Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=[O:41])=[O:40])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:49]([N:51]([CH2:66][CH3:67])[S:52](C1C=CC(CS(Cl)(=O)=O)=CC=1)(=[O:54])=[O:53])[CH3:50]>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:34][CH:35]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([CH2:42][C:43]1[CH:44]=[CH:45][C:46]([S:52](=[O:54])(=[O:53])[N:51]([CH2:66][CH3:67])[CH2:49][CH3:50])=[CH:47][CH:48]=1)(=[O:41])=[O:40])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCN(CC)S(=O)(=O)c1ccc(CS(=O)(=O)Cl)cc1
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: CCN(CC)S(=O)(=O)c1ccc(CS(=O)(=O)NCCc2c(CCOc3ccc(C(=O)O)cc3)c3cc(Cl)ccc3n2C(c2ccccc2)c2ccccc2)cc1

Procedure:
The title compound was prepared from 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoic acid methyl ester (Step 6, Example 1) and (4-Diethylsulfamoyl-phenyl)-methanesulfonyl chloride according to Example 1 Step 7.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1.[S-:16][C:17]#[N:18].[K+]>CS(O)(=O)=O>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([C:17](=[S:16])[NH2:18])=[CH:5][CH:4]=1
Reactant: COc1cccc2c1oc1ccccc12
Reactant: N#C[S-]
Agent: CS(=O)(=O)O
Agent: [K+]
Product: COc1ccc(C(N)=S)c2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a mixture of 4-methoxydibenzo[b,d]furan (1 g, 5.05 mmol) in methane sulphonic acid (11 mL), potassium thiocyanate (1 g, 10.29 mmol) was added at 0-5° C. Subsequently the reaction mass was stirred at room temperature for 3 h. The reaction mixture was poured into crushed ice and filtered. The solid was washed with hexane and dried, to furnish the required product in 70% yield; Rf 0.25 (Ethyl acetate:Hexane (3:7); HPLC (purity); 1H-NMR (CDCl3) δ: 4.08 (s, 3H), 6.97 (d, 1H), 7.26-7.30 (m, 1H), 7.33-7.37 (m, 1H), 7.65 (d, 1H), 7.69 (d, 1H), 7.94 (d, 1H), 8.31 (d, 1H); 91.4%; MS m/z: 258.1 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[CH2:6][O:5]1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CC(C)=O>[CH3:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[N:22]1[CH2:23][CH2:24][N:25]([CH2:2][CH2:3][CH:4]2[CH2:6][O:5]2)[CH2:26][CH2:27]1
Reactant: BrCCC1CO1
Reactant: Cc1cccc(N2CCNCC2)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cccc(N2CCN(CCC3CO3)CC2)c1C
Temperature: 65 °C
Reaction time: 16 h
Yield: 25.8 %

Procedure:
To a mixture of 2-(2-bromoethyl)oxirane obtained in step 1 (0.70 g, 4.61 mmol) and potassium carbonate (1.91 g, 13.8 mmol) in acetone (10 ml), was added 1-(2,3-dimethylphenyl)piperazine hydrochloride (1.04 g, 4.61 mmol) at room temperature. The resulting reaction mixture was stirred at 65° C. for 16 hours. After the reaction complete, the reaction mixture thus obtained was filtered through a plug of Celite. The filtrate was concentrated under reduced pressure to obtain the title compound (0.31 g). The compound was used for the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[S:18][C:17]([C:19]([O:21][CH3:22])=[O:20])=[C:16]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:15]=3)=[C:9]([N+:31]([O-])=O)[CH:8]=2)[CH:4]=[N:3]1.[CH3:34]OC(OC)OC.C(O)=O>CO.[Zn]>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]3[N:13]([C:14]4[S:18][C:17]([C:19]([O:21][CH3:22])=[O:20])=[C:16]([O:23][CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH:15]=4)[CH:34]=[N:31][C:9]=3[CH:8]=2)[CH:4]=[N:3]1
Reactant: COC(OC)OC
Reactant: COC(=O)c1sc(Nc2ccc(-c3cnn(C)c3)cc2[N+](=O)[O-])cc1OCc1ccccc1
Agent: [Zn]
Solvent: O=CO
Solvent: CO
Product: COC(=O)c1sc(-n2cnc3cc(-c4cnn(C)c4)ccc32)cc1OCc1ccccc1
Temperature: 70 °C
Yield: 86.9 %

Procedure:
Methyl 5-{[4-(1-methyl-1H-pyrazol-4-yl)-2-nitrophenyl]amino}-3-[(phenylmethyl)oxy]-2-thiophenecarboxylate (1.0 g, 2.2 mmol) from a different batch than that made in Step A3, was dissolved In MeOH (30 mL). Trimethylorthoformate (6.0 mL, 54 mmol) was added followed by formic acid (0.81 ml, 21.5 mmol). Zinc dust (0.70 g, 11 mmol) was added and the reaction mixture was heated to 70° C. for 2 h and then cooled to rt. The reaction mixture was filtered through a pad of celite which was then washed with 20% MeOH/DCM. The crude reaction mixture was concentrated to remove the MeOH and the remaining mixture was poured into half-saturated aqueous NaHCO3 solution and then extracted with a mixture of 4:1 DCM:i-PrOH. The combined organics were dried over anhydrous MgSO4 and purified by flash chromatography to give 850 mg (89%) of the title compound, methyl 5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-3-[(phenylmethyl)oxy]-2-thiophenecarboxylate. MS (ESI): 445 [M+H]+
Reaction SMILES: C([NH:4][CH:5]([C:11]([O:13]CC)=[O:12])[C:6](OCC)=O)(=O)C.[O-]CC.[Na+].[Na].BrC[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[NH2:4][CH:5]([CH2:6][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: BrCCCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: NC(CCCc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
Diethyl acetamidomalonate (220 g) in 1 L of absolute ethanol was added to a stirred solution of sodium ethoxide in ethanol, prepared by dissolving sodium (24 g) in absolute ethanol (500 mL), under nitrogen. The reaction mixture was refluxed under nitrogen for 30 minutes and then 1-bromo-3-phenylpropane (200 g) was added. The reaction mixture was refluxed overnight, cooled to ambient temperature, the precipitate removed by filtration and the solvent removed in vacuo. Concentrated hydrochloric acid (800 mL) was added to the residue and the reaction mixture was refluxed for 14 hours. The cooled aqueous solution was washed with ether (2×200 mL). The residual ether in the aqueous phase was removed by nitrogen bubbling through the solution. The pH of the aqueous phase was adjusted to 7-8 by the addition of ammonium hydroxide. The title compound was collected by filtration, air dried and recrystallized from ethanol-water to afford 150 g (83%). m.p. 255°-257° C. MS (FAB) m/e 194 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[NH:15][C:14]1=[S:26])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].O.[CH2:29](O)C.[OH-].[NH4+].IC>O>[CH3:1][C:2]([CH3:27])([CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:15]=[C:14]1[S:26][CH3:29])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(CNC(=O)OC(C)(C)C)Cn1c(=S)[nH]c2cnc3ccccc3c21
Reactant: CCO
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: CSc1nc2cnc3ccccc3c2n1CC(C)(C)CNC(=O)OC(C)(C)C

Procedure:
A suspension of tert-butyl 2,2-dimethyl-3-(2-thioxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate (7.78 g, 20.1 mmol) and 100 mL of 1:1 water/ethanol was treated with 20 mL of concentrated ammonium hydroxide and iodomethane (1.50 mL, 24.2 mmol). Two hours later an additional 50 mL of H2O was added, and the precipitate was filtered and rinsed with ether. When the ether was added, the funnel became clogged, so the precipitate was transferred into a flask with the aid of methanol and CH2Cl2. The solvents were removed under reduced pressure to give a light yellow solid. The filtrate was then concentrated under reduced pressure to ˜150 mL of mostly water. Organic material was extracted from this solution using CH2Cl2 (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, combined with the precipitated material, and concentrated under reduced pressure to give tert-butyl 2,2-dimethyl-3-[2-(methylthio)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate (7.81 g) as a light yellow solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[C:4]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=2)[N:7]=[C:6]([CH2:17][CH3:18])[C:5]=1[C:19]#[N:20])[CH3:2].B(Br)(Br)Br.O>C(Cl)Cl>[CH2:21]([N:3]([CH2:1][CH3:2])[C:4]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[N:7]=[C:6]([CH2:17][CH3:18])[C:5]=1[C:19]#[N:20])[CH3:22]
Reactant: CCc1nn(-c2ccc(OC)cc2)c(N(CC)CC)c1C#N
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCc1nn(-c2ccc(O)cc2)c(N(CC)CC)c1C#N
Yield: 97.4 %

Procedure:
The 5-(diethylamino)-3-ethyl-1-(4-methoxyphenyl)-1H-pyrazole-4-carbonitrile (39 mg, 0.13 mmol) from above was dissolved in CH2Cl2 (5 mL) and BBr3 (1 M solution in DCM, 1 mL, 1.0 mmol) was added and stirred over night. CH2Cl2 and water were added and the phases were separated, the aqueous phase was again extracted with EtOAc/CH2Cl2 (1:1). The solution was dried using a phase separator and concentrated under reduced pressure. Purification using preparative HPLC gave 5-(diethylamino)-3-ethyl-1-(4-hydroxyphenyl)-1H-pyrazole-4-carbonitrile (36 mg, 97%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH2:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CC(O)=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH:10][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)C1CC(N)CN1C(=O)OC(C)(C)C
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)C1CC(NCc2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, dissolved in DCM and cooled to 0 centigrade is added a corresponding benzaldehyde, then NaBH(OAc)3 and 5 drops of HOAc. The mixture is warmed to room temperature and stirred overnight. The mixture is diluted with DCM, washed with brine, and dried. After removal of solvent, the crude 4-(benzylamino)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester is obtained (33) and used for the next step without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)=O.C(C1C=C2C(=CC=1)NC=C2)#N.[C:23]([CH2:28][CH:29]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:25][CH2:26][CH3:27])=[O:24]>>[CH3:29][C:28](=[CH:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#Cc1ccc2[nH]ccc2c1
Product: CCOC(=O)C(C)=Cc1ccc2[nH]ccc2c1

Procedure:
Using a similar procedure to that described in Example 12, part c, except starting from 5-formylindole (prepared as described in the literature from 5-cyanoindole: F. Troxler, Helv. Chim. Acta., 51, 1616, (1968)), and using carbethoxyethylidene triphenylphosphorane, ethyl α-methylindol-5-acrylate was obtained (79%) as a low-melting white solid (mp about 50°); partial NMR(250 MHz, DMSO-d6): 1.28(t, 3H, CH2CH3), 2.13(d, J=1.0 Hz, 3H, CCH3), 4.19(q, 2H, CH2CH3), 6.49(m, 1H, H3 -indole), 11.28(br s, 1H, H1 -indole).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH:34]1([NH:37][CH3:38])[CH2:36][CH2:35]1>C1COCC1.CCOC(C)=O>[CH:34]1([N:37]([CH3:38])[S:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:10]3[N:9]=[C:8]([C:6]4[CH:5]=[C:4]([C:24]5[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=5)[CH:3]=[C:2]([CH3:1])[N:7]=4)[CH:13]=[CH:12][CH:11]=3)[CH:15]=2)(=[O:22])=[O:21])[CH2:36][CH2:35]1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: CNC1CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)N(C)C4CC4)c3)n2)n1
Yield: 51.4 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with commercially available N-cyclopropyl-N-methylamine [CAS-no. 5163-20-2] (0.16 ml, 2.05 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.110 g, 51%) as a white solid. MS (ISP) 524.3 [(M+H)+]; mp 157° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+].Br[CH2:21][C:22]1[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]>O>[CH3:1][N:2]([CH2:21][C:22]1[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccccc1CBr
Reactant: CCOC(=O)Cc1ccc(NC)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)Cc1ccc(N(C)Cc2ccccc2C(=O)OCC)cc1
Temperature: 90 °C
Yield: 112.1 %

Procedure:
A mixture of N-methyl-4-ethoxycarbonylmethylaniline (10 g), sodium hydrogencarbonate (5 g) and water (5 ml) was heated to 90° C. on an oil bath. Ethyl 2-bromomethylbenzoate (12.2 g) was gradually added dropwise to the mixture with stirring. Then, the mixture was stirred for 2 hours at 90° C. The reaction mixture was cooled, and extracted with benzene. The extract was washed with water. The benzene layer was extracted with 2 N-HCl. The aqueous layer was neutralized with potassium carbonate while cooling the layer with ice, and extracted with benzene. The benzene layer was dried over anhydrous magnesium sulfate. When the solvent was distilled off under reduced pressure, 20 g of N-methyl-N(2-ethoxycarbonylbenzyl)-4-ethoxycarbonylmethylaniline was obtained as a light-yellow oily material.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[C@@H:5]([CH3:36])[CH2:4]1.[C:37](Cl)(=[O:39])[CH3:38]>>[C:37]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[C@@H:5]([CH3:36])[CH2:4]1)(=[O:39])[CH3:38]
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)C[C@@H]1C
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)[C@@H](C)C1

Procedure:
Starting from N-[(1S*,2S*,4S*)-4-amino-2-methylcyclohexyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f63) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[I-].[Na+].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[C:27]([N+:33]([O-:35])=[O:34])[CH:26]=1>CN(C)C=O>[OH:1][CH2:2][CH:3]([N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[CH2:29][C:28]1[CH:31]=[CH:32][C:25]([Cl:24])=[CH:26][C:27]=1[N+:33]([O-:35])=[O:34])[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CCl
Reactant: COC(=O)C(CO)NS(=O)(=O)c1ccc(OC)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CO)N(Cc1ccc(Cl)cc1[N+](=O)[O-])S(=O)(=O)c1ccc(OC)cc1

Procedure:
To a solution of 0.289 g (1 mmol) of methyl 3-hydroxy-2-(4-methoxybenzenesulfonylamino)propionate in 4 ml of N,N-dimethylformamide cooled in an ice bath was added 40 mg of NaH (60% in oil) (1 mmol). After the gas evolution ceased, 0.165 g (1.1 mmol) of sodium iodide was added, followed by the addition of 0.226 g (1.1 mmol) of 4-chloro-2-nitrobenzyl chloride in 1 ml of dimethylformamide.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)[CH3:10].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:1]1([C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccccc1
Reactant: Br[Mg]c1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: C=C(c1ccccc1)c1ccccc1

Procedure:
Crude DPE (Aldrich or from reaction of phenylmagnesium bromide with acetophenone, acetylation with acetic anhydride and thermal elimination of acetic acid) is distilled through a column having at least 50 theoretical plates (spinning-band column; a Sulzer packed column for larger amounts) to a purity of 99.8%. The usually slightly yellow distillate is filtered through a 20 cm Alox column (Woelm alumina for chromatography, anhydrous), titrated with 1.5N sec-butyllithium to a deep red color and distilled off over a simple still head under reduced pressure (1 mbar). The resulting product is completely colorless and can be used directly in the anionic polymerization.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[CH3:25][N:26]([NH2:28])[CH3:27]>CN(C=O)C>[Cl:15][C:12]([F:14])([F:13])[C:6]1[N:5]=[C:4]([C:16]([F:17])([F:19])[F:18])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([NH:28][N:26]([CH3:27])[CH3:25])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Reactant: CN(C)N
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1NN(C)C
Yield: 83.8 %

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 28, 1.9 ml (0.025 mol) of unsym-dimethylhydrazine in 30 ml of DMF were reacted affording a residue which was recrystallized in hot hexane to give 4.57 g (83.8%) of product as a yellow solid; mp 97°-98° C. C14H15Cl1F5N3O4
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([NH2:16])=[N:12][NH:13][C:14]=2[NH2:15])=[CH:6][CH:5]=1.CN(C)[CH:21]=[CH:22][CH:23]=O>C(O)C.C(O)(=O)C>[F:18][C:2]([F:1])([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([NH2:15])=[N:13][N:12]3[CH:23]=[CH:22][CH:21]=[N:16][C:11]=23)=[CH:6][CH:5]=1
Reactant: CN(C)C=CC=O
Reactant: Nc1n[nH]c(N)c1-c1ccc(OC(F)(F)F)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1nn2cccnc2c1-c1ccc(OC(F)(F)F)cc1
Yield: 107.5 %

Procedure:
In a microwave vessel containing the product from Example 1B (0.4 g, 1.549 mmol) and 3-(dimethylamino)acrylaldehyde (0.155 g, 1.549 mmol) in ethanol (5 mL) was added two drops of acetic acid. The mixture was irradiated with microwave at 140° C. for 15 minutes and concentrated. The resulting solid was purified by flash chromatography on silica gel, eluting with EtOAc/Hexanes (40-70% gradient), to yield the title compound (0.49 g, 59%). MS ESI+ m/z 295.5 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[CH:14]=[N:15][C:16]([NH:19][C:20]3[C:25]([N+:26]([O-])=O)=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:29])=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[CH:14]=[N:15][C:16]([NH:19][C:20]3[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:29])=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(C#Cc2cnc(Nc3c(C)cccc3[N+](=O)[O-])nc2)cc(OC)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(C#Cc2cnc(Nc3c(C)cccc3N)nc2)cc(OC)c1
Temperature: 85 °C
Reaction time: 1 h
Yield: 40.2 %

Procedure:
A mixture of 5-((3,5-dimethoxyphenyl)ethynyl)-N-(2-methyl-6-nitrophenyl)pyrimidin-2-amine (150 mg, 0.38 mmol), Iron (171 mg, 3.04 mmol) and ammonium chloride (246 mg, 4.56 mmol) in ethanol (20 mL) and water (2 mL) was stirred at 85° C. for 1 h. LCMS showed the reaction was completed. The reaction was cooled to RT, and the solid was filtered off. The filtrate was concentrated, and the residue was purified by Prep-HPLC to afford the title compound as a white solid (55 mg, 44%). MS (ES+) C21H20N4O2 requires: 360. found: 361 [M+H]+. 1H-NMR (500 MHz, DMSO-d6) δ ppm 8.76 (s, 1H), 8.50-8.46 (br, 2H), 6.88 (t, 1H, J=7.0 Hz), 6.66 (s, 2H), 6.57 (d, 1H, J=7.5 Hz), 6.54 (s, 1H), 6.44 (d, 1H, J=6.5 Hz), 4.74 (s, 2H), 3.76 (s, 6H), 2.01 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20](O)[CH:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=1.B(F)(F)F.CCOCC>O1CCOCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:3]2[C:4](=[O:12])[O:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=1
Reactant: CC(C)C(O)c1ccc(Br)cc1
Reactant: O=c1cc(O)c2ccccc2o1
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)C(c1ccc(Br)cc1)c1c(O)c2ccccc2oc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.8 %

Procedure:
To a flame-dried flask containing a near-solution of 324 mg of 4-hydroxycoumarin and 573 mg of 1-(4-bromophenyl)-2-methylpropan-1-ol of Preparation 14 in 10 mL of dioxane under an argon atmosphere is added 1.2 mL of boron trifluoride etherate. The resulting yellow solution is left to stir at room temperature overnight. The volatiles are removed and the residue is partioned between diethyl ether and 1N sodium hydroxide. The basic aqueous phase is washed with diethyl ether and acidified to pH=1 with 6N hydrochloric acid. The resulting precipitant is repeatedly extracted with dichloromethane (methanol-chloroform co-solvents). The combined dichloromethane extracts are washed once with dilute sodium bicarbonate to remove most of the unreacted 4-hydroxycoumarin, then brine, dried (magnesium sulfate), and finally concentrated under reduced pressure. The residue is adsorbed onto silica and flash column chromatographed with 50% to 60% ethyl acetate in hexanes to yield 28 mg of the title product as a tan solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)CCCNC(=O)OC(C)(C)C
Temperature: 45 °C
Reaction time: 12 h
Yield: 82.7 %

Procedure:
To a solution of 4-(tert-butoxycarbonylamino)butanoic acid (7.0 g, 34.5 mmol) and K2CO3 (9.5 g, 68.9 mmol) in acetone (70 mL) was added MeI (7.5 g, 51.8 mmol) at rt. The reaction solution was stirred at 45° C. for 12 hrs. The mixture was washed with water and saturated sodium chloride, dried over Na2SO4, and concentrated to afford methyl 4-(tert-butoxycarbonylamino)butanoate (6.2 g, 83%) as a yellow oil. ESI-MS (EI+, m/z): 240 [M+Na]+.