Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:11](Cl)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16](=[O:44])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]1[C@H:27]([CH:28]=[CH:29][Sn](CCCC)(CCCC)CCCC)[CH2:26][CH2:25][C:24]1=[O:43].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][O:15][C:16](=[O:44])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C@@H:23]1[C:24](=[O:43])[CH2:25][CH2:26][C@H:27]1[CH:28]=[CH:29][C:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[O:12]
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: CCCC[Sn](C=C[C@@H]1CCC(=O)[C@H]1CCCCCCC(=O)OC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)CCCCCC[C@@H]1C(=O)CC[C@H]1C=CC(=O)c1cccc2ccccc12
Temperature: 100 °C

Procedure:
A solution of tetrakis(triphenylphosphine)palladium(0) (97 mg, 0.084 mmol) in dry toluene (10 mL) was evacuated under vacuum and was purged with carbon monoxide (3×). Naphthalene-1-carbonyl chloride (320 mg, 1.68 mmol) was added followed by addition of trans-7-[2-oxo-5-(2-tributylstannanyl-vinyl)-cyclopentyl)-heptanoic acid methyl ester (the compound of Preparation 1, Step D, 1.0 g, 1.85 mmol) and 2,6-di-tert-butyl-4-methylphenol (few crystals). The mixture was heated at 100° C. under an atmosphere of carbon monoxide for 24 h. The mixture was cooled to room temperature, diluted with ethyl acetate, and the insolubles were removed by filtration through a pad of Celite®. The filtrate was washed with 10% aqueous ammonium hydroxide, dried (magnesium sulfate), filtered, and concentrated. Purification by flash chromatography (hexanes to 20% ethyl acetate in hexanes) provided the title compound of Step A (162 mg). 1H NMR (CDCl3, 250 MHz) d 8.31 (m, 1H), 8.00 (d, 1H), 7.91 (m, 1H), 7.70 (dd, 1H), 7.55 (m, 3H), 6.91-6.71 (m, 2H), 3.68 (s, 3H), 2.75 (m, 1H), 2.42-2.11 (m, 5H), 2.00 (m, 1H), 1.81-1.20 (m, 9H), 1.94 (t, 2H); MS 407 (M+1), 424 (M+18).
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[C:13](Cl)(Cl)=[O:14].Cl.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[C:29]([C:31]3[CH:40]=[C:39]4[C:34]([CH2:35][CH2:36][NH:37][CH2:38]4)=[CH:33][CH:32]=3)[N:28]=[C:27]([NH2:41])[N:26]=2)[CH2:21][CH2:20]1>>[NH2:41][C:27]1[N:28]=[C:29]([C:31]2[CH:40]=[C:39]3[C:34]([CH2:35][CH2:36][N:37]([C:13]([NH:10][C:9]4[CH:8]=[CH:7][C:6]([N:1]5[CH:5]=[CH:4][CH:3]=[N:2]5)=[CH:12][CH:11]=4)=[O:14])[CH2:38]3)=[CH:33][CH:32]=2)[CH:30]=[C:25]([N:22]2[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]2)[N:26]=1
Reactant: O=C(Cl)Cl
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: Nc1ccc(-n2cccn2)cc1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Nc3ccc(-n5cccn5)cc3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 40 starting from 4-(1H-pyrazol-1-yl)aniline (Maybridge, Cat. #CC 18414), phosgene and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=510.2.
Reaction SMILES: C(O[K])(C)(C)C.[C:7]12([CH2:17][NH:18][C:19]([C:21]3[C:22]4[N:23]([N:27]=[C:28]([CH2:30][OH:31])[CH:29]=4)[CH:24]=[CH:25][CH:26]=3)=[O:20])[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2.CN(C=O)C.Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>C1COCC1>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][O:31][CH2:30][C:28]1[CH:29]=[C:22]2[C:21]([C:19](=[O:20])[NH:18][CH2:17][C:7]34[CH2:8][CH:9]5[CH2:10][CH:11]([CH2:12][CH:13]([CH2:15]5)[CH2:14]3)[CH2:16]4)=[CH:26][CH:25]=[CH:24][N:23]2[N:27]=1)[CH3:43]
Reactant: CCOC(=O)CBr
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cccn2nc(CO)cc12
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)COCc1cc2c(C(=O)NCC34CC5CC(CC(C5)C3)C4)cccn2n1
Reaction time: 0.08 h

Procedure:
A 1.0 M solution of tBuOK in THF (0.3 mL) is added to a mixture of 2-hydroxymethyl-pyrazolo[1,5-a]pyridine-4-carboxylic acid (adamantan-1-ylmethyl)amide (73 mg, 210 μmol) and DMF (1 mL) at 0° C. under N2. After 5 min, ethyl bromoacetate (30 μL, 280 μmol) is added. The cold bath is removed and the mixture is left to stir for 23 h. 50% Sat. aq. NaHCO3 is added and the solution is extracted with EtOAc (20 mL). The organics are dried over Na2SO4, filtered and concentrated. Purification by PTLC (2:1 EtOAc:hexanes) affords the title compound as a pale yellow film. 1H NMR (400 MHz, CDCl3) δ: 8.50 (dd, 1H), 7.57 (d, 1H), 6.88 (s, 1H), 6.81 (dt, 1H), 6.27 (bs, 1H), 4.88 (s, 2H), 4.22 (q, 2H), 4.19 (s, 2H), 3.21 (d, 2H), 1.94-2.04 (m, 3H), 1.56-1.78 (m, 12H), 1.28 (t, 3H). LC-MS m/z (M+H+): 426.3; RT=1.31.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[CH2:18][CH2:19]O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[ClH:3].[CH2:5]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[CH2:18][CH2:19][Cl:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCCC1CCCCN1Cc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cl
Product: ClCCC1CCCCN1Cc1ccccc1

Procedure:
Thionyl chloride (10 ml) was added to a solution of 1-benzyl-2-(2-hydroxyethyl)piperidine (11.64 g, 50 mmol) (Annalen, 1898, 301, 117) in chloroform (150 ml) and the mixture heated under reflux for 45 minutes and evaporated to give crude 1-benzyl-2-(2-chloroethyl)piperidine hydrochloride (16.14 g). A portion of the crude product (6.85 g, 25 mmol) was partitioned between ethyl acetate and 10% aqueous sodium carbonate solution and the organic layer was dried over magnesium sulphate and evaporated. Sodium hydride (2.2 g, 55 mmol; 60% dispersion in oil) was added to a solution of diphenylacetonitrile (9.66 g, 50 mmol) in toluene (100 ml) and the mixture heated at reflux for 1.75 hours, treated with a solution of the above crude residue in toluene (20 ml) and the mixture heated under reflux for 3 hours, allowed to cool to room temperature, washed with water, dried over magnesium sulphate and evaporated. The residue was dissolved in ether and the solution treated with excess ethereal oxalic acid. The resulting precipitate was collected, washed with ether, dried and recrystallised from acetonitrile/ether to give the title compound (5.37 g, 37%) as colourless crystals, m.p. 117°-120° C., which were characterised as a hemihydrate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([F:37])[CH:30]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][N:25]([S:46]([CH3:45])(=[O:48])=[O:47])[CH2:26][CH2:27]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([F:37])[CH:30]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCNCC4)cc3C2=O)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCN(S(C)(=O)=O)CC4)cc3C2=O)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a solution of 3-(3,5-difluorophenyl)-2-(3-fluoro-4-methoxyphenyl)-6-(3-(piperazin-1-yl)propoxy)-1H-inden-1-one (70 mg, 1.2 eq, 0.1 mmol) obtained in Step 2 in CH2Cl2 at 0° C. was added triethylamine (1.5 eq) and methylsulfonyl chloride (1.0 eq). The mixture was stirred for 1 h at room temperature and diluted with CH2Cl2. The mixture was washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexanes=1:1) to obtain the title compound (47%).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[C:26]1(B(O)O)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>O1CCOCC1.O>[C:34]1([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=2)[C:35]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccc(COc2ccc(-c3cccc4ccccc34)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of intermediate 1; 74 mg, 0.2 mmol) in dioxane/water (10:1, 4.4 mL) was degassed for 20 min and then added to a reaction vial containing potassium carbonate (82 mg, 0.6 mmol) and 1-naphthaleneboronic acid (0.6 mmol; available from Aldrich Chemical Company, Inc., Milwaukee, Wis.). The solution was degassed for a further 2 min and then bis(tri-cyclohexylphosphine)palladium (available from Strem Chemicals, Inc., Newburyport, Mass.; 14 mg, 0.02 mmol) was added. The mixture was degassed for 30 seconds and then heated in a microwave oven at 170 degrees for 25 min. The reaction mixture was filtered through silica and the silica washed with dioxane (1 mL), dimethylacetamide (1 mL), and 20% methanol in dichloromethane (1 mL). The filtrate was placed in a vial and 2 M potassium hydroxide solution (0.4 mL) was added. The mixture was stirred at room temperature overnight, and then 1 M HCl was added until a solid formed (approxiamtely 2 mL). The vial was centrifuged and the solvent was removed. The product was dried overnight in the oven to give 3-(4-naphthalen-1-yl-phenoxymethyl)-benzoic acid. Mass spectrum MH+=355.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Cl[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]>[OH-].[K+]>[OH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: OCCCCCCCl
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1ccc(OCCCCCCO)cc1
Temperature: 60 °C
Yield: 80 %

Procedure:
Monomers in which the bulky organic group was a t-butyl group and the alkyl groups were hexyl groups were made as follows. 4-hydroxybenzoic acid was dissolved in 30% ethanolic KOH. About 1% of KI was added as a catalyst. The mixture was heated to about 60° C. and a stoichiometric amount of 6-chloro-1-hexanol was slowly added over about ½ hour. After refluxing the reaction mixture for extended period of time (2-15 hrs) the contents was cooled, the reaction mixture was filtered off, and the filtrate solvent was evaporated under vacuum. Water was added into the residue and acidified with HCl and the precipitate was filtered and crystallized with ethanol, yielding approximately an 80% 4-(6-hydroxyhexyloxy)-benzoic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17]C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
A solution of 4.4 g 4-tert-butoxycarbonylamino-piperidine-1-carboxylic acid benzyl ester in 90 ml dichloromethane was stirred in the presence of 10 ml TFA for 3 h. The product was obtained after evaporation of the solvent and used without further purification.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11](=[O:17])[CH2:12][CH2:13][C:14](O)=[O:15].Cl>O>[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11](=[O:17])[CH2:12][CH2:13][C:14](=[N:2][OH:3])[OH:15]
Reactant: NO
Reactant: O=C(O)CCC(=O)c1cccs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(CCC(O)=NO)c1cccs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 22.6 g. of hydroxylamine hydrochloride and 26 g. of NaOH in 300 ml. of water is stirred and 30 g. of 4-(2-thienyl)-4-oxobutyric acid is added to afford a clear yellow solution. The mixture is stirred for two hours at room temperature and acidified with 3N HCl to pH 2 to give a white precipitate. After stirring an additional half hour, the mixture is cooled in ice and filtered. The filter cake is washed with water and dried to afford the title compound, m.p. 133°-138° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: Nc1ccccc1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.7 ml of chloroacetyl chloride was dropwise added to a solution of 3.0 g of aniline hydrochloride and 7 ml of triethylamine in 30 ml of dichloromethane. The mixture was stirred at room temperature for 3 hours, then washed with water and a saturated aqueous sodium hydrogencarbonate solution in this order, and dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was crystallized from ethyl acetate-n-hexane to obtain 2.45 g of N-(2-chloroacetyl)aniline as a light brown solid. A suspension of 2.45 g of the N-(2-chloroacetyl)-aniline, 2.8 g of 4-methoxymethoxypiperidine, 2.45 g of sodium iodide and 2.3 ml of triethylamine dissolved in 30 ml of acetonitrile was refluxed for 1.5 hours. The reaction mixture was diluted with ethyl acetate. The dilution was washed with water and dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was purified by a silica gel column chromatography (eluant: ethyl acetate: n-hexane=1:1) to obtain 3.64 g of 1-(anilinocarbonylmethyl)-4-methoxymethoxypiperidine as a light yellow oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:10][C:9]=2[O:23][CH3:24])[CH:5]=[CH:4][CH:3]=1.[CH3:25]OC1C=C(C2OC3C=CC=CC=3N=2)C=CC=1B1OC(C)(C)C(C)(C)O1.BrC1C=CC(C)=CN=1>>[CH3:24][O:23][C:9]1[CH:10]=[C:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:12]=[CH:13][C:8]=1[C:6]1[C:5]([CH3:25])=[CH:4][CH:3]=[CH:2][N:7]=1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1-c1cccc(Br)n1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1B1OC(C)(C)C(C)(C)O1
Agent: Cc1ccc(Br)nc1
Product: COc1cc(-c2nc3ccccc3o2)ccc1-c1ncccc1C

Procedure:
Utilizing the general procedure outlined in the synthesis of 2-[4-(6-bromopyridin-2-yl)-3-methoxyphenyl]-1,3-benzoxazole, 2-[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazole (150 mg, 0.43 mmol) was reacted with 2-bromo-5-methylpyridine (73 mg, 0.43 mmol) to afford the desired 2-[3-methoxy-4-(3-methylpyridin-2-yl)phenyl]-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 8.60–8.58 (d, 1H), 7.96–7.90 (m, 3H), 7.80–7.79 (m, 1H), 7.70 (s, 1H), 7.62–7.60 (m, 1H), 7.39–7.36 (m, 2H), 7.10–7.08 (m, 1H), 4.01(s, 3H), 2.43 (s, 3H). MS (ESI) 317 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][N:23]([CH:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1)[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1>C(Cl)Cl.CO>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:30][C:27]2[CH:26]=[CH:25][C:24]([N:23]([CH3:22])[CH:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)=[CH:29][CH:28]=2)=[N:3][CH:4]=1
Reactant: CN1CCC(N(C)c2ccc(N)cc2)CC1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(N(C)c2ccc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N(C)C)n3)cc2)CC1
Yield: 34 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-((2,5-dichloropyrimidin-4-yl)amino)-N,N-dimethylbenzenesulfonamide and N1-methyl-N1-(1-methylpiperidin-4-yl)benzene-1,4-diamine in 34% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 9.45 (s, 1H), 8.60 (d, 1H, J=8.2 Hz), 8.06 (s, 1H), 8.18 (d, 1H, J=8.0 Hz), 7.47 (t, 1H, J=7.7 Hz), 7.31 (d, 2H, J=8.9 Hz), 7.16 (t, 1H, J=7.5 Hz), 6.77 (d, 2H, J=8.9 Hz), 3.51 (tt, 1H, J=11.3, 3.8 Hz), 3.00 (d, 2H, J=10.6 Hz), 2.76 (s, 3H), 2.72 (s, 3H), 2.34 (s, 3H), 2.11 (t, 2H, J=10.2 Hz), 1.90 (q, 2H, J=11.3 Hz), 1.73 (d, 2H, J=12.0 Hz); MS (ESI): 530.3 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][OH:29])=[CH:22][CH:21]=1>C(O)(C)C>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][CH2:28][OH:29])=[CH:24][CH:25]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(CCCO)cc1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Agent: Cl
Solvent: CC(C)O
Product: OCCCc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Yield: 16.1 %

Procedure:
Following general procedure A2, employing iso-propanol as the solvent, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.100 g, 0.33 mmol) was reacted with 3-(4-aminophenyl)propan-1-ol (0.075 g, 0.50 mmol), followed by formation of the hydrochloride salt to afford the title compound (0.022 g, 16%) as an off-white solid. MW=415.36. 1H NMR (DMSO-d6, 500 MHz) δ 14.00 (s, 1H), 9.74 (s, 1H), 7.89 (t, J=2.0 Hz, 1H), 7.71-7.64 (m, 2H), 7.62-7.57 (m, 1H), 7.32 (s, 4H), 6.98 (s, 1H), 3.43 (t, J=6.4 Hz, 2H), 3.15 (t, J=7.7 Hz, 2H), 2.91 (q, J=7.2 Hz, 2H), 2.67-2.63 (m, 2H), 2.24 (quin, J=7.5 Hz, 2H), 1.77-1.71 (m, 2H); APCI MS m/z 379 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]2[CH2:15][N:14]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[C:13](=[O:27])[N:12]2[CH3:28])=[CH:4][CH:3]=1.Br[C:30]([CH3:37])([CH2:34][CH2:35][CH3:36])[C:31]([OH:33])=[O:32].[CH3:38][C:39](C)([O-])C.[K+].OS(O)(=O)=O>CC(O)(C)C.CCO>[CH2:38]([O:33][C:31](=[O:32])[C:30]([CH3:37])([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]2[CH2:15][N:14]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[C:13](=[O:27])[N:12]2[CH3:28])=[CH:4][CH:3]=1)[CH2:34][CH2:35][CH3:36])[CH3:39]
Reactant: CN1C(=O)N(Cc2ccc(C(F)(F)F)cc2)CC1CCCc1ccc(O)cc1
Reactant: CC(C)(C)[O-]
Reactant: CCCC(C)(Br)C(=O)O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCO
Solvent: CC(C)(C)O
Product: CCCC(C)(Oc1ccc(CCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1)C(=O)OCC
Temperature: 45 °C
Reaction time: 0.67 h
Yield: 71 %

Procedure:
A mixture of 4-[3-(4-hydroxy-phenyl)-propyl]-3-methyl-1-(4-trifluoromethyl-benzyl)-imidazolidin-2-one (0.51 g, 1.30 mmol) and 2-bromo-2-methyl-pentanoic acid (2.54 g, 13.0 mmol) in 2-methyl-2-propanol (10 mL) was heated to 45° C. under N2 and then a solution of 1 M potassium tert-butoxide in 2-methyl-2-propanol (27.3 mL, 27.3 mmol) was added dropwise and the reaction was stirred at 45° C. for 40 minutes. The reaction mixture was cooled and quenched with 1 N HCl (50 mL). The mixture was then diluted with water and extracted with Et2O. The organic layer was dried (Na2SO4) and the solvent removed in vacuo to afford crude product that was combined with EtOH (50 mL) and conc. H2SO4 (6 mL). The mixture was heated to reflux for 3 h. The reaction mixture was cooled and the solvent removed in vacuo. The residue was diluted with water and extracted with EtOAc and the organic layer was dried (Na2SO4). The solvent was removed in vacuo to give crude product that was purified by flash chromatography using 5:1 hexanes:acetone to afford 0.491 g (71%) 2-methyl-2-(4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenoxy)-pentanoic acid ethyl ester. This material could be purified by chiral preparative HPLC (conditions,) 1H NMR. MS (ES+) m/z calcd for C29H38N2O4F3 [M+1] 535. Found 535 (100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([C:10]1[N:11]([CH3:22])[S:12](=[O:21])(=[O:20])[C:13]2[CH:19]=[CH:18][S:17][C:14]=2[C:15]=1[OH:16])=[O:9].C(N(CC)CC)C.[C:30](Cl)([Cl:32])=[O:31]>C1(C)C=CC=CC=1>[ClH:32].[CH3:22][N:11]1[C:10]2[C:8](=[O:9])[N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[C:30](=[O:31])[O:16][C:15]=2[C:14]2[S:17][CH:18]=[CH:19][C:13]=2[S:12]1(=[O:21])=[O:20]
Reactant: O=C(Cl)Cl
Reactant: CN1C(C(=O)Nc2ccccn2)=C(O)c2sccc2S1(=O)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN1c2c(oc(=O)n(-c3ccccn3)c2=O)-c2sccc2S1(=O)=O
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3.37 g. (10 mmole) N-(2-pyridyl)-4-hydroxy-2-methyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide (tenoxicam) in 150 ml. toluene under nitrogen is added 1.01 g. (10 mmole) triethylamine and the mixture is cooled to 0° C. The cold solution is then added dropwise to a solution of 1.0 g. (10 mmole) phosgene in 50 ml. toluene at -70° C. over 45 minutes and stirring is continued at -70° to -60° C. for an additional 30 minutes. The reaction mixture is allowed to warm to room temperature and stirred for an hour. The solvent is evaporated in vacuo, the residue triturated with acetone and filtered to obtain the desired product which is purified by recrystallization, e.g., from acetine, ethanol or chloroform.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:22])=[N:4][CH:5]=[C:6]([C:12]=1[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[C:7](OCC)=[O:8].C([NH2:25])=O.CC[O-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[C:3]([Cl:22])=[N:4][CH:5]=[C:6]([C:12]=1[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[C:7]([NH2:25])=[O:8]
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1NCc1cccc(F)c1
Reactant: NC=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cnc(Cl)c(Cl)c1NCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
To a solution of ethyl 5,6-dichloro-4-(3-fluorobenzylamino)nicotinate (260 mg, 0.76 mmol) in DMF (1 mL) was added HCONH2 (0.272 mL, 6.84 mmol) and NaOEt (21% in EtOH, 0.425 mL, 1.14 mmol). After stirring at room temperature for 30 min, the mixture was added water, and the precipitate was collected by filtration to give 5,6-dichloro-4-(3-fluorobenzylamino)nicotinamide (170 mg).