydrous THF (20 mL) under nitrogen. The reaction immediately formed a white suspension and was allowed to stir at room temperature for 18 hours. The suspension was filtered directly into a flask containing 4-methoxybenzenesulfonyl chloride (10.6 mmol, 2.20 g) and diisopropylethylamine (14.2 mmol, 2.47 mL) was added. After stirring at room temperature for 24 hours, the reaction was concentrated to a yellow solid and partitioned between ethyl acetate and 1N HCl. The organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate, and brine, and dried over magnesium sulfate. The product was concentrated to a yellow solid and purified by silica gel chromatography (1:1 hexanes/ethyl acetate) providing 2.53 g (83%) of a white solid. Rf: 0.2 (2:1 hexanes/ethyl acetate); H1-NMR (CDCl3): δ 7.86 (2H,d), 7.00 (2H,d), 6.67 (1H,s), 3.98-3.95 (1H,m), 3.88 (3H,s), 2.00-1.94 (2H,m), 1.75-1.55 (2H,m), 1.35-1.17 (6H,m).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([C:10]([F:13])([F:12])[F:11])=[CH:4][N:3]=1.[NH2:14][C:15]1[C:27]([Cl:28])=[CH:26][C:18]2[C:19](=[O:25])[N:20]([CH3:24])[CH2:21][CH2:22][O:23][C:17]=2[CH:16]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:28][C:27]1[C:15]([NH:14][C:2]2[N:7]=[C:6]([NH:8][CH3:9])[C:5]([C:10]([F:13])([F:12])[F:11])=[CH:4][N:3]=2)=[CH:16][C:17]2[O:23][CH2:22][CH2:21][N:20]([CH3:24])[C:19](=[O:25])[C:18]=2[CH:26]=1
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Reactant: CN1CCOc2cc(N)c(Cl)cc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CNc1nc(Nc2cc3c(cc2Cl)C(=O)N(C)CCO3)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 6.5 %

Procedure:
A mixture of 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (0.5 g, 2.36 mmol), 8-amino-7-chloro-4-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (0.38 mmol) and p-toluene sulphonic acid (0.49 g, 2.6 mmol) in dioxane (10 mL) was heated at 100° C. for 2 h. The mixture was cooled, filtered and the solid washed with dioxane. The solid was dried in a vacuum oven and purified via silica gel column chromatography (20-100% ethyl acetate/isohexane) gave 7-chloro-4-methyl-8-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one as a white solid (10 mg, 28%). LCMS (10 cm_ESCI_Formic_MeCN): [MH+]=402 at 3.04 min. 1H NMR δ (ppm)(400 MHz, CDCl3): 8.41 (1H, s), 8.22 (1H, s), 7.97 (1H, s), 7.77-7.67 (1H, m), 5.29 (1H, s), 4.47-4.39 (2H, m), 3.61-3.51 (2H, m), 3.21-3.18 (3H, m), 3.20-3.07 (3H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:10](OC)(=[O:13])[C:11]#[CH:12].C(OCC)C>CO.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[OH:13][C:10]1[C:7]2[C:2](=[CH:3][CH:4]=[C:5]([O:8][CH3:9])[N:6]=2)[N:1]=[CH:12][CH:11]=1
Reactant: C#CC(=O)OC
Reactant: COc1ccc(N)cn1
Solvent: CO
Solvent: CCOCC
Solvent: c1ccc(-c2ccccc2)cc1
Product: COc1ccc2nccc(O)c2n1
Yield: 8.1 %

Procedure:
5-Amino-2-methoxypyridine (55.0 g, 0.44 mole) in methanol (1000 mL) with methyl propiolate (40 mL, 0.44 mole) was stirred for 48 hours, then evaporated and the product purified by chromatography on silica gel (dichloromethane) followed by recrystallization from dichloromethane-hexane (44.6 g, 48%). The unsaturated ester (10.5 g, 0.05 mole) in warm Dowtherm A (50 mL) was added over 3 minutes to refluxing Dowtherm A, and after a further 20 minutes at reflux the mixture was cooled and poured into diethyl ether. The precipitate was filtered to give a solid (6.26 g, 70%).
Reaction SMILES: [Cl-].[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O.[F:14][C:15]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[C:16]=1[NH2:17].C(N(CC)CC)C>CC(C)=O.CCCCCC.C(Cl)(Cl)Cl.CN(C=O)C>[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH:17][C:16]1[C:15]([F:14])=[CH:21][C:20]([F:22])=[CH:19][C:18]=1[F:23])=[O:13]
Reactant: O=C(O)CCCCCCCCBr
Reactant: Nc1c(F)cc(F)cc1F
Agent: [Cl-]
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: O=C(CCCCCCCCBr)Nc1c(F)cc(F)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.8 %

Procedure:
Oxallyl chloride (95 mg, 0.75 mmol) was added to a chloroform (1 ml) solution of 9-bromononanoic acid (119 mg, 0.5 mmols) and a drop of DMF and the resulting mixture was stirred for 40 minutes at room temperature. The reaction mixture and toluene were azeotroped, and then a chloroform (1 ml) solution of the condensed residue was dropped in to a chloroform (0.5 ml) solution of 2,4,6-trifluoroaniline (74 mg, 0.5 mmols) and triethylamine (76 mg, 0.75 mmols) cooling in ice bath, and stirred for 90 minutes at room temperature. The resulting mixture was concentrated, and the resulting residue was diluted with ethyl accetate. The organic layer was washed with 0.5N-HCl, an aqueous saturated solution of sodium hydrogencarbonate, water, and saturated saline in that order, and dried with anhydrous sodium sulfate, and the solvent was evaporated. Then, the residue was purified through silica gel chromatography (silica gel 20 g, developer; hexane:acetone=20:3). And the resulting crystals were recrystallized from acetone-hexane, and 9-bromo-N-(2,4,6-trifluorophenyl) nonanamide 137 mg (yield: 75%) as colorless needle-like crystals (m.p. 65-66° C.). Potassium carbonate (69 mg, 0.45 mmols) and 18-crown-6 (8 mg, 0.03 mmols) were added to a DMF (1 ml) solution of the resulting anilide (110 mg, 0.3 mmols) and 2-mercaptbenzoxzole (45 mg, 0.3 mmol), and stirred for 3 hours at 80° C. The mixture was diluted with water, and extracted with ethyl accetate. The organic layer was washed with water and saturated saline in that order, and dried with anhydrous sodium sulfate, and the solvent was evaporated. And the resulting residue was purified through silica gel chromatography (silica gel 10 g, developer; hexane:acetone=5:2). And the resulting crystals were recrystallized from acetone-hexane, and the intended product 94 mg (yield: 72%) as colorless needle-like crystals.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][S:18][C:17]([CH3:22])([CH3:21])[C@@H:16]2[C:23]([O:25]C)=[O:24])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH:2]=[C:3]=[CH2:4].[OH-].[Li+].O>O1CCCC1.CO>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][S:18][C:17]([CH3:22])([CH3:21])[CH:16]2[C:23]([OH:25])=[O:24])(=[O:13])=[O:14])=[CH:8][CH:7]=1)[CH:2]=[C:3]=[CH2:4]
Reactant: C=C=CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C=C=CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)C2C(=O)O)cc1
Yield: 34.3 %

Procedure:
The procedure of Example 12 was followed using the product from Example 24 (150 mg, 0.38 mmol), lithium hydroxide (18 mg, 0.76 mmol) in tetrahydrofuran (2 ml), methanol (2 ml), and water (1 ml) to give 50 mg of product (53%, based on unreacted starting material).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15]I)[N:14]=1)=[O:8].[CH:21]([NH2:24])([CH3:23])[CH3:22]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][NH:24][CH:21]([CH3:23])[CH3:22])[N:14]=1)=[O:8]
Reactant: CC(C)N
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CI)cs1
Solvent: C1CCOC1
Product: CC(C)NCc1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 1-(3,4-Dichloro-benzyl)-3-(4-iodomethyl-thiazol-2-yl)-urea intermediate (0.3 mmol) was taken up in tetrahydrofuran (5 ml) and isopropyl amine (20 eq.) was added. The reaction was stirred overnight at room temperature. Added a saturated solution of NaSO3 (40 ml). Extracted this with EtOAc twice. The combined organic extracts were dried over Na2SO4, filtered and solvent removed in vacuo. The crude 1-(3,4-dichlorobenzyl)-3-(4-((isopropylamino)methyl)thiazol-2-yl)urea was used as is.
Reaction SMILES: [Sb].[Cl-].[Cs+].[C:4]([O-:7])(=[O:6])[CH3:5].[K+].[CH2:9]=[CH:10][CH:11]=[CH2:12].O=O>[Pd].[V].C(O)(=O)C>[C:4]([O:7][C:9]([O:7][C:4](=[O:6])[CH3:5])=[CH:10][CH2:11][CH3:12])(=[O:6])[CH3:5]
Reactant: CC(=O)[O-]
Reactant: C=CC=C
Agent: [Pd]
Agent: [V]
Agent: O=O
Solvent: CC(=O)O
Product: CCC=C(OC(C)=O)OC(C)=O

Procedure:
One liter of a silica-alumina catalyst (weight ratio of silica/alumina=10/90) on which palladium, vanadium, antimony, cesium chloride and potassium acetate were supported was packed in a stainless steel reaction vessel with an inner diameter of 1.5 inches, and butadiene, acetic acid, oxygen and nitrogen were supplied so that they might pass through the catalyst layer at rates of 100 l./hr, 200 l./hr, 30 l./hr and 670 l./hr, respectively, and reacted at 170°-190° C. therein. As a result, diacetoxybutene was obtained at a space time yield of 0.75 mol/l.cat·hr and CO2 at a space time yield of 0.048 mol/l.cat·hr. The reaction product containing these substances was subjected to gas-liquid separation under the conditions of 40° C. and 0.5 kg/cm2G, and 99.8% by volume of the gaseous component was circulated back to the reaction system. This means that the amount of butadiene to be taken out, that is, the amount of butadiene treated, was only 0.2% by volume of the gaseous component. The butadiene and oxygen supplies in the steady state were 23.5 l./hr and 9.9 l./hr, respectively, and not supply of nitrogen was required. The amount of the carbon dioxide gas in the system reached 80.2% by volume of the inert gas in the steady state. As a result, diacetoxybutene was obtained at a space time yield of 0.68 mol/l.cat·hr on the 70th day after the start of the reaction, and little drop of activity was seen.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH2:10].[Br:11]N1C(=O)CCC1=O>C(#N)C>[Br:11][C:7]1[CH:6]=[C:5]([CH3:9])[C:4]([NH2:10])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(C)c1N
Solvent: CC#N
Product: COc1cc(Br)cc(C)c1N
Temperature: 145 °C
Yield: 21.6 %

Procedure:
To 2-methoxy-6-methyl-phenylamine (10.0 g) dissolved in acetonitrile (200 mL) was added N-bromosuccinimide (14.3 g) and the reaction mixture was heated to 145° C. for 15 minutes in a sealed microwave process vessel. The crude mixture was filtered through Celite, diluted with diethyl ether (200 mL) and washed with sodium hydroxide (2 M, 2×100 mL) and brine (1×100 mL). The organic phase was dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography to furnish 3.4 g (26%) of the title compound as a black solid. 1H NMR (500 MHz, DMSO-d6): 2.06 (s, 3H), 3.77 (s, 3H), 4.55 (s, 2H), 6.78 (d, 1H), 6.82 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[C:12]2[NH:11][C:10](=[O:13])[CH:9]([CH3:14])[N:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].CN(C)C=O.C12(C)C(C)(C)C(CC1)C[CH2+:31]2[CH:39](C)[C:40]([O:42][CH3:43])=[O:41]>O.C1(C)C=CC=CC=1>[CH3:43][O:42][C:40](=[O:41])[CH:39]([CH3:31])[N:11]1[C:12]2[C:2]([Br:1])=[CH:3][CH:4]=[CH:5][C:6]=2[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[N:8][CH:9]([CH3:14])[C:10]1=[O:13]
Reactant: COC(=O)C(C)[CH2+]1CC2CCC1(C)C2(C)C
Reactant: CC1N=C(c2cccc(F)c2)c2cccc(Br)c2NC1=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)C(C)N1C(=O)C(C)N=C(c2cccc(F)c2)c2cccc(Br)c21
Reaction time: 6 h

Procedure:
A mixture of 0.1 mole of 9-bromo-1,3-dihydro-5-(m-fluorophenyl)-3-methyl-2H-1,4-benzodiazepin-2-one and 0.11 mole of sodium methoxide in about 200 ml. of dimethylformamide is heated at about 95° C. for about 20 minutes. To the mixture is added a solution of 0.11 mole of methyl 2-bormopropionate in about 200 ml. of toluene over a period of about 1 hour at about 95° C., and heating is continued for an additional period of about 6 hours. The reaction mixture is then evaporated in vacuo and the residue thus obtained is stirred with about 500 ml. of water. The resulting suspension is filtered and the solids thus obtained are crystallized from a suitable organic solvent such as ether, methanol, methylene chloride, methylene chloride-methanol and the like to obtain 9-bromo-2,3-dihydro-2-oxo-5-(m-fluorophenyl)-3,α-dimethyl-1H-1,4-benzodiazepin-1-acetic acid methyl ester.
Reaction SMILES: F[B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+]([F:21])(CC1)CC2.[C:22]([O:26][C:27](=[O:44])[C:28]1[C:33]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][C:36]=2[Cl:42])=[CH:32][C:31]([NH2:43])=[N:30][CH:29]=1)([CH3:25])([CH3:24])[CH3:23].CO>CCOC(C)=O.O>[C:22]([O:26][C:27](=[O:44])[C:28]1[C:33]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][C:36]=2[Cl:42])=[C:32]([F:21])[C:31]([NH2:43])=[N:30][CH:29]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Reactant: CC(C)(C)OC(=O)c1cnc(N)cc1Nc1ccc(Br)cc1Cl
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cnc(N)c(F)c1Nc1ccc(Br)cc1Cl
Reaction time: 2 h
Yield: 7.2 %

Procedure:
1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (889 mg, 2.508 mmol) was added to a mixture of 6-amino-4-(4-bromo-2-chlorophenylamino)nicotinic acid tert-butyl ester (42) (1.00 g, 2.51 mmol) in 1:1 MeOH:water (25 mL). After about 2 hours, the reaction mixture was diluted with EtOAc and water. The layers were separated and the organic layer washed with 0.5 N HCl and brine. The aqueous washes were back extracted with EtOAc. The combined organic extracts were dried (Na2SO4) and concentrated. Purification by flash column chromatography using the Biotage system (20:1 hexanes:EtOAc to 15:1 hexanes:EtOAc) provided the desired product (45) as a yellow solid (75 mg, 7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH3:12].[O:13]1CCOCC1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH:12]=[O:13]
Reactant: C1COCCO1
Reactant: Cc1ccnc2ccc(Cl)cc12
Product: O=Cc1ccnc2ccc(Cl)cc12
Yield: 61 %

Procedure:
A solution of 2 (16.04 g, 90.6 mmol) and SeO2 (13.0 g, 117.3 mmol) in 5% aq. 1,4-dioxane (200 mL) was refluxed for 2 h. The precipitated selenium was filtered off and the filtrate was evaporated to dryness in vacuo. The residue was taken into CH2Cl2, and filtered through a short plug of silica gel. The filtrate was concentrated to give a light brown solid. Further purification by crystallization (EtOAc/Hexanes) gave 1 (11.6 g, 61%) as a pale yellow solid Mp 152-153° C. (lit.2 153-154° C). 1H NMR (300 MHz, CDCl3): δ 10.43 (s, 1H), 9.20 (d, 4.4 Hz, 1H), 9.10 (d, 2.2 Hz, 1H), 8.16 (d, 9.1 Hz, 1H), 7.82 (d, 4.4 Hz, 1H), 7.77 (dd, 9.1, 2.2 Hz, 1H). MS m/z: 192 (M+1). Analysis calcd. for C10H6ClNO; C, 62.68; H, 3.16; N, 7.31; Cl, 18.50; found, C, 62.92; H, 3.33; N, 7.23; Cl, 18.60.2
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.CN.[CH:28]([N:31](C(C)C)CC)(C)C>C(Cl)Cl.CN(C=O)C.CCCCCC.CCOCC>[CH2:1]([C:8]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:9]=1[C:10]([NH:31][CH3:28])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)O)c(Cc2ccccc2)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CNC(=O)c1ccc(OC)cc1Cc1ccccc1
Temperature: 25 °C

Procedure:
To an ice bath cooled solution of 10 (11.8 g, 48.8 mmol) in methylene chloride under Argon was added oxalyl chloride (5.10 mL, 58.5 mmol). Added a few drops of DMF and warmed to room temperature. After 18 h the solvent was removed in vacuo. Methylene chloride and methylamine hydrochloride (6.54 g, 97.6 mmol) were added and the contents of the reaction flask were cooled in an ice bath. Diisopropylethylamine was added dropwise using an addition funnel. After 3 h the reaction solution was washed with 5% potassium bisulfate, sat. sodium bicarbonate, and brine. Dried the organic layer with sodium sulfate (anh.) and removed the solvent in vacuo. Trituration with hexane/ether gave 11 as a light solid (8.15 g, 32.0 mmol, 65.5%).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])=[CH:4][C:3]=1[OH:14].[CH:15](I)([CH3:17])[CH3:16].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>C(Cl)Cl.O>[F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])=[CH:4][C:3]=1[O:14][CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)I
Reactant: CON(C)C(=O)c1ccc(F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(F)c(OC(C)C)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
A 2 L round bottom flask equipped with a mechanical stirrer, a N2 inlet, a condenser and a temperature controller, was charged 4-fluoro-3-hydroxy-N-methoxy-N-methylbenzamide (99.6 g, 0.5 mol), isopropyl iodide (110.5 g, 0.65 mol) and Cs2CO3 (195.5 g) and DMF (300 mL). The reaction mixture was heated at 50° C. for 3 h. Isopropyl iodide (17.0 g, 0.1 mol) was added and the reaction was heated at 50° C. for 12 h. The reaction mixture was allowed to cool to rt and water (1 L) and CH2Cl2 (500 mL) were added. The reaction mixture was stirred at rt for 0.5 h, and the organic phase was separated. The aqueous layer was extracted with CH2Cl2 (3×500 mL). The combined organic extracts were washed with water (2×1 L), brine (1 L), dried over MgSO4, filtered and concentrated in vacuo at 40° C. for 18 h to give 4-fluoro-3-isopropoxy-N-methoxy-N-methylbenzamide as an off-white solid (120.0 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[O:4][CH:3]=1.Cl([O-])=[O:14].[Na+].OP([O-])(O)=O.[K+]>C1COCC1.CC(O)(C)C.O>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]([OH:14])=[O:12])[CH:9]=2)[O:4][CH:3]=1
Reactant: O=Cc1cc2c(Cl)coc2cn1
Reactant: [O-][Cl+][O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2c(Cl)coc2cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 105.9 %

Procedure:
3-Chlorofuro[2,3-c]pyridine-5-carbaldehyde (317 mg, 1.74 mmol) is dissolved in THF (10 mL)/t-BuOH (5 mL)/H2O (5 mL), treated with a single portion of sodium chlorite (592 mg, 5.24 mmol) and KH2PO4 (473 mg, 3.48 mmol) and stirred at rt for 18 h. The reaction mixture is concentrated in vacuo to dryness, suspended in water (10 μL), acidified to pH 3.5 with concentrated HCl and stirred at rt for 2 h. The resulting solid is filtered, washed with water and dried in a vacuum oven at 40° C. for 18 h to afford 364 mg of 3-chlorofuro[2,3-c]pyridine-5-carboxylic acid as a white solid. MS (EI) m/z: 197 (M+).
Reaction SMILES: [CH2:1]([C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][C@@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.Br[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:32][O:31][C:29](=[O:30])[CH2:28][CH2:27][N:15]1[CH2:16][CH2:17][CH2:18][C@H:14]1[CH2:13][O:12][C:11]1[CH:19]=[CH:20][C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)CCBr
Reactant: c1ccc(Cc2ccc(OC[C@@H]3CCCN3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCN1CCC[C@H]1COc1ccc(Cc2ccccc2)cc1
Temperature: 60 °C
Yield: 14 %

Procedure:
(S)-2-(4-Benzyl-phenoxymethyl)-pyrrolidine (200 mg, 0.658 mmol) was taken into DMF (2 mL), and methyl 3-bromopropionate (121 mg, 0.724 mmol) was added, followed by potassium carbonate (182 mg, 1.317 mmol). The mixture was heated to 60° C. and left to react overnight. The mixture was diluted with water, and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The compound was then purified by flash chromatography (eluted with 1% methanol in dichloromethane with a 30:1 silica ratio) to obtain the title product (32.6 mg, 0.092 mmol, 14% yield); LCMS; m/z 353.47. found 354.3 (M+1). 1H NMR (400 MHz, CDCL3) δ 3.92 (s, 1H), 1.59 (s, 2H), 1.76-1.78 (m, 1H), 1.93-2.00 (m, 1H), 2.28-2.30 (m, 1H), 2.52-2.55 (m, 2H), 2.67-2.74 (m, 1H), 2.84-2.91 (m, 1H), 3.11-3.15 (m, 1H), 3.20-3.27 (m, 1H), 3.66 (s, 3H), 3.73-3.77 (m, 1H), 3.91-3.92 (m, 2H), 6.81-6.84 (m, 2H), 7.07-7.09 (m, 2H), 7.16-7.29 (m, 5H).