Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[CH:16]=[C:15]([O:20][CH2:21][C:22]#[N:23])[CH:14]=[CH:13]4)=[C:7]([C:24](=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28])[C:6]=2[CH:30]=1.[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[NH4+].CO>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:19]=[CH:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH2:21][C:22]5[NH:33][N:32]=[N:31][N:23]=5)[CH:16]=4)[CH:11]=3)=[C:7]([C:24](=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28])[C:6]=2[CH:30]=1
Reactant: CCCCC(=O)c1c(-c2ccc3cc(OCC#N)ccc3c2)oc2ccc(Cl)cc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCC(=O)c1c(-c2ccc3cc(OCc4nnn[nH]4)ccc3c2)oc2ccc(Cl)cc12
Yield: 76.2 %

Procedure:
Following the procedure described in Step 6, of Example 1, the title compound was prepared from [6-(5-Chloro-3-pentanoyl-benzofuran-2-yl)-naphthalen-2-yloxy]-acetonitrile (0.31 g, 0.74 mmol), sodium azide (0.325 g, 5 mmol) and ammonium chloride (0.268 g, 5 mmol) in DMF (20 mL). Trituration with methanol afforded the title compound as a yellow solid (0.26 g), mp 178-180° C. Mass spectrum (+APCl, [M+H]+) m/z 461. 1HNMR (400 MHz, DMSO-d6): δ8.4 (s, 1H), 8.07-7.99 (m, 3H), 7.85 (dd, 1H, J=8.5, 1.7 Hz), 7.77 (d, 1H, J=8.8 Hz),), 7.64 (d, 1H, J=2.2 Hz),), 7.48 (dd, 1H, J=8.8, 2.2 Hz),), 7.38 (dd, 1H, J=8.8, 2.4 Hz), 5.66 (s, 2H), 2.70 (t, 2H, J=7.4 Hz), 1.56-1.48 (m, 2H), 1.15-1.06 (m, 2H), and 0.69 ppm (t, 3H, J=7.5 Hz). Elemental Analysis for C25H21ClN4O3.0.5H2O: Calculated: C, 64.52; H, 4.66; N, 12.04. Found: C, 64.40; H, 4.42; N, 12.07.
Reaction SMILES: C([O:5][C:6](=[O:46])[CH2:7][N:8](C(OC(C)(C)C)=O)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[S:34][C:35]([CH3:38])=[CH:36][N:37]=3)=[CH:29][CH:28]=2)[NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)(=[O:19])=[O:18])[N:10]=1)(C)(C)C.[OH-].[Na+]>O>[CH3:38][C:35]1[S:34][C:33]([C:30]2[CH:29]=[CH:28][C:27]([CH2:26][CH:15]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)(=[O:18])=[O:19])[C:11]3[N:10]=[C:9]([NH:8][CH2:7][C:6]([OH:46])=[O:5])[CH:14]=[CH:13][CH:12]=3)=[CH:32][CH:31]=2)=[N:37][CH:36]=1
Reactant: Cc1cnc(-c2ccc(CC(NS(=O)(=O)c3ccccn3)c3cccc(N(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n3)cc2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cnc(-c2ccc(CC(NS(=O)(=O)c3ccccn3)c3cccc(NCC(=O)O)n3)cc2)s1
Yield: 54.9 %

Procedure:
Reaction was carried out in the same manner as in Example 19-(b) except for using tert-butyl[tert-butoxycarbonyl(6-{[4-(5-methylthiazol-2-yl)benzyl](pyridin-2-ylsulfonyl)aminomethyl}pyridin-2-yl)amino]acetate (269 mg, 0.404 mmol) obtained in Example 22-(c) in place of tert-butyl[tert-butoxycarbonyl(6-{[4-(pyridin-2-yl)benzyl]-(pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-yl)amino]acetate. After completion of the reaction, water (20 ml) was added to the reaction solution, then it was adjusted to pH 10.9 with a 1N aqueous sodium hydroxide solution, and subsequently insolubles were filtered off. The filtrate was adjusted to pH 5.6 with 1N hydrochloric acid, followed by extraction with ethyl acetate. The separated organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. To the resulting residue were added tert-butyl methyl ether (1 ml) and diisopropyl ether (10 ml), followed by sonication. A precipitated solid was collected by aeration, and then dried under reduced pressure to afford the title compound (113 mg) as a white solid. (Yield: 55%)
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[CH:7]=O.[N+:14]([CH2:17][CH3:18])([O-:16])=[O:15].C([O-])(=O)C.[NH4+].C(O)(=O)C>C(OC(=O)C)C>[Cl:1][C:2]1[C:3]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:4]=2[S:5][C:6]=1/[CH:7]=[CH:18]/[CH2:17][N+:14]([O-:16])=[O:15]
Reactant: O=Cc1sc2ccc(Cl)cc2c1Cl
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])C/C=C/c1sc2ccc(Cl)cc2c1Cl
Temperature: 90 °C

Procedure:
In a sulfonation flask, a mixture containing 6.93 g (0.03 mol) 3,5-dichlorobenzo[b]thio-phene-2-carbaldehyde, 18 g (0.24 mol) nitroethane, 5.8 g (0.075 mol) ammoniumacetate and 60 ml acetic acid is heated at 90° C. for 6 hours. After cooling ethylacetate is added and the organic phase washed three times with water. The organic phase is dried over sodium sulphate and after filration the organic solvent is distilled off in a water jet vacuum. The residue is purified by column chromatography over silicagel (eluent: ethylacetate/heptane 1:5). After chromatography further purification via crystallisation from ethylacetate could be achieved. Yield: 4 g (47% of theory). M.p. 143°-146° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1.ClN1C(=[O:28])CCC1=O.P(=O)(O)(O)O>C(Cl)Cl.O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C:14]1=[O:28]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COCCCOc1ccccc1-n1ccc2ccccc21
Agent: O=P(O)(O)O
Solvent: ClCCl
Solvent: O
Product: COCCCOc1ccccc1N1C(=O)Cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
The compound of step 2 (3.09 g, 11.0 mmol) was dissolved in DCM (83 ml), and N-chlorosuccinimide (1.54 g, 11.6 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The solvent was removed, the resulting solid was dissolved in concentrated acetic acid (45 ml) and heated to 70° C. After the addition of phosphoric acid (9.35 ml, 137 mmol; 85%), the reaction mixture was heated to 120° C. for 2 h. The cooled mixture was diluted with water, extracted with EA, the organic layer separated, dried over sodium sulfate, filtered, and evaporated. The residue was purified by silica gel chromatography (EA/HEP 1:6). 2.38 g of the title compound was obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[C:22]([NH:23][C:24]3[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[CH:25]=3)=[N:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>C(#N)C.C(Cl)Cl>[CH3:33][O:32][C:26]1[CH:25]=[C:24]([NH:23][C:22]2[C:13]([NH:12][S:9]([C:6]3[CH:7]=[N:8][C:3]([CH2:2][N:47]4[CH2:48][CH2:49][N:44]([CH3:43])[CH2:45][CH2:46]4)=[CH:4][CH:5]=3)(=[O:10])=[O:11])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=1
Reactant: CN1CCNCC1
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(CCl)nc2)cc(OC)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(CN3CCN(C)CC3)nc2)cc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.1 %

Procedure:
6-(chloromethyl)-N-{3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}pyridine-3-sulfonamide (100 mg; 0.12 mmol; 1 eq.) and N-ethyl-N-isopropylpropan-2-amine (0.03 ml; 0.25 mmol; 2 eq.) are dissolved in ACN (25 ml) at room temperature then 1-methylpiperazine (0.06 ml; 0.62 mmol; 5 eq.) is added. The reaction mixture is stirred at room temperature for 2 hours. The reaction is quenched by addition of water and neutralized by addition of aqueous Na2CO3. The mixture is concentrated under reduced pressure. The residue obtained is taken up in DCM. The product is extracted with DCM, the organic phase is washed with citric acid 10% then dried over MgSO4. After evaporation of the solvent, the crude residue obtained is purified by flash chromatography to afford 6 mg (9%) of the title compound as a white powder. 1H NMR (DMSO-d6) δ 9.17 (d, J=3 Hz, 1H), 8.30 (m, 1H), 8.24 (dd, J=9 and 3 Hz, 1H), 7.72 (dd. J=9 and 3 Hz, 1H), 7.63 (d, J=9 Hz, 1H), 7.44-7.38 (m, 3H). 7.15 (d, J=3 Hz, 2H), 6.27 (m, 1H), 3.85 (s, 6H), 3.75 (s, 2H), 2.57 (m, 8H), 2.52 (s, 3H). HPLC (max plot) 90%, Rt 3.34 min. LC/MS: MS: (ES+) 550.5, (ES−): 548.5.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:13]1[CH2:17][CH2:16][O:15][C:14]1=[O:18].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(OCC)(=O)C.O>[C:1]1([CH2:7][CH2:8][C:9]([O:11][CH:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1OCCC1Br
Reactant: O=C(O)CCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: O=C(CCc1ccccc1)OC1CCOC1=O

Procedure:
A mixture comprising 13.65 g (90.9 mmol) of 3-phenyl-propanoic acid, 15.0 g (90.9 mmol) of 3-bromo-dihydrofuran-2(3H)-one, 37.7 g of potassium carbonate, and 150 ml of acetone was refluxed under nitrogen current for 9 hours. To the reaction mixture were added 200 ml of water and 400 ml of ethyl acetate, the organic layer was washed with water, a saturated sodium hydrogencarbonate aqueous solution, a saturated sodium chloride aqueous solution, and water in the order, and the organic layer was dried with sodium sulfate. The solvent was concentrated to obtain 24.3 g of brown and oily tetrahydro-2-oxofuran-3-yl 3-phenylpropanoate. The oily compound (5.00 g) (21.3 mmol), 4.32 g (21.3 mmol) of diphenyl sulfoxide, 6 ml of trifluoroacetic anhydride, and 6.7 g (22.3 mmol) of 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonic acid were stirred with ice-cooling for 3 hours, and further at room temperature for 2 hours. Chloroform (200 ml) was added to the reaction solution, the organic layer was washed with water, and the residue was purified by column chromatography (SiO2, chloroform/methanol: 10/1) to obtain 8.2 g of oily compound (A-34).
Reaction SMILES: C[O-].[Na+].[Na].[CH3:5][SH:6].[CH2:7]1[O:16][C:10]([CH2:12][CH2:13][CH2:14]Cl)([CH3:11])[O:9][CH2:8]1>C1(C)C=CC=CC=1.CO>[CH2:7]1[O:16][C:10]([CH2:12][CH2:13][CH2:14][S:6][CH3:5])([CH3:11])[O:9][CH2:8]1
Reactant: CC1(CCCCl)OCCO1
Reactant: CS
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: Cc1ccccc1
Product: CSCCCC1(C)OCCO1
Yield: 100.7 %

Procedure:
To a solution of sodium methoxide prepared by slowly adding 2.4 g (54 mmol) of sodium to 40 mL of methanol was added 4.8 g (48 mmol) of methylmercaptan followed by 6.6 g (40 mmol) of 5-chloro-2-pentanone ethylene ketal. The mixture was refluxed for 4 h and an additional 50 mmol each of sodium and methylmercaptan was added and then refluxed an additional 4 hours to complete the reaction. 50 mL of toluene was added and the mixture washed twice with 10 mL of 1N sodium hydroxide. The toluene layer was dried over magnesium sulfate and evaporated to give 7.1 g of 5-methylthio-2-pentanone ethylene ketal. This was stirred in 60 mL of 70% trifluoroacetic acid for 24 h at room temperature. The mixture was neutralized with sodium carbonate and extracted with 200 mL of ether. The ether extract was dried and evaporated to yield 3.5 g of the desired ketone as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][C:9]2[N:10]=[CH:11][NH:12][C:13](=O)[C:8]=2[CH2:7]1)=[O:5])[CH3:2].[CH2:24]([O:26][C:27]([CH:29]1[N:38]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][C:36]2C(=O)[NH:34][CH:33]=[N:32][C:31]=2[CH2:30]1)=[O:28])[CH3:25].[C:47]([Cl:51])(Cl)(Cl)[Cl:48].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCCl>[CH2:1]([O:3][C:4]([CH:6]1[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][C:9]2[N:10]=[CH:11][N:12]=[C:13]([Cl:48])[C:8]=2[CH2:7]1)=[O:5])[CH3:2].[CH2:24]([O:26][C:27]([CH:29]1[N:38]([C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[CH2:37][C:36]2[C:47]([Cl:51])=[N:34][CH:33]=[N:32][C:31]=2[CH2:30]1)=[O:28])[CH3:25]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCOC(=O)C1Cc2c(nc[nH]c2=O)CN1C(=O)OC(C)(C)C
Reactant: CCOC(=O)C1Cc2nc[nH]c(=O)c2CN1C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: CCOC(=O)C1Cc2c(Cl)ncnc2CN1C(=O)OC(C)(C)C
Product: CCOC(=O)C1Cc2ncnc(Cl)c2CN1C(=O)OC(C)(C)C

Procedure:
To a solution of the mixture of 4-Oxo-4,5,6,8-tetrahydro-3H-pyrido[3,4-d]pyrimidine-6,7-dicarboxylic acid 7-tert-butyl ester 6-ethyl ester and 4-Oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6,7-dicarboxylic acid 6-tert-butyl ester 7-ethyl ester (1.5 g, 4.64 mmol) in DCE (25 mL), carbon tetrachloride (1.34 mL, 13.9 mmol) and triphenylphosphine (2.43 g, 9.28 mmol) are added. The reaction is heated at reflux and after completion of reaction as judged by LCMS. The solvents are removed and the products are isolated using FCC eluting with heptane:EtOAc 80:20. At this point the two products are separated. 4-Chloro-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-6,7-dicarboxylic acid 7-tert-butyl ester 6-ethyl ester MS (ESI) m/z 342.1 (M+1) and 4-chloro-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6,7-dicarboxylic acid 6-tert-butyl ester 7-ethyl ester MS (ESI) m/z 342.1 (M+1) are isolated as an almost 4:1 ratio.
Reaction SMILES: CCN(CC)CC.Cl.[NH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:12].[CH2:22]([O:24][C:25](=[O:29])[C:26](Cl)=[O:27])[CH3:23]>CCOC(C)=O>[N+:19]([C:16]1[CH:15]=[CH:14][C:13]([C:11](=[O:12])[CH2:10][NH:9][C:26](=[O:27])[C:25]([O:24][CH2:22][CH3:23])=[O:29])=[CH:18][CH:17]=1)([O-:21])=[O:20]
Reactant: NCC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)NCC(=O)c1ccc([N+](=O)[O-])cc1
Yield: 59 %

Procedure:
Et3N (8.88 ml) was added to a solution of 2-amino-1-(4-nitrophenyl)ethanone hydrochloride (step B product, 11.5 g) in EtOAc (115 ml). This was followed by drop wise addition of Ethylchlorooxoacetate (7.11 ml). The reaction mixture was refluxed for 2 hours. It was then cooled and quenched with water. The organic layer was separated, dried over Na2SO4 and the solvent was concentrated to get dark brown oil which was purified by column chromatography in 3:7 Ethyl acetate:Pet ether to get yellow solid. The solid was crystallized in ethyl acetate/pet ether to yield 8.9 g (59%) of the title compound. 1HNMR (DMSO-d6, 300 MHz): δ 9.21 (t, 1H), 8.35 (d, 2H), 8.24 (d, 2H), 4.78 (d, 2H), 4.29 (q, 2H), 1.29 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:23]([O:25][C:26](=[O:29])[CH2:27]Br)[CH3:24]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:27][C:26]([O:25][CH2:23][CH3:24])=[O:29])[N:11]=[C:10]([C:13]([F:14])([F:16])[F:15])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Br)cc2)[nH]n1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)Cn1nc(C(F)(F)F)cc1-c1ccc(Br)cc1
Temperature: 80 °C
Yield: 25.7 %

Procedure:
To 6 g of 34a in acetonitrile (150 mL) was added cesium carbonate (13.5 g, 41 mmol) followed by ethylbromoacetate (1.3 mL, 30 mmol) and the reaction mixture heated to 80° C. for 6 h. On completion, the solvent was removed, water (100 mL) added and the crude reaction mixture extracted with ethyl acetate (50 mL×3). Combined organic layer was washed with brine, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography using 10% ethyl acetate in hexane to afford 35 (2 g, 26%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[N:13]([C:16]3[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=3)[C:14]=2[CH3:15])[CH:5]=[CH:6][CH:7]=1.[CH2:24](I)[CH3:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[N:13]([C:16]3[CH:21]=[CH:20][N:19]([CH2:24][CH3:25])[C:18](=[O:22])[CH:17]=3)[C:14]=2[CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c(C)n1-c1cc[nH]c(=O)c1
Product: CCn1ccc(-n2c(C)nc(C#Cc3cccc(Cl)c3)c2C)cc1=O

Procedure:
The title compound, white crystalline solid, MS: m/e=352.2, 354.1 (M+H+), was prepared in accordance with the general method of example 3 from 4-[4-(3-chloro-phenylethynyl)-2,5-dimethyl-imidazol-1-yl]-1H-pyridin-2-one and ethyl iodide.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]([O:9][C@@H:10]2[CH:15]3[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]3)[CH2:11]2)=[O:8])[C:3]2[CH:25]=[CH:26][CH:27]=[CH:28][C:2]1=2.[Br:29][CH2:30][C:31]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)=[O:32]>CCOC(C)=O>[Br-:29].[S:1]1[CH:5]=[C:4]([CH:6]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]([O:9][C@@H:10]2[CH:15]3[CH2:16][CH2:17][N+:12]([CH2:30][C:31](=[O:32])[C:33]4[S:34][CH:35]=[CH:36][CH:37]=4)([CH2:13][CH2:14]3)[CH2:11]2)=[O:8])[C:3]2[CH:25]=[CH:26][CH:27]=[CH:28][C:2]1=2
Reactant: O=C(CBr)c1cccs1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1csc2ccccc12
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(Nc1ccccc1)c1csc3ccccc13)C2)c1cccs1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.4 %

Procedure:
(R)-quinuclidin-3-yl 2-(benzo[b]thiophen-3-yl)-2-(phenylamino)acetate (C19) (90 mg, 0.23 mmol) was dissolved in EtOAc (3 ml), and 2-bromo-1-(thiophen-2-yl)ethanone (51.7 mg, 0.25 mmol) was added. The reaction mixture was stirred at room temperature overnight. The crude was purified by flash chromatography (DCM/MeOH=9/1) to obtain (3R)-3-(2-(benzo[b]thiophen-3-yl)-2-(phenylamino)acetoxy)-1-(2-oxo-2-(thiophen-2-yl)ethyl)-1-azoniabicyclo[2.2.2]octane bromide (50 mg, 36.5% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]([C:14](=[O:31])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=1)[CH3:13].Br[C:34]1[C:35]([CH3:41])=[CH:36][C:37]([Cl:40])=[N:38][CH:39]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]([C:14](=[O:31])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:34]2[CH:39]=[N:38][C:37]([Cl:40])=[CH:36][C:35]=2[CH3:41])[CH:16]=1)[CH3:13]
Reactant: Cc1cc(Cl)ncc1Br
Reactant: COC(=O)COc1ccccc1N(C)C(=O)c1ccc(Cl)c(B2OC(C)(C)C(C)(C)O2)c1
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: [K+]
Solvent: C1COCCO1
Product: COC(=O)COc1ccccc1N(C)C(=O)c1ccc(Cl)c(-c2cnc(Cl)cc2C)c1
Temperature: 95 °C

Procedure:
A mixture of (2-{[4-chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoyl]-methyl-amino}-phenoxy)-acetic acid methyl ester (45 mg, 0.11 mmol), 5-bromo-2-chloro-4-methyl-pyridine (25 mg, 0.12 mmol), Pd(PPh3)4 (6.5 mg, 0.0056 mmol), and K2CO3 (38 mg, 0.28 mmol) in dioxane (600 ul), was heated at 95° C. for 12 hrs. The mixture was purified after a filtration by prep. LCMS to yield (2-{[4-chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-acetic acid methyl ester 3-1. MS [M+H]+: 459.0; tR=7.70 min; (method 2)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[C:4](=O)[C:3]=1[C:16]#[N:17].[OH2:18].[NH2:19][NH2:20]>C(O)C>[NH2:17][C:16]1[C:3]2[C:4](=[O:18])[N:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[Cl:14])[CH:6]=[CH:7][C:2]=2[NH:20][N:19]=1
Reactant: NN
Reactant: O
Reactant: N#Cc1c(Cl)ccn(-c2ccccc2Cl)c1=O
Solvent: CCO
Product: Nc1n[nH]c2ccn(-c3ccccc3Cl)c(=O)c12
Temperature: 90 °C
Yield: 97.5 %

Procedure:
To a solution of 4-chloro-1-(2-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step D (891 mg) in ethanol (6.72 mL) was added hydrazine monohydrate (252 mg) at room temperature. The reaction mixture was heated at 90° C. for 5 hr, and cooled to room temperature. The reaction mixture was concentrated under reduced pressure, to the residue was added water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (854 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:13])[C:11]=1[Cl:12])[C:8](=[O:14])[CH2:7][CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25]CC)=[O:24].[OH-].[K+]>CN(C=O)C.CO.O>[O:14]=[C:8]1[C:9]2[C:4](=[CH:3][C:2]([O:1][CH2:22][C:23]([OH:25])=[O:24])=[C:11]([Cl:12])[C:10]=2[Cl:13])[CH2:5][CH2:6][CH2:7]1
Reactant: O=C1CCCc2cc(O)c(Cl)c(Cl)c21
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(O)COc1cc2c(c(Cl)c1Cl)C(=O)CCC2
Temperature: 60 °C
Yield: 86.5 %

Procedure:
A stirred mixture of 6-hydroxy-7,8-dichloro-1-tetralone (1 g., 0.0044 mole), potassium carbonate (10.69 g., 0.005 mole) and ethyl bromoacetate (0.84 g., 0.005 mole) in DMF (20 ml.) is heated at 60° C. for 11/2 hours. A solution of potassium hydroxide (0.45 g., 0.008 mole) in methanol (40 ml.) is added, the mixture is refluxed for one-half hour and then poured into water (ca. 500 ml.). Upon acidification a white powder separates. It is collected, washed with water, dried and crystallized from ethanol to obtain (1-oxo-7,8-dichloro-1,2,3,4-tetrahydro-6-naphthyloxy)-acetic acid (1.1 g.), melting point 250°-252° C.
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3]([NH2:5])=O.F[B-](F)(F)F.C([O+](CC)CC)C.N[C:20]1[C:21]([NH:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([CH2:36][S:37]([NH:40][CH3:41])(=[O:39])=[O:38])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>O1CCCC1.C(O)C>[OH:1][C@@H:2]([C:3]1[N:29]([C@H:30]2[CH2:31][CH2:32][C@H:33]([CH2:36][S:37]([NH:40][CH3:41])(=[O:38])=[O:39])[CH2:34][CH2:35]2)[C:21]2=[C:22]3[S:28][CH:27]=[CH:26][C:23]3=[N:24][CH:25]=[C:20]2[N:5]=1)[CH3:6]
Reactant: C[C@@H](O)C(N)=O
Reactant: CNS(=O)(=O)C[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: CNS(=O)(=O)C[C@H]1CC[C@H](n2c([C@@H](C)O)nc3cnc4ccsc4c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (2R)-2-hydroxypropanamide (25.8 mg, 0.290 mmol) and triethyloxonium tetrafluoroborate (51.9 mg, 0.273 mmol) in tetrahydrofuran (0.40 mL) was stirred at room temperature for 1 h. After evaporated to dry under reduced pressure, the clear oil was mixed with ethanol (0.20 mL, 3.4 mmol) and added to a solution of 1-{trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}-N-methylmethanesulfonamide (32 mg, 0.090 mmol) in ethanol (0.60 mL) in a microwave vial. The mixture was then heated at 80° C. for 1 h. The mixture was concentrated under reduced pressure. The resultant residue was purified using prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (9.8 mg, 26%). LCMS calculated for C18H25N4O3S2 (M+H)+: m/z=409.1. Found: 409.1.