Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26](=[N:40][NH2:41])[NH:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:42](N1C=CN=C1)(N1C=CN=C1)=[O:43]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]1[N:27]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][CH:29]=2)[C:42]([OH:43])=[N:41][N:40]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1cc(C(=NN)Nc2ccc(N3CCOCC3)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)c1cc(-c2nnc(O)n2-c2ccc(N3CCOCC3)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,4-bis-benzyloxy-5-isopropyl-N-[4-(morpholin-4-yl)-phenyl]-benzene-carbohydrazonamide (F370-IM4: crude product) was suspended in tetrahydrofuran (10 mL), mixed with 1,1′-carbonyldiimidazole (1.12 g, 6.9 mmol) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate (50 mL) and 5% aqueous sodium hydrogencarbonate (50 mL), and the organic layer was separated. The organic layer obtained was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the solvent was distilled off under reduced pressure, and the residue thus obtained was purified by silica gel column chromatography (ethyl acetate 100%). The obtained product was purified by suspending in ethyl acetate to obtain the title compound (F370-IM5: white crystals, 1.2 g, 45% in 3 steps).
Reaction SMILES: [C:1]([NH:14][CH2:15][C:16]1[CH:17]=[C:18]([Si](CC)(CC)CC)[O:19][CH:20]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH2:28].C1C(I)=C(O)C(I)=C2OC3C(C4(OC(=O)C5C(Cl)=C(Cl)C(Cl)=C(Cl)C4=5)C=12)=CC(I)=C(O)C=3I.[O:62]=O>O1CCCC1>[C:1]([NH:14][CH2:15][C:16]1[CH:20]([OH:28])[O:19][C:18](=[O:62])[CH:17]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)NCc1coc([Si](CC)(CC)CC)c1
Reactant: O=O
Reactant: O
Agent: O=C1OC2(c3cc(I)c(O)c(I)c3Oc3c2cc(I)c(O)c3I)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)NCC1=CC(=O)OC1O

Procedure:
A mixture of 4-(N-dodecanoylaminomethyl)-2-triethylsilylfuran (73.2 mg, 0.18 mmol), water (0.05 ml) and Rose Bengal (ca. 3 mg) in tetrahydrofuran (5 ml) was exposed to singlet oxygen at 0° for 1.5 hours. The residue, after solvent removal, was purified by chromatography on preparative silica thin layer plates (developed with ethyl acetate) to
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10](O)=[O:11])[CH:6]=[CH:7][CH:8]=1.C(Cl)(=O)C([Cl:18])=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([Cl:18])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(3-(trifluoromethyl)phenyl)acetic acid (4.78 g, 23.4 mmol) in DCM (46 mL) was added oxalyl chloride (12.9 mL, 25.8 mmol). One drop of DMF was then added and the mixture was stirred for 1.5 hours at room temperature. The mixture was concentrated to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[O:25]1[CH2:30][CH2:29][N:28]([C:31](=[O:36])[C:32]([NH:34][NH2:35])=[O:33])[CH2:27][CH2:26]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C1COCC1.O>[F:10][C:9]([F:11])([F:12])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:35][NH:34][C:32](=[O:33])[C:31]([N:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)=[O:36])=[O:22])[N:14]=2)[CH:4]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: NNC(=O)C(=O)N1CCOCC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NNC(=O)C(=O)N1CCOCC1
Temperature: -60 °C
Reaction time: 1 h
Yield: 169.3 %

Procedure:
A solution of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.2 g, 0.569 mmol) and 2-morpholino-2-oxoacetohydrazide (0.02 g, 0.175 mmol) in THF (3 mL) was cooled to −60° C. T3P (0.098 g, 0.569 mmol) (0.50 mL) was added dropwise followed by DIPEA (0.11 g, 0.854 mmol) and stirred at −60° C. for 1 h. The reaction mixture was transferred into 25 mL of iced water and extracted with ethyl acetate (2×25 mL). Combined organic layers were washed with brine, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to give 0.3 g of crude product, which was purified by chromatography (0-4% MeOH/CH2Cl2) to give 0.15 g of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(2-morpholino-2-oxoacetyl) acrylohydrazide (Yield 50%). 1H NMR (400 MHz, DMSO-d6) δ 10.70-10.88 (m, 2H), 9.56 (s, 1H), 8.57 (s, 2H), 8.29 (s, 1H), 7.52-7.55 (d, J=10.4 Hz, 1H), 6.0-6.03 (d, J=10.4 Hz, 1H), 3.51-3.64 (m, 8H). LCMS m/z 507.25 [M+H]+, tR=2.012 min.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([CH3:17])=[CH:11]2.CN([CH:21]=[O:22])C>>[CH:21]([C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([O:7][CH3:6])[CH:9]=2)[NH:13][C:12]=1[CH3:17])=[O:22]
Reactant: COc1ccc2[nH]c(C)cc2c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2[nH]c(C)c(C=O)c2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To 60 mL of DMF at 0° C. was added 10.1 mL of phosphorous oxychloride dropwise. The resulting solution was stirred 10 min at 0° C., then was treated dropwise with a solution of 5-methoxy-2-methylindole (16.2 g, 100 mmol) in 25 mL of DMF. The orange solution was wanned to 40° C. for 45 min, then cooled and quenched with ice. The mixture was then poured into 300 mL of ice water and treated with 100 mL of 10N NaOH. The resulting slurry was heated to reflux for 4 h, then cooled and filtered. The solid was rinsed with water and air-dried to give 18.7 g of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:13])[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(=O)([O-])[O-].[K+].[K+].I[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C)C=O>[CH3:1][O:2][CH2:3][C:4]([CH:5]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:6]([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:7])=[O:13]
Reactant: COCC(=O)CC(=O)OC(C)(C)C
Reactant: CCOC(=O)CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCC(C(=O)COC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.4 %

Procedure:
To a suspension of tert-butyl 4-methoxy-3-oxobutanoate (3.09 g) and potassium carbonate (2.50 g) in dimethylformamide (20 mL) was added ethyl 5-iodopentanoate (4.62 g) and the mixture was stirred at ambient temperature for 15 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1-5:1) to give 1-tert-butyl 7-ethyl 2-(methoxyacetyl)heptanedioate as colorless oil (4.33 g).
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])C.[O:7]=[CH:8][C:9]1[CH:17]=C[C:14](O)=[C:11](OC)[CH:10]=1.Cl[CH2:19]Cl>>[CH3:19][O:3][CH2:1][O:4][CH2:5][C:6]1[CH:17]=[C:9]([CH2:8][OH:7])[CH:10]=[CH:11][CH:14]=1
Reactant: ClCCl
Reactant: COc1cc(C=O)ccc1O
Reactant: CCOC(C)=O
Product: COCOCc1cccc(CO)c1

Procedure:
1H NMR (CDCl3) δ2.03, 3.41, 4.59, 4.68, 4.70, 7.3 ppm. TLC Rf 0.36 (1:1 ethyl acetate in dichloromethane, vanillin staining).
Reaction SMILES: [C:1](=[O:4])([O-:3])[O-].[K+].[K+].CN(C=O)C.[CH3:12][N:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH2:24][CH2:25][CH2:26][NH:27][CH2:28][C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]1=[O:35].Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>C(OCC)(=O)C>[CH2:41]([O:40][C:38](=[O:39])[CH2:37][O:3][C:1](=[O:4])[N:27]([CH2:26][CH2:25][CH2:24][O:23][C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[N:13]([CH3:12])[C:14](=[O:35])[CH:15]=[CH:16]2)[CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)[CH3:42]
Reactant: O=C([O-])[O-]
Reactant: Cn1c(=O)ccc2cc(OCCCNCc3ccncc3)ccc21
Reactant: CCOC(=O)CBr
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COC(=O)N(CCCOc1ccc2c(ccc(=O)n2C)c1)Cc1ccncc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Potassium carbonate (1.66 g) was added to a DMF solution (50 ml) of 1-methyl-6-{3-[(pyridin-4-ylmethyl)amino]propoxy}-1H-quinolin-2-one (1.5 g). The mixture was cooled to 0° C., and ethyl bromoacetate (1.16 ml) was added to the mixture and stirred at room temperature overnight. The reaction mixture was added to ice water, and extraction with ethyl acetate was performed. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol=20:1→10:1). The purified product was condensed under reduced pressure. The residue was recrystallized from ether, and dried to give the title compound(0.55 g) as a white powder.
Reaction SMILES: C1CCCCC1.C([Li])(CC)C.[F:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[CH:16]=[CH:17][CH:18]=1.[I:29]I>O.C1COCC1>[F:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[CH:16]=[CH:17][C:18]=1[I:29]
Reactant: II
Reactant: Fc1cccc(-c2ccc3ccccc3c2)c1
Agent: [Li]C(C)CC
Solvent: O
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: Fc1cc(-c2ccc3ccccc3c2)ccc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
A 50.21 ml cyclohexane solution of sec-butyl lithium in a concentration of 1.01M was dropped into a 200 ml THF solution of 4.90 g (=22.05 mmol) of the above 2-(3-fluorophenyl)naphthalene at −70° C. After the dropping was finished, the reaction solution was stirred at the same temperature for 1 hour, added with a 200 ml THF solution of 12.87 g (=50.71 mmol) of iodine through dropping and then slowly heated to room temperature. After being stirred for 18 hours, the reaction solution was added into iced water dissolved with Na2S2O3.5H2O, and then the reaction mixture was extracted twice with toluene. The extract was washed thrice with water and then dried with anhydrous MgSO4. After the solvent was evaporated under a reduced pressure, the obtained orange solid of 8.61 g was purified with silica gel chromatography using heptane/toluene in a ratio of 5:1 as the eluent to obtain a pinkish solid of 7.86 g, which was recrystallized with a mixed solvent of Solumix/heptane/toluene in a ratio of 5:5:1 to obtain 6.00 g of 2-(3-fluoro-4-iodophenyl)naphthalene as yellowish crystals.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.CN1CCCC1=O.[NH2:19][CH2:20][CH2:21][CH:22]([OH:24])[CH3:23].C(N(CC)CC)C>O>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([NH:19][CH2:20][CH2:21][CH:22]([OH:24])[CH3:23])=[CH:7][C:6]=1[CH3:8])([O-:11])=[O:10]
Reactant: CC(O)CCN
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(NCCC(C)O)ccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 99.6 %

Procedure:
2 g of 5-fluoro-2-nitrotoluene were added to a solution of 20 ml of N-methylpyrrolidinone, 1.38 g of 4-amino-2-butanol and 1.57 g of triethylamine. The reaction medium was heated at 60° C. for 10 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The resulting medium was extracted with ethyl acetate and the organic phase was then concentrated under vacuum. 2.88 g of 4-(4-nitro-3-methylphenylamino)butan-2-ol (31) were obtained.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:33][C:32]([CH3:34])=[CH:31][C@@H:30]([CH2:35][CH:36]=[CH2:37])[C:28](=[O:29])[CH2:27][C@H:26]([OH:38])[C@@H:25]([CH3:39])[C@@H:24](/[C:40](/[CH3:51])=[CH:41]/[C@H:42]2[CH2:47][C@@H:46]([O:48][CH3:49])[C@H:45]([OH:50])[CH2:44][CH2:43]2)[O:23][C:21](=[O:22])[C@H:20]2[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[C:13](=[O:14])[C:11](=[O:12])[C@:9]2([OH:52])[O:10][C@@H:5]([C@@H:6]([O:54][CH3:55])[CH2:7][C@H:8]2[CH3:53])[C@@H:4]([O:56][CH3:57])[CH2:3]1>C(OCC)(=O)C.[Pd]>[OH:52][C:9]12[O:10][CH:5]([CH:6]([O:54][CH3:55])[CH2:7][CH:8]1[CH3:53])[CH:4]([O:56][CH3:57])[CH2:3][CH:2]([CH3:1])[CH2:33][C:32]([CH3:34])=[CH:31][CH:30]([CH2:35][CH2:36][CH3:37])[C:28](=[O:29])[CH2:27][CH:26]([OH:38])[CH:25]([CH3:39])[CH:24]([C:40]([CH3:51])=[CH:41][CH:42]1[CH2:43][CH2:44][CH:45]([OH:50])[CH:46]([O:48][CH3:49])[CH2:47]1)[O:23][C:21](=[O:22])[CH:20]1[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]1)[C:13](=[O:14])[C:11]2=[O:12]
Reactant: C=CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Agent: [Pd]
Agent: C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Solvent: CCOC(C)=O
Product: CCCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC

Procedure:
A solution of the FR-900506 substance (50 mg) in ethyl acetate (2 mi) was subjected to catalytic reduction using 10% palladium on carbon (10 mg) under atmospheric pressure at room temperature for 20 minutes. The reaction mixture was filtered and the filtrate was evaporated to dryness, which was purified on thin layer chromatography. Development with a mixture of chloroform and acetone (5:1 v/v) gave 1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-17-propyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (50.0 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][C:37](O)=[O:38])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][C:37](=[O:38])[NH:1][C:2]2[CH:3]=[C:4]3[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]4=[C:7]([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[NH:8][C:9]([CH:10]=2)=[C:5]34)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)Nc2cc3c4c(c(-c5ccccc5)[nH]c4c2)C=NNC3=O)CC1
Yield: 85.1 %

Procedure:
Preparation of example 88 from the title compound of Example 7 (hydrochloride) (44 mg, 0.141 mmol), 4-(2-carboxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (43 mg, 0.169 mmol), triethylamine (0.059 mL, 0.423 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (64 mg, 0.169 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gel chromatography (eluted with 8:5:2 CH2Cl2:hexane:methanol), also in an analogous manner, afforded the title compound (62 mg, 0.120 mmol) as a yellow powder in 85% yield.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25]CS.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[C:5]([C:11]#[N:12])=[C:6]([S:8][CH2:10][CH2:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2cccnc2)c1C#N
Reactant: SCCc1ccccn1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(SCCc2ccccn2)nc(N)nc1-c1cccnc1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyridin-3-yl-pyrimidine-5-carbonitrile, 2-pyridylethylmercaptan and DBU in DME. EI-MS m/e (%): 334 (M+, 35), 333 ([M—H]+, 100), 138 (52), 106 (33).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=1[NH2:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[C:24](Cl)(Cl)=[S:25]>C(Cl)(Cl)Cl.O>[Si:1]([O:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=1[NH:11][C:24]([NH:11][C:10]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:9]=1)=[S:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: S=C(Cl)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1cc([N+](=O)[O-])ccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cc([N+](=O)[O-])ccc1NC(=S)Nc1ccccc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
N-(2-tert-Butyldimethysilyloxy-4-nitrophenyl)-N'-phenyl-thiourea was prepared by treating a biphasic solution of 2-tert-butyldimethysilyloxy-4-nitroaniline(80 mg, 0.308 mmol) and NaHCO3 in CHCl3 :H2O(2.5:1, 7 mL) with thiophosgene at 0° C. The solution was allowed to warm to 23° C. and the reaction was continued overnight The CHCl3 layer was separated and dried over sodium sulfate. The solution was concentrated in vacuo and the residue was dissolved in toluene and treated with aniline (100 uL) at 23 ° C. for 12 h. The reaction mixture was concentrated and the residue was purified by flash chromatography (10% EtOAc/hexanes) to afford the titled compound as a yellow solid (120.8 mg, 98%) mp: 144°-145° C.; 1H NMR (CD3OD/CDCl3): δ 8.65 (d, 1H, J=10.0 Hz), 7.58 (d, 1H, J=10.0 Hz), 7.47 (d, 1H, J=1.25 Hz), 7.26 (m, 4H), 7.10 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.O.[NH2:24][NH2:25]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:11]([C:12]([NH2:13])=[N:24][NH:25]3)=[CH:14][CH:15]=2)[CH:5]=[C:4]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2cc(-c3ccccc3)nc(N)n2)cc1F
Solvent: CCO
Solvent: O
Product: Nc1nc(-c2ccccc2)cc(-c2ccc3c(N)n[nH]c3c2)n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
Into a 25 mL sealable tube under argon were added 4-(2-amino-6-phenyl-4-pyrimidinyl)-2-fluorobenzonitrile (0.052 g, 0.18 mmol) and EtOH (5 mL). Hydrazine monohydrate (0.35 mL, 7.17 mmol) was added, the vial was sealed, and the reaction mixture was stirred overnight at 95° C. The reaction was cooled to room temperature and concentrated. The resulting solid was sonicated in a mixture of EtOH (1 mL) and water (10 mL), filtered, washed with water, and dried under vacuum at 40° C. to afford the title compound as a yellow solid (44 mg, 77%). LC-MS (ES) m/z=303 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 5.43 (s, 2H), 6.74 (s, 2H), 7.46-7.59 (m, 3H), 7.69-7.84 (m, 3H), 8.12 (s, 1H), 8.23 (m, 2H), 11.63 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[O:6][CH2:7][C:8]#[N:9].Cl.[OH:16][NH2:17]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[O:6][CH2:7][C:8](=[N:17][OH:16])[NH2:9]
Reactant: NO
Reactant: COc1ccc(OCC#N)cc1OC
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1ccc(OCC(N)=NO)cc1OC
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(3,4-dimethoxyphenoxy)acetonitrile (3.8 g) in MeOH—H2O (1:1), hydroxyamine hydrochloride was added and the mixture was stirred at 100° C. for 3 hours. After distilling off the solvent under reduced pressure, the residue was recovered by filtration and washed with water and hexane to give a crude form of the titled compound (4.9 g).
Reaction SMILES: CN1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]([C:16](Cl)=O)[C:8]2[CH:7]=[CH:6][CH:5]=CC1=2.[CH3:19][N:20]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]([C:34]([O:36]C)=[O:35])[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]1=2>ClCCl.O1CCCC1>[CH3:19][N:20]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]([C:34]([OH:36])=[O:35])[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]1=2.[CH:13]1[CH:12]=[CH:11][C:10]([C:9]2[CH:16]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)C1c2ccccc2N(C)c2ccccc21
Reactant: CN1c2ccccc2C(C(=O)Cl)c2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1c2ccccc2C(C(=O)O)c2ccccc21
Product: c1ccc(-c2ccccc2)cc1

Procedure:
A solution of 0.24 parts of 10-methylacridan-9-carboxylic acid chloride (78) in 10 mL dichloromethane and 0.145 parts of 4-phenylphenol (76) in 5 mL of dichloromethane and 1 mL of tetrahydrofuran is treated as described in example I, to give 0.21 parts of 4,4′-biphenyl 10-methylacridan-9-carboxylate. This compound has the following structure.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].O.[C:11](Cl)(Cl)=[S:12]>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[N:4]=[C:11]=[S:12]
Reactant: Nc1ccc(I)cc1Cl
Reactant: S=C(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: S=C=Nc1ccc(I)cc1Cl
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a stirred solution of 2-chloro-4-iodoaniline (1.0 g, 3.9 mmol) in DCM (50 mL) was added water (20 mL) followed by thiophosgene (476 mg, 4.1 mmol). The reaction mixture was stirred overnight before the layers were separated and the organic layer dried (Na2SO4) and evaporated in vacuo to give the desired product as a brown solid (1.0 g, 86%). δH (CDCl3) 7.79 (1H, d, J 1.9 Hz), 7.58 (1H, dd, J 1.9, 8.4 Hz), 6.97 (1H, d, J 8.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)=[CH:11][C:10]([C:28](Cl)=[O:29])=[N:9]1.C(N(CC)C(C)C)(C)C.[NH:40]1[CH2:49][CH2:48][CH:43]([C:44]([O:46][CH3:47])=[O:45])[CH2:42][CH2:41]1>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)=[CH:11][C:10]([C:28]([N:40]2[CH2:49][CH2:48][CH:43]([C:44]([O:46][CH3:47])=[O:45])[CH2:42][CH2:41]2)=[O:29])=[N:9]1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(=O)Cl)nn3-c3ccccc3Cl)s2)c1
Reactant: COC(=O)C1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)c2cc(-c3ccc(-c4cccc(S(C)(=O)=O)c4)s3)n(-c3ccccc3Cl)n2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 8.2 %

Procedure:
To a solution of 1-(2-chlorophenyl)-5-(5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)-1H-pyrazole-3-carbonyl chloride (0.23 mmol crude from previous step) in CDCl3 (12 ml) was added N,N-diisopropylethylamine (150 μL, 0.86 mmol) and a small amount of DMAP. The resulting mixture was treated with methyl isonipecotate (62 μL, 0.46 mmol). After stirring for 3 hours at ambient temperature the reaction was quenched by dilution with H2O, and dilution with CH2Cl2. The layers were separated and the basic aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude product. This material was purified by flash column chromatography eluting with a gradient from 0% to 16% MeCN in CH2Cl2 to afford methyl 1-{[1-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]carbonyl}piperidine-4-carboxylate (11 mg, 8% yield) as a white powder. MS(ES): 584 [M+H]+.