Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](Cl)[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C:5]1=[O:25])(=O)C.[CH3:26][N:27]([CH2:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH3:28].[OH-].[Na+]>CN(C=O)C.CO>[CH3:28][N:27]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([NH:34]/[C:16](=[C:6]2\[C:5](=[O:25])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[CH:35][CH:36]=1)[CH3:26]
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccc(C)cc2)c2cc([N+](=O)[O-])ccc21
Reactant: CN(C)Cc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(/C(Nc2ccc(CN(C)C)cc2)=C2/C(=O)Nc3ccc([N+](=O)[O-])cc32)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(p-tolyl)-methylidene)-5-nitro-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[C:10]2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:5][CH:4]=1.[N+:26]([C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)([O-:28])=[O:27].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:26]([C:29]1[CH:34]=[CH:33][C:32]([O:24][C:23](=[O:25])/[CH:22]=[CH:21]/[C:9]2[CH:8]=[CH:7][C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:10]=2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:31][CH:30]=1)([O-:28])=[O:27]
Reactant: COc1cccc(-c2c(/C=C/C(=O)O)ccc3ccc(OC)cc23)c1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1cccc(-c2c(/C=C/C(=O)Oc3ccc([N+](=O)[O-])cc3)ccc3ccc(OC)cc23)c1
Yield: 89.7 %

Procedure:
As in Example 113, (E)-3-[7-methoxy-1-(3-methoxyphenyl)-2-naphthalenyl]-2-propenoic acid (0.982 g) was reacted with 4-nitrophenol (0.493 g) in dichloromethane (10 mL) in the presence of 1,3-dicyclohexylcarbodiimide (606 g) at room temperature overnight. The usual work up provided 1.2 g of (E)-3-[7-methoxy-1-(3-methoxyphenyl)-2-naphthalenyl]-2-propenoic acid 4-nitrophenyl ester.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)(=O)=O.[NH:17]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:26]=[O:27])[C:20]=2[CH:19]=[CH:18]1>>[F:14][C:13]([F:16])([F:15])[C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[CH2:6][N:17]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:26]=[O:27])[C:20]=2[CH:19]=[CH:18]1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CS(=O)(=O)OCc1cccc(C(F)(F)F)c1
Product: O=Cc1cccc2c1ccn2Cc1cccc(C(F)(F)F)c1
Yield: 98.6 %

Procedure:
The same procedures used in Example 1 were repeated except for using 3.68 g of 3-trifluoromethylbenzyl methanesulfonate and 2.00 g of indole-4-carbaldehyde to give 4.12 g of 1-(3-trifluoromethylbenzyl) indole-4-carbaldehyde as yellow crystals. The yield thereof was found to be 99%.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=[O:35])[CH2:29][C:30](OCC)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][NH2:37].[C-]#N.[Na+]>CCO>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=[O:35])[CH2:29][C:30]([NH:37][CH3:36])=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: CCOC(=O)CC(=O)N1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: CNC(=O)CC(=O)N1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Reaction time: 48 h
Yield: 87 %

Procedure:
A solution of (S)-ethyl 3-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-3-oxopropanoate (120 mg, 0.25 mmol) in a ˜33% methylamine solution in EtOH (5 mL) was treated with catalytic amount of sodium cyanide and allowed to stir for 48 h. The reaction mixture was then evaporated, washed with water and air dried to afford the title compound as a pale yellow foam (102 mg, 87%). LC/MS (Method B) 3.34 min, [M+1]+ 366.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].[CH2:39]([C:41]1[CH:49]=[CH:48][C:44]([C:45](Cl)=[O:46])=[CH:43][CH:42]=1)[CH3:40]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:45](=[O:46])[C:44]4[CH:48]=[CH:49][C:41]([CH2:39][CH3:40])=[CH:42][CH:43]=4)=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)c3ccc(CC)cc3)cc1)n2C)c1ccccn1
Yield: 64 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and 4-ethylbenzoylchloride. Yield: 64% of theory, C36H37N7O4 (631.7) Rf value: 0.78 (silica gel; dichloromethane/methanol=9:1) ##EQU130##
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(O)C>[OH:11][C:12]1[C:6]2[C:4](=[CH:3][C:2]([I:1])=[CH:8][CH:7]=2)[N:5]=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Nc1cccc(I)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2cc(I)ccc2c1O
Temperature: 25 °C

Procedure:
3-Iodoaniline (8.50 mL) and diethyl ethoxymethylenemalonate (14.30 mL) are heated at 130° C. for 1 hour. The reaction is cooled to room temperature and 70 mL diphenyl ether is added. The solution is heated at 250° C. for 1.5 hours with removal of ethanol by a Dean-Stark trap. The reaction is cooled to room temperature and the resulting solid filtered, washed with hexanes, and dried. The solid is triturated in ethyl acetate to give 12.82 g of ethyl 4-hydroxy-7-iodoquinoline-3-carboxylate. A mixture of this ester (0.35 g) and 4-chlorobenzylamine (3.0 mL) are heated at 180° C. for 1 hour. The reaction is cooled to 70° C. and poured into 50 mL diethyl ether. A tan solid which crystallizes slowly out of diethyl ether is obtained. The solid is recrystallized from ethyl acetate/hexanes to give the desired product (0.22 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][C:5]12[NH:15][C:14](=[O:16])[NH:13][C:12]1=[O:17].[N+:18]([O-])([OH:20])=[O:19]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:18]([O-:20])=[O:19])[CH:11]=1)[NH:8][CH2:7][CH2:6][C:5]12[NH:15][C:14](=[O:16])[NH:13][C:12]1=[O:17]
Reactant: O=C1NC(=O)C2(CCNc3ccc(Cl)cc32)N1
Reactant: O=[N+]([O-])O
Product: O=C1NC(=O)C2(CCNc3c([N+](=O)[O-])cc(Cl)cc32)N1
Temperature: 0 °C
Yield: 98 %

Procedure:
5.00 g. (0.0199 mol) of 6'-chloro-1',2',3',4'-tetrahydro-spiro(imidazolidine-5,4'-quinoline)-2,4-dione, formula (V), prepared as described in U.S. Pat. No. 4,235,911, was added to 500 ml of concentrated nitric acid precooled to 7° C. measured internally. After one minute the reaction mixture was poured into 4 liters of ice water and extracted with 2×1 liter of ethyl acetate. The combined organic layers were washed with 1 liter of water, dried over magnesium sulfate, filtered and concentrated to a yellow solid. The solid was slurried in ether/hexane (1/3) filtered and dried in vacuo to provide 5.8 g. (98%) of the title product, m.p. 271° to 274° C. dec.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]([F:27])([F:26])[CH2:24]I>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[O:8][CH2:24][C:23]([F:27])([F:26])[F:22]
Reactant: FC(F)(F)CI
Reactant: CCOC(=O)Cc1cc(Cl)c(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cc(Cl)c(OCC(F)(F)F)c(Br)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 29.4 %

Procedure:
To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate (2 g, 6.8 mmol), potassium carbonate (2.35 g, 17.0 mmol) in dry DMF (20 mL), was slowly added trifluoro ethyl iodide (8.58 g, 4.0 mL, 40.8 mmol) at room temperature, the reaction mixture was slowly heated to 100° C. and heating was continued for 4 h. Upon which the reaction mixture was poured onto water and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water, dried over Na2SO4 and evaporated under reduced pressure. Purification by column chromatography over silica gel (hexane/EtOAc) to gave compound ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-acetate (0.750 g, 30% yield). 1H NMR (CDCl3, 400 MHz): 7.43 (s, 1H); 7.34 (s, 1H); 4.4 (q, 2H), 4.13 (q, 2H); 3.55 (t, 1H); 1.93 (m, 1H), 1.58 (m, 1H); 1.45 (m, 1H); 1.24 (t, 3H), 0.92 (d, 6H);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21]OS(C)(=O)=O)=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[S:8][C:7]=2[CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][N:42]4[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]4)=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)[S:8][C:7]=2[CH:35]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(C#CCOS(C)(=O)=O)cc2)cc1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(C#CCN3CCCCC3)cc2)cc1

Procedure:
The product from Step 3 (205 mg, 0.4 mmol) was combined with cesium carbonate (197 mg, 0.6 mmol), piperidine (44 mL, 0.44 mmol) in dimethylformamide at room temperature. After four hours the reaction was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate. After filtration, concentration the title compound (120 mg) was obtained.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[C:13]([CH:18]([CH3:21])[CH2:19][OH:20])=[N:14][CH:15]=[CH:16][CH:17]=1>C(Cl)Cl>[Cl:11][C:12]1[C:13]([CH:18]([CH3:21])[CH:19]=[O:20])=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(CO)c1ncccc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C=O)c1ncccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.1 %

Procedure:
To a −78° C. solution of dimethylsulfoxide (4.04 g, 3.67 mL, 51.7 mmol) in methylene chloride (25 mL) was added a solution of oxalyl chloride (3.28 g, 2.26 mL, 25.9 mmol) in methylene chloride (5 mL) over two minutes. The reaction mixture was stirred for 15 minutes, and then a solution of the product of Example 38C (0.74 g, 4.31 mmol) in methylene chloride (25 mL) was added over 8 minutes. The reaction was allowed to warm to ambient temperature and quenched with water. The quenched reaction mixture was extracted with methylene chloride, and the organic layer washed with brine and concentrated. The residue was chromatographed on silica gel eluting with 25% ethyl acetate-hexane to give the title compound (0.71 g, 97%). 1H NMR (300 MHz, DMSO-d6) δ ppm 9.73 (s, 1H), 8.53 (dd, J=1.5, 4.7, 1H), 8.00 (dd, J=1.4, 8.1, 1H), 7.40 (dd, J=4.7, 8.1, 1H), 4.28 (q, J=7.0, 1H), 1.34 (d, J=7.0, 3H). MS (DCI) m/z 170 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1Br
Reactant: OB(O)c1ccc(Cl)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: Cc1ccccc1
Solvent: O
Product: O=Cc1ccccc1-c1ccc(Cl)cc1

Procedure:
To 2-bromobenzaldehyde (2.3 ml) and tetrakis(triphenylphosphine)palladium(0) (0.35 g) in toluene (50 mL), was added 4-chlorophenylboronic acid (4.0 g) and 2M Na2CO3 (70 ml). The mixture was heated under reflux for one hour. The reaction was cooled, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and the combined aqueous layers back-extracted with ethyl acetate. The combined organic layers were dried over Na2SO4. The crude material was purified by flash chromatography using 97.5/2.5 hexane/ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][NH:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][N:22]([C:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:41])[CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Clc1ccc2c(c1Nc1ccnc3[nH]c4c(c13)CNCC4)OCO2
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccccc1)N1CCc2[nH]c3nccc(Nc4c(Cl)ccc5c4OCO5)c3c2C1
Temperature: 25 °C
Yield: 10 %

Procedure:
(5-Chloro-benzo[1,3]dioxol-4-yl)-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (100 mg, 0.29 mmol) and DIEA (0.15 mL, 0.88 mmol) were dissolved in 1,2-dichloroethane (2 mL) and stirred at room temperature. Benzoyl chloride (0.03 mL, 0.35 mmol) was added dropwise, and the reaction was stirred for 1 h at room temperature. The reaction solution was concentrated. The crude material was dissolved in DMSO (3 mL) and filtered. The filtrate was purified directly via prep-LC-MS to provide 67 (13 mg, 10% yield) as a white fluffy solid. LC-MS (M+H=447, obsd.=447).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[C:6]([O:8][CH2:9][CH3:10])[CH:7]=1.O=P(Cl)(Cl)[Cl:14]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[C:5]([Cl:14])=[N:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOc1cc(Br)c[n+]([O-])c1
Solvent: ClCCl
Product: CCOc1cc(Br)cnc1Cl
Temperature: 45 °C
Yield: 33.3 %

Procedure:
To a solution of 3-bromo-5-ethoxypyridine 1-oxide (40 g, 183 mmol) in DCM (200 mL) at 0° C. was slowly added POCl3 (159 mL, 1701 mmol) over 30 min. Then the resulting solution was warmed to 45° C. for 15 h. The mixture was concentrated and extracted with DCM (2×200 mL), dried over Na2SO4 and concentrated to give 5-bromo-2-chloro-3-ethoxypyridine (30 g, 60.9 mmol, 33.2% yield): 1H NMR (400 MHz, CD3OD) δ 8.00-7.99 (d, J=2.0 Hz, 1H), 7.65-7.64 (d, J=2.0 Hz, 1H), 4.17-4.12 (m, 2H), 1.44 (t, J=7.0 Hz, 2H); ES-LCMS m/z 235 (M+H).
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[C:10]([O:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11].[C:25]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26].N1C=CN=C1>O>[O:6]([C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[C:10]([O:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:11])[Si:29]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:31])[CH3:30]
Reactant: O=C(OCCOc1ccccc1)c1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)OCCOc2ccccc2)c1
Reaction time: 10 h

Procedure:
Into a 250 mL round bottom flask was added 30 mL of dry dimethyl formamide. Five parts of hydroxy ester (53) and 3.5 parts of tert-butyldimethyl silyl chloride were added. to the reaction flask with stirring. Three parts of Imidazole was added in portions and stirring was continued for 10 hours. The reaction mixture was diluted with 80 mL of water and the product was extracted with ethyl acetate. The organic layer was washed with water and dried on anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give an oil, yield 6.80 parts. This material was pure enough for next step of the reaction. The reaction proceeded as follows:
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)Cl.[CH2:11]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([CH3:29])=[CH:24][CH2:25][O:26]2)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[CH2:11]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([CH3:29])=[C:24]([CH:4]=[O:5])[CH2:25][O:26]2)=[CH:21][CH:20]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC1=CCOc2cc(OCc3ccccc3)ccc21
Reactant: CN(C)C=O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CC1=C(C=O)COc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To DMF (1 mL) was added dropwise POCl3 (0.25 mL) at 0° C., followed by stirring at room temperature for 30 minutes. To the reaction mixture was added dropwise a solution of 7-(benzyloxy)-4-methyl 2H-chromene (280 mg) in DCM (1 mL), followed by stirring at room temperature for 3 hours. The reaction liquid was poured into ice-water, followed by extraction with EtOAc three times. The organic layer was combined, washed with water and brine in this order, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=85:15 to 70:30) to obtain 7-(benzyloxy)-4-methyl-2H-chromene-3-carbaldehyde (234 mg) as a pale yellow powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:11]=3[CH:12]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1.O>CN(C=O)C>[C:34]([C:33]1[CH:36]=[CH:37][C:30]([O:29][CH2:28][CH2:27][CH2:26][O:1][C:2]2[CH:3]=[C:4]([C:8]3[O:9][C:10]4[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:11]=4[CH:12]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:31][CH:32]=1)#[N:35]
Reactant: N#Cc1ccc2oc(-c3cccc(O)c3)cc2c1
Reactant: N#Cc1ccc(OCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCCOc2cccc(-c3cc4cc(C#N)ccc4o3)c2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A mixture of 2-(3-hydroxphenyl)-5-cyanobenzofuran (125) (1.176 g, 5 mmol) and K2CO3 (0.829 g, 6 mmol) in dry DMF (25 mL) was heated up to 60° C. 4-(3-Bromopropoxy)benzonitrile (129) was added in one portion and the reaction was kept at 80-100° C. overnight. The mixture was cooled down to room temperature and poured into iced water (100 mL) and stirred for 30 min. A precipitate formed was separated by filtration, washed with water (50 mL) and ethanol (50 mL). Drying under high vacuum and recrystallization from the mixture of DMF and ethanol afforded the desired product as white solid (1.65 g, 84%): mp 157-158° C. (DMF/EtOH). 1H NMR (DMSO-d6) δ8.24 (d, J=1.6 Hz, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.78 (d, J=8.8 Hz, 2H), 7.77 (dd, J=8.6, 1.6 Hz, 1H), 7.61 (s, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.52 (m, 1H), 7.45 (dd, J=7.8, 7.8 Hz, 1H), 7.16 (d, J=8.8 Hz, 2H), 7.07 (dd, J=7.8, 1.7 Hz, 1H), 4.35-4.15 (m, 4H), 2.30-2.15 (m, 2H). HPLC (method B) tR 9.63 min (100.0 area %). Anal. (C25H18N2O3) C, H, N.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([NH:23][C:24]2[C:29]([Cl:30])=[CH:28][N:27]=[C:26]([NH2:31])[C:25]=2[N+:32]([O-])=O)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(=O)C>[Zn]>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([NH:23][C:24]2[C:29]([Cl:30])=[CH:28][N:27]=[C:26]([NH2:31])[C:25]=2[NH2:32])[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Nc2c(Cl)cnc(N)c2[N+](=O)[O-])C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Nc2c(Cl)cnc(N)c2N)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 0.17 h
Yield: 90.2 %

Procedure:
N(4)-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)-silyl]oxy}methyl)cyclopentyl]-5-chloro-3-nitropyridine-2,4-diamine (0.875 g, 0.00165 mol) and zinc (0.431 g, 0.00659 mol) was added to acetic acid (40.0 mL, 0.704 mol) with stirring for 10 mins. The mixture was stirred for 10 min and the solid was filtered off. The filtrate was concentrated, dissolved in EtOAc (50 mL) washed with water (2×10). To the organic phase was added 2 ml Et3N and the mixture was washed with 10 mL water. The organic layer was concentrated and purified by flash chromatography (30% EtOAc/hexanes) to afford the title compound (0.746 g, 90%) as a white solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:21]=[CH:20][C:12]([O:13][C:14]3[C:15](=[O:19])[CH2:16][CH2:17][CH:18]=3)=[CH:11][CH:10]=2)O1.[F-].[Cs+].[C:25]([O:28][C@H:29]1[C@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@:33]2([C:45]3[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([CH2:52]Br)[CH:46]=3)[O:44][C@@:30]1([CH2:54][O:55][C:56](=[O:58])[CH3:57])[CH2:31][O:32]2)(=[O:27])[CH3:26]>O1CCOCC1.C(OC(=O)C)C>[C:25]([O:28][C@H:29]1[C@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@:33]2([C:45]3[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([CH2:52][C:9]4[CH:10]=[CH:11][C:12]([O:13][C:14]5[C:15](=[O:19])[CH2:16][CH2:17][CH:18]=5)=[CH:20][CH:21]=4)[CH:46]=3)[O:44][C@@:30]1([CH2:54][O:55][C:56](=[O:58])[CH3:57])[CH2:31][O:32]2)(=[O:27])[CH3:26]
Reactant: CC1(C)OB(c2ccc(OC3=CCCC3=O)cc2)OC1(C)C
Reactant: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(CBr)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OC5=CCCC5=O)cc4)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Temperature: 110 °C
Yield: 35.1 %

Procedure:
To a solution of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)cyclopent-2-enone (295 mg, 0.989 mmol), CsF (296 mg, 1.95 mmol) in dioxane (3.1 mL), (1R,2S,3S,4R,5S)-1-(acetoxymethyl)-5-(3-(bromomethyl)-4-chlorophenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate (369.4 mg, 0.65 mmol, Intermediate 2) and Pd(PPh3) (60 mg, 0.05 mmol) were added under N2 atmosphere. The reaction mixture was heated to 110° C. for 1 h. After completion of the reaction as confirmed by TLC, the reaction mixture was diluted with ethylacetate (100 mL), washed with water (20 mL) and brine (20 mL) successively. The organic layer was dried over Na2SO4 and the volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 2:8 Acetone:hexane) to provide title compound (150 mg, 35%) as off-white solid.