Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:3]=1[CH3:20].[Br:21][C:22]1[CH:23]=[CH:24][C:25]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[C:26]([NH2:28])[CH:27]=1.Cl>O1CCOCC1.CO>[Br:21][C:22]1[CH:23]=[CH:24][C:25]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)=[C:26]([NH:28][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:3]=2[CH3:20])[CH:27]=1
Reactant: Nc1cc(Br)ccc1N1CCOCC1
Reactant: Cc1c(-c2ccccc2F)nc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1c(-c2ccccc2F)nc2cc(F)ccc2c1Nc1cc(Br)ccc1N1CCOCC1

Procedure:
Prepared according to Procedure K, Method 1 using 4-chloro-7-fluoro-2-(2-fluorophenyl)-3-methylquinoline (118 mg, 407 μmol), 5-bromo-2-morpholinobenzenamine (105 mg, 407 μmol) and 4.0N hydrochloric acid (0.10 mL, 407 μmol) in 1,4-dioxane in MeOH (1.00 mL) to afford a yellow solid after purification by chromatography on silica gel, eluting with EtOAc-DCM-hexane solvent mixture. Mass Spectrum (ESI) m/e=510.0 & 512.0 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:41]=[CH:40][C:16]([CH2:17][N:18]([CH2:27][C:28]3[CH:39]=[CH:38][C:31]([O:32][CH2:33][C:34]([O:36]C)=[O:35])=[CH:30][CH:29]=3)[S:19]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>CO.C1COCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:41]=[CH:40][C:16]([CH2:17][N:18]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:38][CH:39]=3)[S:19]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)(=[O:20])=[O:21])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)S(=O)(=O)c3cccs3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)O)cc3)S(=O)(=O)c3cccs3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.5 %

Procedure:
To a solution of methyl (4-{[{4-[(4-butylphenyl)ethynyl]benzyl}(2-thienylsulfonyl)amino]-methyl}phenoxy)acetate (30 mg, 0.051 mmol) in MeOH/THF (4 ml, (1/1)) was added an aqueous solution of NaOH (2 mL, 1N). The reaction mixture was stirred at rt for 2 hrs. Then an aqueous solution of HCl (9 mL, 1N) was added and extracted with Et2O (2×10 mL). The combined organic layers were dried over Na2SO4 and the solvents were removed under reduced pressure to give 30 mg (97%) of the title compound as a green oil. HPLC, Rt: 5.3 min (purity: 95.3%). LC/MS, M+(ESI): 574.2, M−(ESI): 572.3. 1H NMR (CDCl3) δ: 7.60 (m, 2H), 7.44 (d, J=8.3 Hz, 2H), 7.38 (d, J=7.9 Hz, 2H), 7.17 (d, J=7.9 Hz, 2H), 7.12 (m, 1H), 7.05 (m, 4H), 6.80 (d, J=8.7 Hz, 2H), 4.66 (s, 2H), 4.33 (s, 2H), 4.31 (s, 2H), 2.63 (t, J=7.5 Hz, 2H), 1.61 (m, 2H), 1.37 (m, 2E), 0.94 (t, J=7.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4](Cl)[C:3]=1[N:13]1[C:17]([S:18]([CH:21]([F:23])[F:22])(=[O:20])=[O:19])=[C:16]([Cl:24])[N:15]=[C:14]1[Br:25].[CH3:26][S-:27].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[C:3]([N:13]2[C:17]([S:18]([CH:21]([F:23])[F:22])(=[O:20])=[O:19])=[C:16]([Cl:24])[N:15]=[C:14]2[Br:25])=[C:4]([S:27][CH3:26])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=S(=O)(c1c(Cl)nc(Br)n1-c1c(Cl)cc(C(F)(F)F)cc1Cl)C(F)F
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CSc1cc(C(F)(F)F)cc(Cl)c1-n1c(Br)nc(Cl)c1S(=O)(=O)C(F)F
Temperature: 25 °C
Reaction time: 14 h
Yield: 35.2 %

Procedure:
To a solution of 500 mg (0.984 mmole) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-2-bromo-4-chlorodifluoromethylsulfonyl-imidazole in 2 ml of tetrahydrofuran was added a solution of 69 mg (0.984 mmole) of sodium methanethiolate in 0.3 ml of water. The resulting mixture was stirred at RT for 14 hours, after which it was partitioned between water and diethyl ether. The organic layer was separated, dried over anhydrous sodium sulfate and stripped of solvent. The residue was purified by preparative TLC using 20% ethyl acetate in hexane to give 180 mg (35% yield) of the product, mp 116° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]([C:27]2[S:28][C:29]([C:32]([NH:34][NH2:35])=[O:33])=[CH:30][CH:31]=2)=[O:26])[CH:19]=1>CS(C)=O>[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]([C:27]2[S:28][C:29]([C:32]([NH:34][N:35]=[C:15]([C:12]3[C:13]([OH:14])=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[S:10][CH:11]=3)[CH3:17])=[O:33])=[CH:30][CH:31]=2)=[O:26])[CH:19]=1
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: NNC(=O)c1ccc(C(=O)Nc2cccnc2)s1
Solvent: CS(C)=O
Product: CC(=NNC(=O)c1ccc(C(=O)Nc2cccnc2)s1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 100 °C
Yield: 94 %

Procedure:
28 mg of 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene and 26 mg of 5-hydrazinocarbonylthiophene-2-carboxylic acid 3-pyridylamide were dissolved in 2 mL of dimethyl sulfoxide and heated at 100° C. for 18 hours, and the solvent was evaporated. Recrystallization from chloroform-diethyl ether gave the desired product (yield 94%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[C:5]([CH3:12])=[C:4]2[O:13][CH2:14][O:15][C:3]=12.[CH:16]([O:19][C:20]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:21]=1[C:22](O)=[O:23])([CH3:18])[CH3:17]>>[CH3:1][C:2]1[C:11]2[CH2:10][N:9]([C:22]([C:21]3[CH:25]=[C:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:27]=[CH:28][C:20]=3[O:19][CH:16]([CH3:18])[CH3:17])=[O:23])[CH2:8][CH2:7][C:6]=2[C:5]([CH3:12])=[C:4]2[O:13][CH2:14][O:15][C:3]=12
Reactant: Cc1c2c(c(C)c3c1OCO3)CNCC2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: Cc1c2c(c(C)c3c1OCO3)CN(C(=O)c1cc(S(C)(=O)=O)ccc1OC(C)C)CC2

Procedure:
Prepared in analogy to example 1.1 from 4,9-dimethyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1). MS (m/e): 446.3 (M+H+).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[NH4+].[Cl-].[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([NH:22][CH3:23])[CH2:18][CH2:17]2)[N:15]=1)[C:11]#[N:12]>CN(C=O)C>[Cl:7][C:8]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([NH:22][CH3:23])[CH2:18][CH2:17]2)[CH:13]=[C:10]([C:11]2[NH:12][N:3]=[N:2][N:1]=2)[CH:9]=1
Reactant: CNC1CCN(c2cc(C#N)cc(Cl)n2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC1CCN(c2cc(-c3nnn[nH]3)cc(Cl)n2)CC1
Temperature: 120 °C
Yield: 37.1 %

Procedure:
Sodium azide (131 mg, 2.02 mmol) and NH4Cl (108 mg, 2.02 mmol) were added to a solution of 2-chloro-6-[4-(methylamino)piperidin-1-yl]isonicotinonitrile (Intermediate 63, 507 mg, 2.02 mmol) in anhydrous DMF (3 ml). The mixture was heated at 120° C. under nitrogen gas for 1 h where LCMS showed the expected mass. The mixture was filtered and was purified by semi-preparative HPLC eluting with acetonitrile/water (0.1% TFA) and the title compound was concentrated in vacuo to give a hygroscopic brown solid (220 mg).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[F:10][C:11]([F:17])([CH:14]([F:16])[F:15])[CH2:12][OH:13].[H-].[Na+]>>[F:10][C:11]([F:17])([CH:14]([F:16])[F:15])[CH2:12][O:13][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1
Reactant: OCC(F)(F)C(F)F
Agent: [H-]
Agent: [Na+]
Product: N#Cc1ccc(OCC(F)(F)C(F)F)cc1

Procedure:
In a first step, p-chlorobenzonitrile is reacted with 2,2,3,3-tetrafluoropropanol in the presence of bases, for example sodium hydride, with exchange of the p-chlorine atom to give 4-(2,2,3,3-tetrafluoropropoxy)benzonitrile. The second step is to reduce the 4-(2,2,3,3-tetrafluoropropoxy)benzonitrile by metal hydrides, for example diisobutylaluminum hydride, 4-(2,2,3,3-tetrafluoropropoxy)benzaldehyde being formed. The 4-(2,2,3,3-tetrafluoropropoxy)benzaldehyde is reacted stereoselectively with ethyl diethylphosphonoacetate in a third reaction step to give ethyl (E)-4-(2,2,3,3-tetrafluoropropoxy)cinnamate.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8](C(O)=O)[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:14].C(Cl)(=O)[C:16]([Cl:18])=[O:17]>C(Cl)Cl.CN(C=O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:16]([Cl:18])=[O:17])=[CH:10][C:5]=2[O:4][C:3]1=[O:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1c(=O)oc2ccc(C(=O)O)cc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c(=O)oc2cc(C(=O)Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-methyl-2-oxo-2,3-dihydro-benzooxazole-5-carboxylic acid (820 mg, obtained in Example 116, step 5) in CH2Cl2 (10 mL) were added two drops of DMF and oxalylchloride (0.58 mL). The mixture was stirred at room temperature for 1 hour and was then concentrated to dryness. 1,2-Dimethoxyethane (20 mL) was added and the solvent was evaporated again to give the crude acid chloride (3-methyl-2-oxo-2,3-dihydro-benzooxazole-5-carbonyl chloride). To a suspension of zinc powder (555 mg) in 1,2-dimethoxyethane (10 mL) was added tetrakis(triphenylphosphine)palladium(0) (49 mg). A suspension of the acid chloride in 1,2-dimethoxyethane (5 mL) was added. The mixture was cooled in an ice bath and a solution of 2-bromomethyl-1-chloro-4-methoxy-benzene (1.0 g, [CAS Reg. No. 3771-13-9]) in 1,2-dimethoxyethane (5 mL) was slowly added over a period of 15 minutes. The mixture was stirred for 10 minutes at 0° C. and then for 2 hours at r.t. The reaction mixture was poured into ice and basified with sat. NaHCO3. The aqueous phase was then extracted two times with ethyl acetate and the organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, heptane:ethyl acetate=6:4) to give the title compound as a colorless solid (510 mg, 36%). MS (neg. ion, m/e)=330.3 [(M−H)−].
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=[O:7])=[O:2].[CH2:13]([Mg]Br)[CH:14]=[CH2:15]>O1CCCC1>[OH:2][CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=[O:7])[CH2:15][CH:14]=[CH2:13]
Reactant: Cc1ccc(C(=O)O)cc1C=O
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CCC(O)c1cc(C(=O)O)ccc1C
Temperature: -5 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
Into a 100-mL 3-necked round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-formyl-4-methylbenzoic acid (compound 4.1, 2.00 g, 12.2 mmol) in tetrahydrofuran (50 mL). The mixture was cooled to −10 to 0° C. then allylmagnesium bromide (1M in Et2O, 24.4 mL, 24.4 mmol) was added drop-wise. The resulting mixture was stirred for 1 hr at −10-0° C., then carefully quenched with saturated aqueous NH4Cl (50 mL) and diluted with ethyl acetate (200 mL). The organic layer was washed with saturated aqueous NH4Cl (80 mL) and brine (2×80 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to yield the title compound as a light red solid (2.4 g, crude), which was used in the next step without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=3)=[CH:40][CH:39]=2)[C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:50][C:51]1[S:52][CH:53]=[CH:54][N:55]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=3)=[CH:40][CH:39]=2)[C:35]([NH:50][C:51]2[S:52][CH:53]=[CH:54][N:55]=2)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(-c2ccncc2)cc1
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(-c2ccncc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of triphenylphosphine (59 mg, 0.22 mmol) in methylene chloride (1 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (39 mg, 0.22 mmol). The reaction mixture was stirred at 0° C. for 20 min and then treated with 3-cyclopentyl-2-(4-pyridin-4-yl-phenyl)-propionic acid (55 mg, 0.19 mmol). The resulting reaction mixture was stirred at 0° C. for 10 min and then allowed to warm to 25° C. where it was stirred for 20 min. The reaction mixture was then treated with 2-aminothiazole (41 mg, 0.41 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 20/1 methylene chloride/methanol) to afford impure 3-cyclopentyl-2-(4-pyridin-4-yl-phenyl)-N-thiazol-2-yl-propionamide as an orange foam. The impure foam was treated with a solution of hexanes/ethyl acetate (5 mL, 1:3), and a precipitate formed. The reaction mixture was placed in the freezer for 15 h, and the solid was collected by filtration to afford 3-cyclopentyl-2-(4-pyridin-4-yl-phenyl)-N-thiazol-2-yl-propionamide (26 mg, 37%) as a pale orange solid: mp 213-215° C.; EI-HRMS m/e calcd for C22H23N3OS (M+) 377.1562, found 377.1564.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[Cl:27][C:28]1[CH:35]=[C:34]([OH:36])[CH:33]=[CH:32][C:29]=1[CH:30]=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:30][C:29]4[CH:32]=[CH:33][C:34]([OH:36])=[CH:35][C:28]=4[Cl:27])[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: O=Cc1ccc(O)cc1Cl
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(Cc3ccc(O)cc3Cl)CC2)cc1

Procedure:
Using the general procedure described in Example 3, N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (0.045 mmol) was reacted with 2-chloro-4-hydroxybenzaldehyde to provide 22 mg of the title product as the free base. Treatment with hydrochloric acid and concentration in vacuo yielded the salt of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[CH3:13]O.S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH3:13])=[O:7]
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)C=Cc1ccccc1F
Temperature: 0 °C
Reaction time: 4 h

Procedure:
15 gm of 2-fluorocinnamic acid was suspended into 100 ml of methanol. While maintaining the suspension at 0° C., 1.7 gm of thionyl chloride was added slowly. After the addition, the mixture was stirred for 30 minutes at 0° C. and for 4 hour at room temperature. The residue obtained by the removal of the solvent was subjected to silica gel column chromatography using chloroform as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 17.8 gm of the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[C:5]([O:17][CH3:18])[CH:4]=1)=[O:2].[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:19]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][C:6]1[CH:15]=[CH:16][C:3]([CH:1]=[O:2])=[CH:4][C:5]=1[O:17][CH3:18])(=[O:21])[CH3:20]
Reactant: COc1cc(C=O)ccc1OCCCCCCO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1cc(C=O)ccc1OCCCCCCOC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
A flame-dried, 250 mL round bottom flask was charged, under argon, with 2 (10 g, 39.6 mmol) and this was dissolved in 50 mL of anhydrous pyridine and the flask was protected from light. To this solution was added acetic anhydride (9.3 mL, 98.8 mmol) dropwise at a rate of 0.5 mL/minute. The solution was stirred at room temperature for 30 minutes at which time all of the starting material had been consumed. The solvent was evaporated with reduced pressure and then toluene was added to remove excess pyridine. Evaporation of the solvent in vacuo gave 11.5 g (99%) of 3 as an off-white solid. Rf=0.74 (33% ethyl acetate/hexane). Mp 74.0-75.0° C. 1H NMR (400 MHz, DMSO-d6): δ9.83 (s, 1), 7.53 (dd, J=1.6 Hz, 8.4 Hz, 1), 7.39 (d, J=2.0 Hz, 1),), 7.17 (d, J=8.4 Hz, 1), 4.07 (t, J=6.4 Hz, 2), 4.00 (pt, J=6.4 Hz, 6.8 Hz, 2), 3.83 (s, 3), 2.00 (s, 3) 1.74 (m, 2), 1.58 (m, 2), 1.4-1.35 (m, 4) ppm.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc([N+](=O)[O-])cc23)c1
Product: O=[N+]([O-])c1cccc(CNc2nc(-n3ccnc3)nc3sc([N+](=O)[O-])cc23)c1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-nitro-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-nitro-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.CC(C)([O-])C.[K+].[N+]([C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1)([O-])=O>CN(C)C=O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 82 %

Procedure:
Methyl 4-(4-phenoxyphenoxy)benzoate is synthesized as follows. A mixture of 15.00 g (80.6 mmoles) of 4-phenoxyphenol, 130 ml of N,N-dimethylformamide and 75 ml of toluene is agitated under nitrogen atmosphere. Potassium t-butoxide (9.32 g, 80.6 mmoles) is added with vigorous stirring and the mixture is heated to reflux. An azeotrope of t-butanol and toluene (85 ml) is collected at temperatures of 120° C. to 135° C. and is discarded. The mixture is cooled to ambient temperature, and a solution of 14.59 g (80.6 mmoles) of methyl 4-nitrobenzoate in 30 ml of N,N-dimethylformamide is added over a period of 15 minutes with cooling in a water bath. The mixture is heated at 100° C. for 14 hours, cooled to 20° C., and quenched with 1500 ml of ice water. The precipitate is filtered, dried in air and dissolved in 500 ml of acetone. The solution is filtered to remove insolubles, and the filtrate is concentrated by evaporation and cooled to precipitate methyl 4-(4-phenoxyphenoxy)benzoate. The recovered product weighs 21.23 g (82 percent yield) and has a melting point of 114° C. as determined by DSC.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[C:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:3]=1[C:4]#[N:5].[NH2:17][S:18](N)(=[O:20])=[O:19]>O1CCOCC1>[S:18]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[C:11][CH2:12][Si:13]([CH3:14])([CH3:16])[CH3:15])[C:3]=1[C:4]#[N:5])(=[O:20])(=[O:19])[NH2:17]
Reactant: NS(N)(=O)=O
Reactant: C[Si](C)(C)CC#Cc1cccc(N)c1C#N
Solvent: C1COCCO1
Product: C[Si](C)(C)CC#Cc1cccc(NS(N)(=O)=O)c1C#N
Yield: 5 %

Procedure:
A solution of 2-amino-6-(3-(trimethylsilyl)prop-1-ynyl)benzonitrile (Example 253b) (557 mg, 2.0 mmol) and NH2SO2NH2 (0.96 g, 10 mmol) in dry 1,4-dioxane (50 mL) was refluxed under nitrogen for 2 days. The solvent was evaporated under reduced pressure, and the residue was purified by chromatography on silica gel eluting with 70% EtOAc in hexanes to give the title compound (31 mg, 5%) as a white solid. MS 308 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30](OCC)=[O:31])[CH2:25][CH2:24]2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:5]([CH3:35])[O:4][N:3]=1.[H-].[H-].[H-].[H-].[Al+3].[Li+]>C1COCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3([N:23]2[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][OH:31])[CH2:27][CH2:28]2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:5]([CH3:35])[O:4][N:3]=1
Reactant: CCOC(=O)CN1CCN(C2(c3ccccc3)C(=O)Nc3ccc(-c4c(C)noc4C)cc32)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1ccc2c(c1)C(c1ccccc1)(N1CCN(CCO)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
To a solution of Ethyl 2-(4-(5-(3,5-dimethylisoxazol-4-yl)-2-oxo-3-phenylindolin-3-yl)piperazin-1-yl)acetate (100 mg, 0.21 mmol) in THF (5 mL) was added lithium aluminium tetrahydride (38 mg, 1.05 mmol) at 0° C., the reaction mixture was stirred at RT for 2.0 h. After cooling to 0° C., the reaction was quenched by addition of aq. saturated NH4Cl solution (50 mL). The mixture was diluted with water and extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo to yield crude product which were purified on flash column chromatography to afford the title compound as a white solid (30 mg, 33%). 1H NMR (400 MHz, DMSO-d6): δ H 10.69 (s, 1H), 7.22-7.51 (m, 7H), 6.96 (d, J=8.0 Hz, 1H), 4.31 (s, 1H), 3.40-3.45 (m, 2H), 2.13-2.40 (m, 13H), 2.02 (s, 3H). MS (ESI) m/e [M+1]+ 433.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].Cl.[CH2:8]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)[CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.COCCOC>[Br:2][CH2:3][CH2:4][CH2:5][NH:6][C:27](=[O:28])[C:26]1[CH:25]=[CH:24][C:23]([NH:22][CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:31][CH:30]=1
Reactant: NCCCBr
Reactant: CCCCCCCCCC=CCCCNc1ccc(C(=O)Cl)cc1
Agent: Br
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CCCCCCCCCC=CCCCNc1ccc(C(=O)NCCCBr)cc1

Procedure:
To a slurry of 21.80 g. of 3-bromopropylamine hydrobromide in 200 ml. of glyme at 3° C. is added a solution of 23.9 g. of 4-(4-tetradecenylamino)benzoyl chloride hydrochloride in 65 ml. of glyme, concurrently with 26 ml. of triethylamine diluted to 39 ml. with 1,2-dimethoxyethane. The solution is warmed to reflux and 0.2 g. of 4-dimethylaminopyridine is added. The solution was heated for four hours and cooled overnight. The solid is removed and the mother liquor diluted with 200 ml. of water to yield a solid which is crystallized from cyclohexane and recrystallized from acetonitrile to yield the product.