Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:8]1([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12][O:11][CH:10]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCOC(C(=O)OCc2ccccc2)C1
Temperature: 80 °C
Yield: 95.5 %

Procedure:
In a 500-mL round-bottom flask, the 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (5.0 g, 22 mmol) was dissolved in DMF (75 mL). Benzyl bromide (3.6 ml, 30 mmol) was added via syringe, followed by potassium carbonate (4.8 g, 35 mmol). The sides of the glass were rinsed down with dmf (25 mL), and an air condenser was affixed, the reaction mixture was heated at 80° C. in an oil bath for 14 h. The reaction was cooled to ambient temperature and concentrated. The residue was transferred to a separatory funnel with 60% ether-hexane (300 mL), and the organic layer was extracted with water (75 mL), half-saturated brine (30 mL), and saturated brine (30 mL), then was dried over sodium sulfate and concentrated. The residue was purified through silica gel (500 mL) using 20% to 30% EtOAc-hexane to afford the title compound (6.81 g, 21 mmol). MS m/z 266 (M+1-isobutylene).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[CH:6][CH:5]=[N:4]1)[CH3:2].[CH3:9][S:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[C:15]([CH3:22])[C:14]=1[C:23]([O:25][CH3:26])=[O:24])(=[O:12])=[O:11].C1(N=C=NC2CCCCC2)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)(CC)(C)C>[CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([S:10]([CH3:9])(=[O:12])=[O:11])=[C:14]([C:23]([O:25][CH3:26])=[O:24])[C:15]=2[CH3:22])[CH:5]=[N:4]1)[CH3:2]
Reactant: COC(=O)c1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Reactant: CCn1nccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(C(=O)OC)c2C)c1O
Yield: 61.7 %

Procedure:
1.12 g (0.01 mol) of 1-ethyl-5-hydroxypyrazole was dissolved in 30 ml of t-amyl alcohol, and 2.72 g (0.01 mol) of 4-methanesulfonyl-3-methoxycarbonyl-2-methylbenzoic acid, 2.27 g (0.011 mol) of N,N'-dicyclohexylcarbodiimide and 0.76 g (0.0055 mol) of anhydrous potassium carbonate were sequentially added thereto. The mixture was reacted at 80° C. for 6 hours under stirring. After completion of the reaction, t-amyl alcohol was distilled off under reduced pressure, and then water was added to the residue to dissolve the soluble component. The mixture was subjected to filtration to separate out the insolubles. The aqueous solution thus obtained was washed twice with chloroform, and then concentrated hydrochloric acid was added to adjust pH<1. The precipitated oil component was extracted with chloroform. The chloroform layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue thus obtained was recrystallized from water/ethanol to obtain 2.26 g of the desired product. (Yield: 62%, melting point: 150°-152° C.)
Reaction SMILES: [CH2:1]([O:4][C:5]([CH:7]1[CH2:12][CH2:11][CH:10]([CH:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][OH:15])[CH2:9][CH2:8]1)=[O:6])[CH2:2][CH3:3].[Li+].CC([N-]C(C)C)C>C1COCC1>[CH2:1]([O:4][C:5]([C@H:7]1[CH2:12][CH2:11][C@H:10]([CH:13]([NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:14][OH:15])[CH2:9][CH2:8]1)=[O:6])[CH2:2][CH3:3]
Reactant: CCCOC(=O)C1CCC(C(CO)NC(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCOC(=O)[C@H]1CC[C@H](C(CO)NC(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
4-(1-tert-Butoxycarbonylamino-2-hydroxy-ethyl)-cyclohexanecarboxylic acid propyl ester (1-4) (4.26 g, 0.0129 mol, 1 eq) was dissolved in anhydrous THF (200 mL) under argon in a 1 L RB flask. The solution was cooled with an acetone-dry ice bath to −78° C. LDA (2.0 M solution) (51.7 mL, 0.103 mol, 8 eq) was added dropwise at −70° C. The reaction mixture was stirred at −70° C. for 2 hours. The reaction was quenched with MeOH (40 mL). The pH was adjusted to pH=4˜5 with 5% HCl. The mixture was extracted with Et2O (3×330 mL). The combined extracts were washed with brine (1×300 mL). After drying over Na2SO4 and filtration, the filtrate was concentrated under vacuum to dryness. The residue was purified on a silica gel column eluting with EtOAc/Hexanes 20˜40%) to give 3.78 g (88.7% yield) of the intermediate 1-5 as a mixture of cis- and trans-isomers. The 1H NMR (DMSO-d6) data is depicted in FIG. 4.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:6][C:5]=1[NH2:15])([O-])=O.Cl.C(O[C:20](=N)[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])C>CCO.[Pd]>[S:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[C:8]1[CH:7]=[CH:6][C:5]2[N:15]=[C:20]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[NH:1][C:4]=2[CH:9]=1
Reactant: Nc1ccc(-c2cccs2)cc1[N+](=O)[O-]
Reactant: CCOC(=N)CC(=O)OCC
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cc1nc2ccc(-c3cccs3)cc2[nH]1
Reaction time: 3 h

Procedure:
2-Nitro4-(2-thienyl)phenylamine (1.0 eq) and 10% Pd/C (0.1 eq) were suspended in anhydrous EtOH at room temperature. The reaction flask was evacuated and subsequently filled with H2. The resulting mixture was allowed to stir under a hydrogen atmosphere for 3 hours. Ethyl 3-ethoxy-3-iminopropanoate hydrochloride (2.0 eq) was then added and the resulting mixture was heated at reflux for 12 hours. After this time, the solution was filtered through a plug of Celite, concentrated, dissolved in 50 ml of 2N HCl and washed with CH2Cl2. The aqueous layer was brought to pH 12 with concentrated NH4OH(aq) and extracted with CH2Cl2. The combined organic layers were dried with MgSO4 and concentrated to yield a brown oil which was purified by silica gel chromatography (5:95 MeOH:CH2Cl2) to provide a yellow solid. LC/MS m/z 287.1 (MH+), Rt 1.98 minutes.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[C:3]1=[O:9].O.O.O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:20].[Mg+2].C(=O)(O)[O-].[Na+]>CO.O>[CH3:8][CH:4]1[CH2:5][CH2:6][CH2:7][CH:2]([CH3:1])[O:20][C:3]1=[O:9]
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Reactant: CC1CCCC(C)C1=O
Agent: O=C([O-])O
Agent: [Mg+2]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1CCCC(C)C(=O)O1
Reaction time: 8 h
Yield: 47.5 %

Procedure:
A 250 mL round bottom flask was charged with 2,6-dimethylcyclohexanone (2.162 mL, 2.0 g, 15.85 mmol) and 126 mL of a 1:1 methanol/water mixture. The solution stirred as magnesium monoperoxyphthalate hexahydrate (MMPP, 15.68 g, 31.7 mmol) and sodium bicarbonate (2.66 g, 31.7 mmol) were added. The reaction proceeded overnight at room temperature with stirring. The following day the crude product was extracted into ethyl acetate, washed sequentially with saturated sodium bicarbonate, brine and dried over anhydrous sodium sulfate before concentrating in vacuo to give 1.07 g (47.5% yield) of 3,7-dimethyloxepan-2-one (61) as a clear, colorless oil.
Reaction SMILES: [F:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][S:8][C:4]=2[CH:3]=1.C(O)(=O)C>[Fe].C(OCC)(=O)C>[NH2:12][C:11]1[C:2]([F:1])=[CH:3][C:4]2[S:8][N:7]=[C:6]([CH3:9])[C:5]=2[CH:10]=1
Reactant: Cc1nsc2cc(F)c([N+](=O)[O-])cc12
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1nsc2cc(F)c(N)cc12
Temperature: 65 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
A solution of 6-fluoro-3-methyl-5-nitro-1,2-benzisothiazole (0.740 g, 3.50 mmol), 5% acetic acid (25.0 mL) and ethyl acetate is heated to 65° C., treated with iron powder (0.980 g, 17.5 mmol), stirred at 65° C. for one hour, cooled to room temperature, and filtered to remove solids. The organic phase is separated, washed sequentially with water, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title product as an orange solid (0.610 g) which is identified by NMR spectral analyses.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH:17]1([NH:23][C:24]([N:26]2[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.Cl>C(O)CC(C)C>[CH:17]1([NH:23][C:24]([N:26]2[CH2:32][CH2:31][CH2:30][N:29]([C:2]3[N:11]=[C:10]([NH2:12])[C:9]4[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=4)[N:3]=3)[CH2:28][CH2:27]2)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C(NC1CCCCC1)N1CCCNCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Agent: Cl
Solvent: CC(C)CCO
Product: COc1cc2nc(N3CCCN(C(=O)NC4CCCCC4)CC3)nc(N)c2cc1OC
Reaction time: 8 h

Procedure:
A solution prepared by dissolving 479 mg. (2 mmole) of 2-chloro-4-amino-6,7-dimethoxyquinazoline and 451 mg. (2 mmole) of N-cyclohexylcarbamoyl-homopiperazine (oily substance, showing IR absorption spectrum at 3340, 2920, 1630 cm-1) in 10 ml of isoamyl alcohol was refluxed for 4 hours, followed by standing overnight. The precipitates were collected by filtration to obtain 310 mg. of the desired hydrochloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[Br:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:13]1[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]1
Reactant: Brc1ccccc1Br
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccccc2Br)CC1

Procedure:
The title compound was prepared from dibromobenzene and 1-methylpiperazine in a similar manner to Example 110 (a).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C@H:11]3[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=O)[CH3:19])[CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH2:18]([NH:17][C@H:13]1[CH2:14][CH2:15][CH2:16][C@H:11]([O:10][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)[CH2:12]1)[CH3:19]
Reactant: CC(=O)N[C@H]1CCC[C@H](Oc2ccc3[nH]ncc3c2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCN[C@H]1CCC[C@H](Oc2ccc3[nH]ncc3c2)C1
Reaction time: 12 h
Yield: 82.6 %

Procedure:
The trans-N-[3-(1H-indazol-5-yloxy)cyclohexyl]-acetamide (0.077 g, 0.28 mmol) obtained in Example 398 was added to a suspension of lithium aluminum hydride (0.040 g, 1.05 mmol) in tetrahydrofuran (5 ml) and stirred for 12 hours with heating under reflux. The resulting solution was cooled on an ice bath, followed by adding dropwise thereto water (0.05 ml), a 2N-aqueous sodium hydroxide solution (0.10 ml) and water (0.15 ml) in that order. Thereafter, the insoluble material was removed by filtration using Celite. The filtrate was purified by a silica gel chromatography (eluent: chloroform/methanol/30%-aqueous ammonia=10/1/0 to 100/10/1) to obtain trans-N-ethyl-3-(1H-indazol-5-yloxy)cyclohexanamine (0.060 g, 83%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C@H:7]1[CH2:9][C@H:8]1[C:10](O)=[O:11])=O.O.[NH2:17][NH2:18]>C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]2[CH:7]3[CH:8]([C:10](=[O:11])[NH:17][N:18]=2)[CH2:9]3)[CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cccc(C(=O)[C@H]2C[C@H]2C(=O)O)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1cccc(C2=NNC(=O)C3CC23)c1
Yield: 60 %

Procedure:
600 mg (2.9 millimoles) of cis-2-(m-aminobenzoyl)-cyclopropanecarboxylic acid, 20 ml of ethanol and 0.16 g (3.2 millimoles) of hydrazine hydrate are refluxed for 6 hours. After filtering off the product at 10° C. and drying it under reduced pressure at 50° C., 0.35 g (60% of theory) of 2-(m-aminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one are isolated as colorless crystals, which are identical with the compound from Example 33.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]#[N:8])=[CH:2]1.[C:9]1(=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[C:9]1(=[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[C:7]#[N:8])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: N#CCc1ccsc1
Reactant: O=C1CCCCCC1
Product: N#CC(=C1CCCCCC1)c1ccsc1

Procedure:
The expected intermediate is obtained in the manner described in General Protocol A starting from 3-thienylacetonitrile and cycloheptanone.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)=[O:4].[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=1>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:10](=[O:12])[C:9]2[CH:13]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=[CH:7][C:8]=2[N+:14]([O-:16])=[O:15])=[N:19][CH:20]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(C(=O)O)c1
Product: COC(=O)c1ccc([N+](=O)[O-])c(C(=O)Nc2ccc(Cl)cn2)c1

Procedure:
Using a similar procedure to that described in Example 8-A, 5-methoxycarbonyl-2-nitrobenzoic acid (20 g, 89 mmol) and 2-amino-5-chloropyridine (11 g, 85 mmol) afforded, after recrystallization from toluene, 23.6 g (83%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:21][CH2:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Cl)(=[O:28])=[O:27]>C(N(C(C)C)C(C)C)C>[OH:21][CH2:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:14][CH2:13]1)(=[O:28])=[O:27]
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=S(=O)(CCCCCCCl)NCCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1)NCCCO
Yield: 91.6 %

Procedure:
1-[(4-Chlorophenyl)phenylmethyl]piperazine (505.9 mg, 1.76 mmol) and N-(3-hydroxypropyl)-6-chlorohexanesulfonamide (500.0 mg, 1.94 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-(3-hydroxypropyl)-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfonamide (819.3 mg) as a pale yellow oil (yield based on 1-[(4-chlorophenyl)phenylmethyl]piperazine: 91.4%).
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[NH2:18][C:19]1[C:34]([Cl:35])=[CH:33][C:22]([C:23]([NH:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[O:24])=[C:21]([OH:36])[CH:20]=1.Br[CH2:38][CH2:39][CH2:40][N:41]1[C:45](=[O:46])[C:44]2=[CH:47][CH:48]=[CH:49][CH:50]=[C:43]2[C:42]1=[O:51]>C(#N)C>[NH2:18][C:19]1[C:34]([Cl:35])=[CH:33][C:22]([C:23]([NH:25][CH2:26][CH2:27][N:28]([CH2:29][CH3:30])[CH2:31][CH3:32])=[O:24])=[C:21]([O:36][CH2:38][CH2:39][CH2:40][N:41]2[C:45](=[O:46])[C:44]3=[CH:47][CH:48]=[CH:49][CH:50]=[C:43]3[C:42]2=[O:51])[CH:20]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a suspension of the tetra-n-butylammonium salt of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (15.8 g, 30 mmoles) (prepared in Preparation 3) in acetonitrile (50 ml) was added N-(3-bromopropyl)phthalimide and the mixture stirred for 16 hours at ambient temperature and 1 hour at 65°-70° C. This was concentrated in vacuo and the residue partitioned between water and a 1:1 mixture of ether and methylene chloride. The organic phase was washed several times with water, dried and concentrated to small volume causing crystallization. This was filtered and the solid washed with ether to give 12.3 g (86.7%) of the title product as white solid, mp. 141°-143°.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[OH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=1>>[OH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:28])=[CH:22][CH:21]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: O=C(Cc1ccc(O)cc1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(4-hydroxyphenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.30 (dd, J=7.9, 1.2 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.97-8.00 (m, 1H), 7.89-7.92 (m, 1H), 7.18 (s, 2H), 6.75 (d, 2H), 3.81-3.83 (m, 4H), 3.53 (s, 2H), 3.07-3.11 (m, 4H); MS (ESI−) M/Z 379 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.C([Sn](CCCC)(CCCC)[C:20]([O:22][CH2:23][CH3:24])=[CH2:21])CCC.[F-].[K+]>CN(C)C=O.O.CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:23]([O:22][C:20]([C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1)=[CH2:21])[CH3:24]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=C(OCC)c1nc(SC)ncc1C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (3.0 g, 12.89 mmol), tributyl(1-ethoxyvinyl)stannane (4.79 ml, 14.18 mmol) and bis(triphenylphosphine)palladium dichloride (0.452 g, 0.645 mmol) in N,N-dimethylformamide (43 mL) was heated to 70° C. for 1 hour. The mixture was cooled, treated with a solution of KF (1.5 g in 3 mL water) and stirred overnight at room temperature. The mixture was diluted with water and ether and filtered through diatomaceous earth. The layers were separated and the aqueous layer was extracted into ether. The combined extracts were rinsed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (0-20% gradient ethyl acetate in hexane) to provide the title compound. MS ESI(+) m/z 269.0 [M+H]+.
Reaction SMILES: [NH2:1][N+:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[OH:26][C:27]1[CH:34]=[C:33]([CH3:35])[C:30]([CH:31]=O)=[C:29]([CH3:36])[CH:28]=1.C(N(CC)CC)C>CO>[CH3:12][O:11][C:9]([C:4]1[CH:5]=[CH:6][C:7]2[N:2]([N:1]=[C:31]([C:30]3[C:33]([CH3:35])=[CH:34][C:27]([OH:26])=[CH:28][C:29]=3[CH3:36])[N:8]=2)[CH:3]=1)=[O:10]
Reactant: Cc1cc(O)cc(C)c1C=O
Reactant: COC(=O)c1ccc(N)[n+](N)c1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2nc(-c3c(C)cc(O)cc3C)nn2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 18 %

Procedure:
To a stirred solution of methyl 1,6-diaminopyridin-1-ium-3-carboxylate; 2,4,6-trimethylbenzenesulfonate (8 g, 21.68 mmol) in methanol (100 mL) is added 4-hydroxy-2,6-dimethyl-benzaldehyde (3.25 g, 21.68 mmol) and triethylamine (8.77 mL, 65.04 mmol) at 0° C. and the reaction mixture is stirred at room temperature for 48 hours. The reaction mixture is concentrated and extracted with EtOAc (100 mL). The combined organic extracts are washed with water (2×100 mL), saturated ammonium chloride solution (50 mL), brine solution (50 mL), and dried over anhydrous sodium sulphate, filtered, and evaporated to dryness. The crude material is purified by silica gel chromatography (combiflash 40 g redisep Rf column) and is eluted with 40-60% EtOAc in hexane to give the title compound as a pale yellow solid (1.2 g, 18%). LCMS m/z 298 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:7]([C:18](=[O:20])[NH2:19])[C:8]1[C:9]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:10]=2[S:11][CH:12]=1)([CH3:6])=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].CNCCNC.Br[CH:34]=[CH:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[C:38]([F:43])[CH:37]=1>[Cu]I.CN(C)C(=O)C>[CH2:1]([O:3][P:4]([CH:7]([C:8]1[C:9]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:10]=2[S:11][CH:12]=1)[C:18](=[O:20])[NH:19][CH:34]=[CH:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[C:38]([F:43])[CH:37]=1)([CH3:6])=[O:5])[CH3:2]
Reactant: Fc1ccc(C=CBr)cc1F
Reactant: CCOP(C)(=O)C(C(N)=O)c1csc2ccc(Cl)cc12
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Product: CCOP(C)(=O)C(C(=O)NC=Cc1ccc(F)c(F)c1)c1csc2ccc(Cl)cc12
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A 3 L 4-necked round-bottomed flask equipped with addition funnel, mechanical stirrer, nitrogen inlet, heating mantle and thermocouple was charged with [carbamoyl-(5-chloro-benzo[b]thiophen-3-yl)-methyl]-methyl-phosphinic acid ethyl ester (10.5 g, 0.03 mol), K2CO3 (8.0 g, 0.03 mol), N,N-dimethylacetamide (DMA) (40 mL, anhydrous 99.8%), N,N′-dimethyl-ethylenediamine (1.6 g, 0.018 mol) and copper (I) iodide (1.14 g, 0.006 mol) and the resulting mixture heated to about 80° C. under nitrogen. To the resulting mixture was then added 4-(2-bromo-vinyl)-1,2-difluoro-benzene (7.9 g, 0.036 mol) slowly, over a about 20 minutes, at 80° C. and the resulting mixture stirred at this temperature for about 5 hours. The resulting mixture was then quenched while hot with H2O (60 mL), and diluted with EtOAc (70 mL), added slowly through an addition funnel. The resulting biphasic mixture was cooled to 50-55° C. and at this temperature the layers were separated. The organic layer was washed with H2O (50 mL), 0.5N HCl aq.solution (50 mL) and brine (50 mL), then filtered and concentrated under reduced pressure to about half the original volume (35-40 mL). The concentrated solution was heated to slow reflux and then heptane (25 mL) was added slowly at this temperature. The resulting suspension was cooled to 5-10° C. over a period of 1 hr, diluted with additional heptane (10 mL) and aged at this temperature for about 2 hrs. The resulting solid precipitate was filtered, rinsed with cold heptane/EtOAc (4/1) solvent mixture (10 ml), and dried 55° C. in a vacuum oven overnight, to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[OH:12])([CH3:4])[CH3:3].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:25](O)=[O:26]>>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([CH:8]=[C:7]([CH3:11])[C:6]=1[OH:12])[CH:25]=[O:26])([CH3:1])[CH3:3]
Reactant: Cc1cccc(C(C)(C)C)c1O
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: Cc1cc(C=O)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, 76.65 g of 2-(1,1-dimethylethyl)-6-methylphenol (Aldrich), 65.42 g of hexamethylenetetramine and 700 ml of trifluoroacetic acid were stirred at reflux temperature for about 24 hours, then allowed to cool and evaporated. The residue from the evaporation was taken up in 1500 ml of water and 1000 ml of chloroform and neutralized to pH 7 with solid sodium carbonate. The resultant layers were separated and the aqueous layer was washed with chloroform. The organic layer was dried over sodium sulfate overnight, after which it was again washed with a volume of chloroform and evaporated. The resultant residue was then taken up in 375 ml of toluene, heated on a steam bath and then allowed to cool to room temperature overnight. Subsequent workup gave 28.3 g of the desired subtitled intermediate.