Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C@H:6]2[C:33](=[O:34])[N:32]3[CH2:35][C@@H:29]([CH2:30][C@H:31]3[C:36]([NH:38][C@:39]3([C:44](=[O:52])[NH:45][S:46]([CH:49]4[CH2:51][CH2:50]4)(=[O:48])=[O:47])[CH2:41][C@H:40]3[CH:42]=[CH2:43])=[O:37])[O:28][C:18]3=[N:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:26]([OH:27])=[C:17]3[CH2:16][CH:15]=[CH:14][CH2:13][CH2:12][C@@H:11]3[CH2:53][CH2:54][CH2:55][C@H:10]3[O:9][C:8](=[O:56])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:57]([N:60]=[C:61]=[O:62])([CH3:59])[CH3:58]>ClC(Cl)C.CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[CH3:58][CH:57]([NH:60][C:61](=[O:62])[O:27][C:26]1[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:19]=[C:18]2[O:28][C@H:29]3[CH2:35][N:32]([C:33](=[O:34])[C@H:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[NH:7][C:8](=[O:56])[O:9][C@@H:10]4[CH2:55][CH2:54][CH2:53][C@H:11]4[CH2:12][CH2:13][CH:14]=[CH:15][CH2:16][C:17]=12)[C@H:31]([C:36](=[O:37])[NH:38][C@:39]1([C:44](=[O:52])[NH:45][S:46]([CH:49]2[CH2:50][CH2:51]2)(=[O:47])=[O:48])[CH2:41][C@H:40]1[CH:42]=[CH2:43])[CH2:30]3)[CH3:59]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCC=CCc1c(nc3ccccc3c1O)O2)C(=O)NS(=O)(=O)C1CC1
Reactant: CC(C)N=C=O
Agent: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CC/C=C/Cc1c(nc3ccccc3c1O)O2)C(=O)NS(=O)(=O)C1CC1
Agent: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CC/C=C/Cc1c(nc3ccccc3c1OC(=O)NC(C)C)O2)C(=O)NS(=O)(=O)C1CC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(Cl)Cl
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCC=CCc1c(nc3ccccc3c1OC(=O)NC(C)C)O2)C(=O)NS(=O)(=O)C1CC1
Temperature: 50 °C

Procedure:
To a solution of (3aR,7S,10S,12R,21E,24aS)-7-cyclopentyl-N-{(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-19-hydroxy-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,23,24,24a-tetradecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-10-carboxamide (Example 17) (30 mg) in dichloroethane (0.6 mL) was added isopropylisocyanate (0.037 mL) then DMAP (4.6 mg). The reaction mixture was heated to 50° C. for 1 hour. After cooling back to room temperature, the mixture was diluted with ethyl acetate and water was added. The mixture was extracted with ethyl acetate (3×). The combined organics were dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase HPLC (40% ACN-100% ACN/0.05% TFA/water) yielded 27 mg of the desired product after workup with NaHCO3 and ethyl acetate. HRMS (ES+) m/z 875.3981 (M+H)+.
Reaction SMILES: C([NH:5][C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:9]=[C:8]([C:18]2[CH:19]=[N:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([N:32]4[CH2:37][CH2:36][N:35]([CH:38]([CH3:40])[CH3:39])[CH2:34][CH2:33]4)=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)[CH:7]=1)(C)(C)C.N1(C=O)CCNCC1>>[NH2:5][C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:9]=[C:8]([C:18]2[CH:19]=[N:20][CH:21]=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([N:32]4[CH2:37][CH2:36][N:35]([CH:38]([CH3:40])[CH3:39])[CH2:34][CH2:33]4)=[O:31])=[CH:28][CH:29]=3)[CH:23]=2)[CH:7]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc(-c3cncc(-c4cc(NC(C)(C)C)nc(-c5ccccn5)c4)c3)cc2)CC1
Agent: O=CN1CCNCC1
Product: CC(C)N1CCN(C(=O)c2ccc(-c3cncc(-c4cc(N)nc(-c5ccccn5)c4)c3)cc2)CC1

Procedure:
This compound is prepared from [4-(6′-tert-Butylamino-[2,2′;4′,3″]terpyridin-5″-yl)-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone (Example 2.73) analogously to 4-(6′-Amino-[2,2′;4′,3″]terpyridin-5″-yl)-phenyl]-piperazin-1-yl-methanone (Example 2.50).
Reaction SMILES: [OH-].[Na+].C(O)C[OH:5].[Cl:7][C:8]1[C:9]([Cl:21])=[C:10]([Cl:20])[C:11]([Cl:19])=[C:12]2[C:17](=[O:18])[O:16][C:14](=[O:15])[C:13]=12>O>[Cl:7][C:8]1[C:9]([Cl:21])=[C:10]([Cl:20])[C:11]([Cl:19])=[C:12]([C:17]([OH:16])=[O:18])[C:13]=1[C:14]([OH:5])=[O:15]
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: OCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C(=O)O
Reaction time: 0.33 h

Procedure:
A 20 g quantity of sodium hydroxide was dissolved in 1000 g of water, and 200 g of ethylene glycol was added to the solution. Subsequently, 143 g of tetrachlorophthalic anhydride was added to the mixture, and the resulting mixture was heated to 95° to 98° C. to obtain a solution. A 122.5 g quantity of 40% aqueous solution of Cr2 (SO4)3 was diluted with 200 g of water and then added dropwise to the obtained solution at the same temperature, over a period of 40 minutes. The resulting mixture was thereafter stirred for 20 minutes, and provided a grayish green precipitate. Subsequently, 10% aqueous solution of sodium hydroxide was added dropwise to the reaction mixture to adjust the pH thereof to about 3. About 13 g of sodium hydroxide was so used. The mixture was further stirred for 2 hours, then cooled and filtered at about 50° C. The resulting reaction product was washed with water and dried, giving 140 g of Cr complex compound of tetrachlorophthalic acid. This complex compound was found to have good thermal stability (as tested at temperatures of below 350° C. in the same manner as described in Example 1).
Reaction SMILES: [SH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH2:16]([C:18]([CH2:25]OS(C)(=O)=O)([CH2:21][CH2:22][CH2:23][CH3:24])[CH:19]=[O:20])[CH3:17].C(N(CC)CC)C.Cl>COCCOCCOC>[C:4]([C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[S:1][CH2:25][C:18]([CH2:16][CH3:17])([CH2:21][CH2:22][CH2:23][CH3:24])[CH:19]=[O:20])(=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccccc1S
Reactant: CCCCC(C=O)(CC)COS(C)(=O)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: COCCOCCOC
Product: CCCCC(C=O)(CC)CSc1ccccc1C(=O)c1ccccc1
Yield: 57.8 %

Procedure:
A mixture of 31 g (0.144 mol) of 2-mercaptobenzophenone, prepared according to the procedure described in WO 93/16055, 24.4 g (0.1 mole) of 2-ethyl-2-(mesyloxymethyl)-hexanal (1), 14.8 g (0.146 mole) of triethylamine, and 80 mL of 2-methoxyethyl ether was held at reflux for 24 h. The reaction mixture was poured into 3N HCl and extracted with 300 mL of methylene chloride. The methylene chloride layer was washed with 300 mL of 10% NaOH, dried over MgSO4 and concentrated in vacuo to remove 2-methoxyethyl ether. The residue was purified by HPLC (10% EtOAc-hexane) to give 20.5 g (58%) of 2 as an oil.
Reaction SMILES: [CH2:1]([NH2:7])[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.Cl[CH2:9][CH2:10][N:11]([CH2:34][CH2:35]Cl)[C:12]1[CH:32]=[C:31]([Cl:33])[C:15]2[O:16][C:17]3[C:26]([CH3:27])=[CH:25][C:24]([C:28]([OH:30])=[O:29])=[CH:23][C:18]=3[S:19](=[O:22])(=[O:21])[CH2:20][C:14]=2[CH:13]=1.[CH3:37]O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:37][O:30][C:28]([C:24]1[CH:25]=[C:26]([CH3:27])[C:17]2[O:16][C:15]3[C:31]([Cl:33])=[CH:32][C:12]([N:11]4[CH2:10][CH2:9][N:7]([CH2:1][CH:2]5[CH2:3][CH2:4][CH2:5][O:6]5)[CH2:35][CH2:34]4)=[CH:13][C:14]=3[CH2:20][S:19](=[O:22])(=[O:21])[C:18]=2[CH:23]=1)=[O:29]
Reactant: NCC1CCCO1
Reactant: CO
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N(CCCl)CCCl)cc1CS2(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(CC4CCCO4)CC3)cc(Cl)c1O2
Temperature: 110 °C

Procedure:
Tetrahydrofurfurylamine (0.776 mL, 7.5 mmol) was added to a mixture of Example 102j (0.6 g, 1.25 mmol) and tetrabutylammonium iodide (0.004 g) in methanol (5 mL), under argon, in a pressure reactor vessel heated at 110° C. for 5 h. The reaction mixture was cooled, concentrated, treated with methanolic HCl (15 mL) and refluxed for 4 h. The reaction mixture was cooled, concentrated and extracted with n-butanol. The organic layer was washed with water, brine, dried, concentrated and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound as an off-white solid. Yield: 0.332 g, (51%); 1H NMR (DMSO-d6): δ 1.5 (m, 2H, CH2), 1.78 (m, 2H, CH2), 1.92 (m, 2H, CH2), 2.67 (s, 3H, CH3), 3.19 (t, 4H, 2CH2), 3.63 (q, 1H, CH2), 3.78 (q, 1H, CH2), 3.9 (s, 3H, OCH3), 3.99 (m, 2H, CH2), 5.17 (s, 2H, CH2), 7.6 (d, 1H, Ar), 7.15 (d, 1H, Ar), 8.11 (s, 1H, Ar), 8.16 (s, 1H, Ar); MS: m/e (ES+) 522 (M+1).
Reaction SMILES: [OH-].[K+].C([O:7][C:8](=[O:23])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])(C)(C)C.Cl>O.CO>[OH:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([OH:23])=[O:7]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCCCCCCCCCO
Temperature: 25 °C

Procedure:
A solution of potassium hydroxide (8.60 g, 153 mmol) in water (100 mL) was added to a solution of the above ester (9.20 g, 30.6 mmol) in methanol (100 mL) and the resulting mixture was heated at 60 C for 2 days. The mixture was cooled to room temperature; then it was washed with hexanes (2×70 mL) and concentrated in vacuo. Concentrated hydrochloric acid (32%, 20 mL, 0.65 mol) was added dropwise and the mixture was extracted with ethyl acetate (2×150 mL). The combined organic layers were dried over anhydrous magnesium sulfate and evaporated to dryness to yield 14-hydroxy-tetradecanoic acid as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][NH2:22]>[OH-].[Na+]>[ClH:15].[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][NH:22][CH3:21])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Product: CNCCCN1CCc2cc(OC)c(OC)cc2CC1=O
Product: Cl

Procedure:
First, 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloro-propane (5.9 g, 0.020 mol) and methylamine (14 g, 0.45 mol) are heated to 130° C. for 1 hour in a sealed tube. Then, the cooled reaction product is taken up in semi-concentrated sodium hydroxide solution and extracted with methylene chloride. After the extract has been dried and concentrated, the hydrochloride is precipitated from acetone/ether with ethereal hydrochloric acid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>>[N:10]1([C:2]2[N:3]=[C:4]([N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:5]=[C:6]([Cl:8])[N:7]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: C1CCNC1
Product: Clc1cc(N2CCCC2)nc(N2CCCC2)n1
Yield: 74 %

Procedure:
U.S. Pat. No. 4,996,318 discloses that treatment of 2,4,6-trichloropyrimidine (I) with pyrrolidine (II) at 20°-25° for 4 hrs gives 2,4-di(1-pyrrolidinyl)-6-chloropyrimidine (III) in 74.0% yield. The yield of 4,6-di(1-pyrrolidinyl)-2-chloropyrimidine (IV) was not disclosed.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]=O.S(=O)(=O)(O)O.[NH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][C:17]([C:25]#[N:26])=[C:16]2[NH:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]([Cl:35])[CH:29]=1.[BH4-].[Na+]>O1CCCC1.CN(C)C=O.O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][C:17]([C:25]#[N:26])=[C:16]2[NH:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]([Cl:35])[CH:29]=1
Reactant: O=CCCCCl
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1N
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NCCCCCl
Reaction time: 2 h

Procedure:
To a solution of 1.12 g of 4-chlorobutanal and 5.3 ml of 3M sulfuric acid in 11 ml of tetrahydrofuran, at 0° C., was added an solution of 2.0 g of 6-amino-4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-3-quinolinecarbonitrile in 40 ml of dimethylforamide. To this was added portionwise 0.4 g of sodium borohydride. After 1 hr another 1.0 g of aldehyde, 10 ml of dimethylforamide, and 5 ml of 3M sulfuric acid was added followed by the portionwise addition of 0.8 g of sodium borohydride. After 2 hrs, the mixture was poured into water and the Ph was adjusted to 9. The mixture was extracted with ethyl acetate several times. The organic solution was dried over magnesium sulfate and the solvent was removed giving the title compound as an oil which was used without additional purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6](N)=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.N(OS(=O)(=O)O)=[O:15]>C(Cl)Cl.O>[Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:15])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: O=NOS(=O)(=O)O
Reactant: COc1cc(Br)cc(C)c1C(N)=O
Solvent: ClCCl
Solvent: O
Product: COc1cc(Br)cc(C)c1C(=O)O
Reaction time: 2 h
Yield: 96 %

Procedure:
4-Bromo-2-methoxy-6-methylbenzamide (2.0 g, 8.2 mmol), dissolved in CH2Cl2, was added dropwise to nitrosyl sulfuric acid (14.0 mL) in water (6.0 mL) at 0° C. and stirred for 2 hours. The reaction mixture was poured over ice and extracted with CH2Cl2, and the solvent was removed under reduced pressure to afford a light pink solid (1.93 g, 96%). 1H NMR (300 MHz, CDCl3): δ 7.07 (s, 1H), 7.00 (s, 1H), 3.93 (s, 3H), 2.46 (s, 3H).
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].[CH3:5][O-:6].[Na+].[Br:8][C:9]1[CH:10]=[C:11]2C(=[CH:17][CH:18]=1)O[CH:14]([C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1)[CH2:13]/[C:12]/2=[N:30]\[C:31]#[N:32]>CO>[Br:8][C:9]1[CH:10]=[C:11]2[C:12]3([O:4][N:3]([CH3:2])[C:31]([NH2:32])=[N:30]3)[CH2:13][CH:14]([C:19]3[CH:20]=[CH:21][C:22]([O:25][C:26]([F:27])([F:28])[F:29])=[CH:23][CH:24]=3)[O:6][C:5]2=[CH:17][CH:18]=1
Reactant: C[O-]
Reactant: N#C/N=C1\CC(c2ccc(OC(F)(F)F)cc2)Oc2ccc(Br)cc21
Reactant: CNO
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1OC2(CC(c3ccc(OC(F)(F)F)cc3)Oc3ccc(Br)cc32)N=C1N
Reaction time: 0.17 h
Yield: 21.4 %

Procedure:
To a solution of methylhydroxylamine HCl salt (110 mg, 1.317 mmol) in anhydrous MeOH (15 mL) was added NaOMe (25 w % in MeOH, 0.23 mL, 1.02 mmol), followed by (E)-N-(6-bromo-2-(4-(trifluoromethoxy)phenyl)chroman-4-ylidene)cyanamide (540 mg, 1.32 mmol). After stirring for 10 min, the solvent was removed in vacuo. The residue was redissolved in DCM (20 mL). The mixture was filtered and the solvent was removed in vacuo, which was purified by preparative TLC to give 50 mg crude product of 6-bromo-2′-methyl-2-(4-(trifluoromethoxy)phenyl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (100 mg, 20%).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])([OH:3])=[O:2].ClC(Cl)(Cl)C(=N)O[C:19]([CH3:22])([CH3:21])[CH3:20].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>ClCCl.C1CCCCC1>[C:5]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:5]=1[CH2:4][C:1]([O:3][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:2])([CH3:13])([CH3:6])[CH3:4]
Reactant: Cc1ccc(CC(=O)O)c(C(=O)O)c1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCCCC1
Product: Cc1ccc(CC(=O)OC(C)(C)C)c(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 166.7 %

Procedure:
To a suspension of 2-carboxymethyl-5-methyl-benzoic acid (2.544 g, 13.1 mmol) in anhydrous dichloromethane (70 ml) held at 0° C. was added tert-butyl 2,2,2-trichloroacetimidate (11.47 mg, 52.4 mmol, 2 equivalents) in cyclohexane (85 ml). BBr3 (0.52 ml) was then added, and the reaction mixture was raised to room temperature and stirred for 16 hr. Solid NaHCO3 was added to quench the reaction, the solid precipitate was filtered off and washed with ether. The combined organic washing was evaporated to dryness, and the residue obtained was purified by silica gel chromatography to obtain 2-tert-butoxycarbonylmethyl-5-methyl benzoic acid tert-butyl ester 3.345 g (83.3%) as an oil. 1H NMR (CDCl3): 7.718 (1H, s), 7.227 (1H, d, J=7.57 Hz), 3.910 (2H, s), 2.362 (3H, s), 1.584 (9H, s), 1.443 (9H, s). FABMS (+Ve) m/z 307 [MH+], 251 [MH+—C4H8], 195 [MH30 —2C4H4]. Anal. calcd. for C18H26O4: C, 70.6; H, 8.6. Found: C, 70.82; H, 8.53.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N+:15]([O-:17])=[O:16])=[CH:6][C:7]([N+:12]([O-])=O)=[C:8]([CH:11]=2)[CH:9]=O)[CH2:3][CH2:2]1.[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCO.C(Cl)Cl>[CH:1]1([C:4]2[C:5]([N+:15]([O-:17])=[O:16])=[CH:6][C:7]3[C:8](=[CH:9][N:25]([C:22]4[CH:21]=[CH:20][C:19]([CH3:18])=[CH:24][N:23]=4)[N:12]=3)[CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1cc(C2CC2)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: Cc1ccc(N)nc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCO
Product: Cc1ccc(-n2cc3cc(C4CC4)c([N+](=O)[O-])cc3n2)nc1
Temperature: 100 °C
Yield: 43.3 %

Procedure:
To a stirred solution of (iv) (50 mg, 0.212 mmol) in EtOH (750 mL) was added 5-methylpyridin-2-amine (25 mg, 0.23 mmol) and the resultant solution stirred at RT for 2d, after which time a solid precipitated from solution. Triphenylphosphine (167 mg, 0.64 mmol) was added in a single portion and the reaction then heated at 100° C. in a sealed tube for 4 h. Upon cooling to RT, the reaction mixture was diluted with DCM (2 mL) and the organics were washed with aq. 30% hydrogen peroxide solution (2 mL). The organics were separated and filtered through a plug of MgSO4 and then purified by automated column chromatography (Biotage SP4, Grace 4 g silica cartridge) eluting with EtOAc:n-heptane (gradient elution, 0% equil. (2 CV), 0% (1 CV), 0 to 100% (35 CV), 100% (5 CV)) to give (v) (27 mg, 43%). ESI-MS: calculated [M+H]+ 295.1, observed [M+H]+ 295.2.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]1([Se]Cl)C=CC=CC=1.OO>>[CH3:14][CH:8]1[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1.[C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl[Se]c1ccccc1
Reactant: O=C1CCC(c2ccccc2)CC1
Agent: OO
Product: CC1CC(=O)CCC1c1ccccc1
Product: O=C1C=CC(c2ccccc2)CC1

Procedure:
The intermediate 3-methyl-4-phenylcyclohexanone is prepared, first by the reaction of 4-phenylcyclohexanone with phenylselenenyl chloride and aqueous 30% hydrogen peroxide, yielding 4-phenyl-2-cyclohexenone, and then the reaction of the cyclohexenone with 1.4M methyllithium and aqueous ammonium chloride, affording 3-methyl-4-phenylcyclohexanone. The cyclohexanone is then reacted with cyanoguanidine as previously described. Example 15 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.C(N(CC)CC)C.[Cl:19][C:20]([Cl:25])([Cl:24])[C:21](Cl)=[O:22].N>C(Cl)Cl>[Cl:19][C:20]([Cl:25])([Cl:24])[C:21]([NH:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1)=[O:22]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Nc1cnc2c(c1)CCCC2
Agent: N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cnc2c(c1)CCCC2)C(Cl)(Cl)Cl
Reaction time: 0.12 h
Yield: 96 %

Procedure:
To 130 ml of methylene chloride are added 12.69 g of Compound 1 obtained in the above step (1) and 2.4 ml of triethylamine, and a solution of 10.5 ml of trichloroacetyl chloride in 30 ml of methylene chloride is dropwise added with ice cooling and under stirring over a period of 7 minutes. The reaction mixture is stirred at room temperature for 20 minutes, mixed with saturated saline, made weakly alkaline with aqueous ammonia and the organic layer is separated. The aqueous layer is shaken with methylene chloride. The organic layers are combined, washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated to remove the solvent. The residue is chromatographed on a silica gel column, eluting with 10% methanol/methylene chloride. The product is recrystallized from ethyl acetate to give 24.21 g of the titled compound 2. Yield: 96%
Reaction SMILES: [NH2:1][C:2]1[N:3]([C@H:19]([CH:25]2[CH2:30]CCC[CH2:26]2)[CH2:20][CH2:21][C:22](O)=[O:23])[CH2:4][C:5]2[CH:11]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:9]=[CH:8][C:6]=2[N:7]=1.C(Cl)(=O)C(Cl)=O.[CH2:37]([OH:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl>[CH2:37]([O:44][C:22](=[O:23])[CH2:21][CH2:20][CH:19]([N:3]1[CH2:4][C:5]2[CH:11]=[C:10]([O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:9]=[CH:8][C:6]=2[N:7]=[C:2]1[NH2:1])[CH:25]([CH3:30])[CH3:26])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: OCc1ccccc1
Reactant: NC1=Nc2cnc(Oc3ccccc3)cc2CN1[C@@H](CCC(=O)O)C1CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)C(CCC(=O)OCc1ccccc1)N1Cc2cc(Oc3ccccc3)ncc2N=C1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (4-(2-amino-6-phenoxy-4H-pyrido[3,4-d]pyrimidin-3-yl)-4-(S)-cyclohexyl-butyric acid (0.1 g, 0.25 mmol) in DCM (10 mL) was added oxalyl chloride (2.0M in DCM, 0.8 mL, 2 mmol). The resulting mixture was stirred at room temperature one hour. An aliquot from the reaction mixture was quenched in MeOH and analyzed by MS-HPLC which indicated that all of the acid was converted to the corresponding acid chloride. The solvent and excess oxalyl chloride was removed by vacuum. DCM (10 mL) was added followed by benzyl alcohol (0.089 mL, 0.8 mmol). The resulting solution was stirred at room temperature for one hour. The solvent was removed under vacuum to yield an oil which was purified by Gilson HPLC to yield the title compound as a solid, as its corresponding TFA salt.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:11](=[O:12])[C:10]([O:13][CH3:14])=[CH:9][N:8]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[N:7]=1)=[O:5].[CH3:22][Mg+].[Br-]>C1COCC1>[C:4]([C:6]1[C:11](=[O:12])[C:10]([O:13][CH3:14])=[CH:9][N:8]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[N:7]=1)(=[O:5])[CH3:22]
Reactant: C[Mg+]
Reactant: COc1cn(-c2cccnc2)nc(C(=O)N(C)OC)c1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2cccnc2)nc(C(C)=O)c1=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of N,5-dimethoxy-N-methyl-4-oxo-1-pyridin-3-yl-1,4-dihydropyridazine-3-carboxamide (0.40 g, 1.4 mmol) in THF (10 ml) was added dropwise 1 M MeMgBr in THF (3.0 ml, 3.0 mmol) at −78° C. After stirring at −78° C. for 2 h, the mixture was quenched with water (0.5 ml) and stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The residue was partitioned between CHCl3 (25 ml) and brine. The aqueous layer was extracted with CHCl3 (25 ml×3). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (0.21 g, 62% yield) as yellow crystals: 1H NMR (300 MHz, CDCl3): δ ppm 2.70 (3H, s), 3.97 (3H, s), 7.49-7.56 (1H, m), 7.95 (1H, s), 8.01-8.08 (1H, m), 8.72 (1H, dd, J=4.7, 1.3 Hz), 8.95 (1H, d, J=2.6 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[N:16]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[S:38](=[O:40])(=[O:39])[NH:37][C:36](=[O:41])[CH2:35]5)=[CH:30][CH:29]=4)[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[N:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:15]([CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:42]4[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]4)=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[N:16]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[S:38](=[O:40])(=[O:39])[NH:37][C:36](=[O:41])[CH2:35]3)=[CH:30][CH:29]=2)[CH:17]=1
Reactant: C1CNCCN1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Br)cc4)cc3)cc2)S(=O)(=O)N1
Product: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(N5CCNCC5)cc4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{4-[2-(4′-Bromo-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (268 mg, 0.4 mmol) was treated as described in general procedure R using excess piperazine (346 mg, 4 mmol) to give the desired compound 5-{-4-[4-(2,4-dichloro-phenyl)-2-(4′-piperazin-1-yl-biphenyl-4-ylmethyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.