Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5](Cl)=[C:4]2[N:9]=[CH:10][CH:11]=[CH:12][C:3]=12.[CH3:13][C@H:14]1[NH:19][CH2:18][CH2:17][N:16]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])[CH2:15]1>ClCCl>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:19]2[CH2:18][CH2:17][N:16]([C:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:21])[CH2:15][C@H:14]2[CH3:13])=[C:4]2[N:9]=[CH:10][CH:11]=[CH:12][C:3]=12
Reactant: Clc1nnc(Cl)c2ncccc12
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(Cl)c2cccnc12
Temperature: 100 °C
Yield: 43.5 %

Procedure:
To a reaction vial was added 5,8-dichloropyrido[2,3-d]pyridazine 78 (165 mg, 825 μmol) and (R)-(3-methylpiperazin-1-yl)(phenyl)methanone (337 mg, 1.65 mmol). The mixture was heated to 100° C. for 2 h. After cooling to room temperature, the resultant glassy product was dissolved in dichloromethane (40 mL) and washed with 1×5 mL NaHCO3 and 1×5 mL of brine. The organic layer was dried over MgSO4, filtered and concentrated. Purification by silica gel column chromatography using a gradient of 70% ethyl acetate in hexanes to 90% EtOAc in hexanes afforded the regioisomeric products. The first eluting product (R)-(4-(5-chloropyrido[2,3-d]pyridazin-8-yl)-3-methylpiperazin-1-yl)(phenyl)methanone 79 (132 mg, 44% yield) was the major product, the second eluting product (R)-(4-(8-chloropyrido[3,2-d]pyridazin-5-yl)-3-methylpiperazin-1-yl)(phenyl)methanone 80 (74 mg, 24% yield) was the minor product. Data for 79: 1H-NMR (400 MHz, CDCl3): δ 9.10 (brs, 1H), 8.47 (dd, J=8.2, 1.6 Hz, 1H), 7.83 (dd, J=8.2, 4.3 Hz, 1H), 5.46 (br m, 1H), 4.97-4.40 (series of m, 2H), 3.99-3.20 (series of m, 4H), 1.40 (br m, 3H). MS 367.1 (calc'd) 368.0 (M+H, found). Data for (R)-(4-(8-chloropyrido[3,2-d]pyridazin-5-yl)-3-methylpiperazin-1-yl)(phenyl)methanone: 1H-NMR (400 MHz, CDCl3): δ 9.27 (dd, J=4.3, 1.6, 1H), 8.39 (J=8.6, 1.6 Hz, 1H), 7.83 (dd, J=8.2, 4.3 Hz, 1H), 7.45 (s, 5H), 4.31 (br s, 1H), 4.11 (br s, 1H), 2.68 (m, 5H), 1.27 (br s, 3H). MS 367.1 (calc'd) 368.0 (M+H, found).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)=[C:18]([Cl:33])[CH:17]=3)=[N:12][CH:11]=[N:10][C:9]=2[CH:8]=[CH:7]1.C(N(CC)CC)C.C([O:44][C:45]([C:48](Cl)=[O:49])([CH3:47])[CH3:46])(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:33][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[C:14]3[N:6]([CH2:5][CH2:4][NH:3][C:48](=[O:49])[C:45]([OH:44])([CH3:47])[CH3:46])[CH:7]=[CH:8][C:9]=3[N:10]=[CH:11][N:12]=2)[CH:21]=[CH:20][C:19]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(O)C(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg) and triethylamine (0.40 mL) in tetrahydrofuran (5.0 mL) was added 1-chlorocarbonyl-1-methylethyl acetate (0.12 mL) at room temperature. After stirring at room temperature for 3 days, aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. To a solution of the residue in ethanol (3.0 mL) was added 1N aqueous sodium hydroxide solution (1.5 mL) at room temperature. After stirring at room temperature for 24 hrs, the mixture was extracted with ethyl acetate. The organic layer washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate→ethyl acetate:methanol=9:1) to give the title compound (133 mg) as colorless crystals.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([CH:18]=O)[C:12]=3[CH2:11][CH2:10][C:9]2=[O:20])=[CH:3][CH:2]=1.[S:27]=[C:28]1[NH:32][C:31](=[O:33])[CH2:30][S:29]1>C1(C)C=CC=CC=1.N1CCCCC1.C(O)(=O)C>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:17]3[C:12](=[C:13]([CH:18]=[C:30]4[S:29][C:28](=[S:27])[NH:32][C:31]4=[O:33])[CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]2=[O:20])=[CH:3][CH:2]=1
Reactant: O=Cc1cccc2c1CCC(=O)N2Cc1ccc(-c2ccccc2)cc1
Reactant: O=C1CSC(=S)N1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=C1NC(=S)SC1=Cc1cccc2c1CCC(=O)N2Cc1ccc(-c2ccccc2)cc1
Yield: 116.6 %

Procedure:
1.50 g of 1-(biphenyl-4-ylmethyl)-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde and 0.761 g of 2-thioxo-1,3-thiazolidin-4-one were suspended in 20 ml of toluene. Two drops of piperidine and two drops of acetic acid were added to the suspension, followed by heating and refluxing for 4 hours. After allowing to cool, the solid thus precipitated was collected by filtration, and dried, giving 2.34 g (91% yield) of 1-(biphenyl-4-ylmethyl)-5-(4-oxo-2-thioxothiazolidine-5-ylidenemethyl)-3,4-dihydro-1H-quinolin-2-one as a yellow powder.
Reaction SMILES: Br.[N:2]1([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])O.[Na+].N1(C2C=C3C(=CC=2)NC(=O)CC3)CCNCC1.[Cl:41][C:42]1[CH:50]=[CH:49][C:45]([C:46](Cl)=[O:47])=[CH:44][CH:43]=1>CN(C=O)C.O.C(N(CC)CC)C>[Cl:41][C:42]1[CH:50]=[CH:49][C:45]([C:46]([N:5]2[CH2:6][CH2:7][N:2]([C:8]3[CH:9]=[C:10]4[C:15](=[CH:16][CH:17]=3)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]4)[CH2:3][CH2:4]2)=[O:47])=[CH:44][CH:43]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1CCc2cc(N3CCN(C(=O)c4ccc(Cl)cc4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.9 %

Procedure:
6-(1-Piperazinyl)-3,4-dihydrocarbostyril monohydrobromide (3.5 g) was suspended in 40 ml of DMF. After adding 960 mg of sodium hydrogencarbonate, the suspension was stirred at room temperature for 30 minutes to convert the starting compound to 6-(1-piperazinyl)-3,4-dihydrocarbostyril. Then, to the mixture was added 2.34 ml of triethylamine and the mixture was stirred at room temperature while slowly adding dropwise 10 ml of DMF solution containing 2.5 g of 4-chlorobenzoyl chloride. After completion of addition the reaction mixture was stirred for 30 minutes. The reaction mixture was poured into a large amount of water and extracted with chloroform. The extract was washed with saturated sodium hydrogen carbonate solution and subsequently with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and residual crystals were recrystallized from methanol to give 0.7 g of 6-[4-(4-chlorobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 233°-235° C., pale yellow needles.
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.C(O)C.O.[NH2:23]N>C(O)(=O)C>[NH:1]([C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1)[NH2:23]
Reactant: NC1=Nc2ccccc2C(c2ccccc2)=NC1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: NNC1=Nc2ccccc2C(c2ccccc2)=NC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2.35 parts of 2-amino-5-phenyl-3H-1,4-benzodiazepine, 50 parts by volume of ethanol and 1.2 parts by volume of glacial acetic acid is added 1.5 parts by volume of 100% hydrazine hydrate and the mixture is stirred for 1 hour at room temperature. Treatment of the mixture in a similar manner to Example 2 yields 2-hydrazino-5-phenyl-3H-1,4-benzodiazepine as white crystals. Recrystallization from a mixture of methylene chloride and benzene yields white crystals melting at 116° to 118° C. (effervescence).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:10][C:4]=2[CH:3]=1.[CH2:17]([O:19][C:20](Cl)=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([N:10]1[C:4]2[CH:3]=[C:2]([Br:1])[N:7]=[CH:6][C:5]=2[CH:8]=[C:9]1[C:11]1[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=1)=[O:21])[CH3:18]
Reactant: Cn1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)n1c(-c2cnn(C)c2)cc2cnc(Br)cc21

Procedure:
Prepared according to Preparation 128 using 6-bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 22) and ethylchloroformate. 1H-NMR (500 MHz, CDCl3): δ 1.38 (t, J=7.1 Hz, 3H), 3.95 (s, 3H), 4.45 (q, J=7.1 Hz, 2H), 6.56 (s, 1H), 7.62 (s, 1H), 7.63 (s, 1H), 8.12 (s. 1H), 8.53 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.CCCCCC>C(Cl)Cl>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=3[NH:4][C:3]2=[O:20])=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(NC1N=C(c2ccccc2F)c2ccccc2NC1=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,3-Dihydro-3-(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (100 mg, 0.37 mmol) and p-chlorobenzoyl chloride (52 μl, 0.41 mmole) were combined at room temperature in 5 ml of methylene chloride. The resulting solution was protected from moisture and stirred at room temperature overnight. The reaction mixture was diluted with 70 ml of methylene chloride and washed with sodium bicarbonate solution (sat.) and brine. The organic extracts were dried (MgSO4) and concentrated to give 150 mg of crude product. Chromatography on silica gel (chloroform - methanol - ammonia, 95:5:0.5 v/v) and trituration with hexane yielded the analytical product as a white powder, m.p. 258°-259° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C@H:5]([CH3:10])[CH2:6][C:7]([OH:9])=[O:8].Cl[C:13]([O:15][CH3:16])=[O:14]>>[CH3:1][O:2][C:3](=[O:11])[CH:4]([C:13]([O:15][CH3:16])=[O:14])[C@H:5]([CH3:10])[CH2:6][C:7]([OH:9])=[O:8]
Reactant: COC(=O)Cl
Reactant: COC(=O)C[C@H](C)CC(=O)O
Product: COC(=O)C(C(=O)OC)[C@H](C)CC(=O)O

Procedure:
Scheme 1 illustrates an exemplary method for making a compound of the formula 1.3. Starting from (R)-5-methoxy-3-methyl-5-oxopentanoic acid, reaction with methyl chloroformate gives (R)-5-methoxy-4-(methoxycarbonyl)-3-methyl-5-oxopentanoic acid, which can be esterified with, for example, trimethylsilyl chloride and methanol to give compound 1.3, (R)-trimethyl 2-methylpropane-1,1,3-tricarboxylate.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH:4](=O)[CH:5]([CH3:7])[CH3:6].[NH2:9][N:10]1[CH:15]([CH3:16])[CH2:14][CH2:13][CH2:12][CH:11]1[CH3:17].Cl>O.CO>[CH3:17][CH:11]1[CH2:12][CH2:13][CH2:14][CH:15]([CH3:16])[N:10]1[NH:9][CH:4]([CH:5]([CH3:7])[CH3:6])[C:1]#[N:2]
Reactant: CC1CCCC(C)N1N
Reactant: [C-]#N
Reactant: CC(C)C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)C(C#N)NN1C(C)CCCC1C
Temperature: 25 °C
Reaction time: 192 h

Procedure:
A solution of 4.9 g of sodium cyanide in 10 ml of water and a solution of 7.2 g of isobutyraldehyde in 30 ml of methanol are added dropwise with ice-cooling to a mixture of 6.4 g of 1-amino-2,6-dimethylpiperidine, 60 ml of water and 8.6 ml of concentrated hydrochloric acid. After stirring at room temperature for 8 days, the methanol is stripped off on a rotary evaporator and the solution is extracted with dichloromethane. The combined organic phases are washed with water of pH 5 containing acetic acid, dried and concentrated. 11.2 g of 2-((2,6-dimethylpiperidino)amino)-3-methylbutyronitrile remain, which are employed in the following step without further purification.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][NH:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]([C:23](=[O:34])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=1)[CH2:18][CH2:17][CH2:16]2.I[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>>[CH2:40]([O:39][C:37]([CH2:36][N:12]([CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]([C:23](=[O:34])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=1)[CH2:18][CH2:17][CH2:16]2)=[O:38])[CH3:41]
Reactant: CCOC(=O)CI
Reactant: N#Cc1ccc(CCC(=O)N2CCCc3cc(NCc4ccc5ccccc5c4)ccc32)cc1
Product: CCOC(=O)CN(Cc1ccc2ccccc2c1)c1ccc2c(c1)CCCN2C(=O)CCc1ccc(C#N)cc1

Procedure:
Prepared from 6-[(naphthalin-2-ylmethyl)-amino]-1-[3-(4-cyano-phenyl)-propionyl]-1,2,3,4-tetrahydro-quinoline (see Example 14(2)) and ethyl iodoacetate
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:23]([N+:24]([O-])=O)=[CH:22][C:21]([F:27])=[C:20]([CH3:28])[C:10]=1[C:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].CCOC(C)=O>C1COCC1.O>[NH2:24][C:23]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([C:20]([CH3:28])=[C:21]([F:27])[CH:22]=1)[C:11]([O:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:12]
Reactant: Cc1c(F)cc([N+](=O)[O-])c(OCc2ccccc2)c1C(=O)Oc1ccccc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(F)cc(N)c(OCc2ccccc2)c1C(=O)Oc1ccccc1
Yield: 108.1 %

Procedure:
A solution of compound 65 (700 g, 1.84 mol) in THF (7 L) was cooled to 12° C. and stirred while adding a solution of Na2S2O4 (1599 g, 9.18 mol) in water (7.0 L) was added to the reaction with stirring. The exotherm was controlled by addition rate so that the reaction mixture temperature was below 17° C. The reaction mixture was then allowed to stir for 15 hours prior to adding 15.3 L EtOAc. The layers were separated and the organic layer was washed with successively with water (2×4 L and brine (1×4 L). The organic was dried over Na2SO4 and concentrated to give 699 g of a brownish solid that was recrystallized from heptane/toluene to afford 532 g (82.7%) of desired compound 66 obtained as an off-white solid.
Reaction SMILES: C1[O:3][CH:2]1[CH2:4][OH:5].[C:6](Cl)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:26](=[O:29])([OH:28])[O-].[K+]>N1C=CC=CC=1>[O:28]1[C:2]([CH2:4][OH:5])([OH:3])[CH:26]1[O:29][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C([O-])O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCC1CO1
Agent: [K+]
Solvent: c1ccncc1
Product: OCC1(O)OC1OC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 64.7 %

Procedure:
0.74 g of (RS)-glycidol and 2.8 g of trityl chloride in 5 ml of pyridine are reacted overnight. A solution of 2 g of potassium bicarbonate is then added while stirring. After evaporation, partition of the residue between water and methylene chloride and chromatography on silica gel with toluene there are obtained 2.25 g of (RS)-epoxy-1-O-tritylglycerol.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH3:24])=[C:9]1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]([O:36][CH3:37])=[O:35]>CC(C)=O>[CH3:37][O:36][C:34](=[O:35])[CH2:33][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([CH3:25])=[C:10]3[CH3:24])=[CH:22][CH:21]=1
Reactant: COC(=O)CBr
Reactant: Cc1c(C)n(Cc2ccccc2)c2ccc(-c3ccc(O)cc3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(-c2ccc3c(c2)c(C)c(C)n3Cc2ccccc2)cc1

Procedure:
The desired product was prepared using a procedure similar to step 1 of example 4. Thus, 4-(1-benzyl-2,3-dimethyl-1H-indol-5-yl)-phenol (0.300 g, 0.916 mmol) was reacted with K2CO3 (0.152 g, 1.099 mmol) and methyl bromoacetate (0.168 g, 1.099 mmol) in acetone (10 ml) to give the product (0.233 g, 0.583 mmol, 64%) as a purple solid, mp 133-136° C. 1H NMR (DMSO-d6) δ 2.24 (s, 3H), 2.28 (s, 3H), 3.71 (s, 3H), 4.82 (s, 2H), 5.39 (s, 2H), 6.98 (d, J=8.6 Hz, 4H), 7.20 (t, J=7.2 Hz, 1H), 7.26-7.29 (m, 3H), 7.37 (d, J=8.4 Hz, 1H), 7.58 (d, J=8.7 Hz, 2H), 7.62 (s, 1H); [ESI(+)], m/z 400 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[O:7])=[CH:4][CH:3]=1.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[Cl:16][C:10]1[C:11]([Cl:15])=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:18][CH:17]=1)=[O:7]
Reactant: O=C(Nc1cccc(Cl)c1Cl)c1ccc(O)cc1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Reaction time: 4 h
Yield: 93.7 %

Procedure:
28.2 g of 4-hydroxy-N-(2,3-dichlorophenyl)-benzamide, 20.0 g of ethyl bromoacetate and 20.7 g of potassium carbonate were dispersed in 150 ml of N,N-dimethylformamide, and the dispersion was stirred at a temperature of from 120° to 140° C. for 4 hours. After completion of the reaction, the reaction solution was poured into 500 ml of a 2% hydrochloric acid aqueous solution. The crude product obtained by collecting precipitates by filtration, was recrystallized from toluene to obtain 34.5 g of desired ethyl 4-(2,3-dichlorophenyl-carbamoyl)-phenoxyacetate. Yield: 93.4% Melting point: 126°-129° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:6]#[N:7].[C-:12]#[N:13].[K+]>C(O)C>[C:12]([CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:6]#[N:7])#[N:13]
Reactant: Cc1cc(C#N)cc(CBr)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Product: Cc1cc(C#N)cc(CC#N)c1
Temperature: 25 °C
Yield: 51.3 %

Procedure:
To a stirred ethanol (150 mL), was added 3-(bromomethyl)-5-methylbenzonitrile (48 g, 0.228M), potassium cyanide (27 g, 0.42M), and distilled water (77 mL). The mixture was then refluxed for 3 hr. After cooling to room temperature, the reaction mixture was evaporated in vacuo and the residue was partitioned between ether and water. The ether layer was taken, dried with anhydrous magnesium sulfate, filtered, evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ether:hexane (1:1)) to afford 18.3 g (51%) of 3-(cyanomethyl)-5-methylbenzonitrile as a pale yellow solid. m.p. 63-64° C. 1H NMR (300 MHz, CDCl3) δ 2.42 (3H, s), 3.77 (2H; s), 7.42 (2H, s), 7.45 (1H, s).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5].[C:12](OC(=O)C)(=[O:14])[CH3:13].[C:19](OCC)(=[O:21])[CH3:20]>>[C:12]([O:1][C:2]1[CH:9]=[C:8]([O:10][C:19](=[O:21])[CH3:20])[CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(C)=O
Reactant: O=Cc1c(O)cc(O)cc1O
Product: CC(=O)Oc1cc(O)c(C=O)c(OC(C)=O)c1

Procedure:
2,4,6-Trihydroxybenzaldehyde (4) (4.62 g, 30 mmol), acetic anhydride (6.13 g, 60 mmol) and a catalytic amount of N,N-dimethylaminopyridine (DMAP) in dry ethyl acetate (EtOAc) (100 mL) were refluxed overnight. The reaction mixture was filtrated, water (50 mL) was added and the water phase extracted with EtOAc (4×25 mL). The combined organic phases were washed with water (2×25 mL) and dried (MgSO4). The crude product was recrystallized from 1,2-dimethoxyethane (DME) to give the titled compound as white crystals, m.p. 103-105° C. Yield 4.3 g. (60%). 1H NMR (300 MHz, CDCl3): δ=2.29 (3H, s), 2.36 (3H, s), 6.61 (1H, s), 6.63 (1H, s), 10.04 (1H, s), 11.77 (1H, s); 13C NMR (75 MHz): δ=20.6 (CH3), 21.0 (CH3), 107.6 (CH), 108.1 (CH), 111.0 (C), 153.5 (C), 157.2 (C), 163.9 (C), 169.7 (C═O), 168.1 (C═O), 191.8 (HCO).
Reaction SMILES: C1C2C(COC(=O)[NH:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:34])[C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[OH:33])=[C:20]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH:19]=3)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C1COCC1.CN(C=O)C>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:34])[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[OH:33])=[C:20]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:19]=1
Reactant: O=C(Nc1ccc(NC(=O)c2ccc(F)cc2O)c(OCc2ccccc2)c1)OCC1c2ccccc2-c2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: Nc1ccc(NC(=O)c2ccc(F)cc2O)c(OCc2ccccc2)c1
Yield: 51 %

Procedure:
[3-Benzyloxy-4-(4-fluoro-2-hydroxy-benzoylamino)-phenyl]-carbamic acid 9H-fluoren-9-yl-methyl ester (75) (0.192 g, 0.334 mmol) was dissolved in a mixture of THF (3 mL) and DMF (1 mL). Piperidine (0.57 g, 6.68 mmol) was added. The mixture was shaken at room temperature in a Teflon septum capped vial for 20 minutes. TLC indicated complete de-protection at this point. The mixture was concentrated to give an oil. Purification by flash chromatography using a gradient of hexane and EtOAc (5–100% EtOAc in hexane for 25 minutes followed by 100% EtOAc for 5 minutes) gave the desired product (76) upon concentration (0.060 g, 0.170 mmol, 51% yield). LC-MS (ESI): (exact mass: 352.12) m/e=353.3 [M+1]+ (100%), 705.3 [2M+1]+ (5%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([N:12]([CH3:14])[CH3:13])=[CH:7][C:6]=1[CH3:15])=O.[NH2:16][C:17]([NH2:19])=[S:18]>CCO>[CH3:13][N:12]([CH3:14])[C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([C:3]2[N:16]=[C:17]([NH2:19])[S:18][CH:2]=2)=[C:6]([CH3:15])[CH:7]=1
Reactant: Cc1cc(N(C)C)cc(C)c1C(=O)CBr
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1cc(N(C)C)cc(C)c1-c1csc(N)n1
Yield: 60.7 %

Procedure:
A mixture of 2-bromo-1-(4-(dimethylamino)-2,6-dimethylphenyl)ethanone (1-3, 0.900 g, 3.33 mmol) and thiourea (0.250 g, 3.33 mmol) in 95% EtOH (4.8 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (30 mL) and saturated aqueous Na2CO3 (1.0 mL). The resultant precipitate was filtered and purified by flash column chromatography on silica gel to give 4-(4-(dimethylamino)-2,6-dimethylphenyl)thiazol-2-amine (1-4, 0.50 g) as brown solids in 61% yield: 1H NMR (500 MHz, CDCl3) δ 6.45 (s, 2 H), 6.25 (s, 1 H), 4.90 (bs, 2 H), 2.93 (s, 6 H), 2.15 (s, 6 H).
Reaction SMILES: Br[Si:2]([CH3:5])([CH3:4])[CH3:3].C([O:9][P:10]([CH2:16][CH:17]1[CH2:19][CH2:18]1)(=[O:15])[O:11]C(C)C)(C)C>>[CH3:3][Si:2]([O:9][P:10]([CH2:16][CH:17]1[CH2:19][CH2:18]1)(=[O:15])[O:11][Si:2]([CH3:5])([CH3:4])[CH3:3])([CH3:5])[CH3:4]
Reactant: CC(C)OP(=O)(CC1CC1)OC(C)C
Reactant: C[Si](C)(C)Br
Product: C[Si](C)(C)OP(=O)(CC1CC1)O[Si](C)(C)C
Temperature: 5 °C

Procedure:
Bromotrimethylsilane (43 mL, 0.326 mol) was added dropwise to cyclopropylmethyl-phosphonic acid diisopropyl ester (18.00 g, 81.8 mmol) stirred in a reaction flask chilled to 5° C. The resulting solution was allowed to warm to ambient temperature, stirred for three hours, and then concentrated by rotary evaporation yielding crude cyclopropylmethyl-phosphonic acid bis(trimethylsilyl) ester which was used without further purification.