Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:12])([CH3:11])[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:21][CH2:22][CH2:23][C:24]1[C:29]([OH:30])=[C:28]([C:31]([CH3:33])=[O:32])[CH:27]=[CH:26][C:25]=1[OH:34]>>[C:31]([C:28]1[CH:27]=[CH:26][C:25]([O:34][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:12])([CH3:11])[C:7]([O:9][CH3:10])=[O:8])=[C:24]([CH2:23][CH2:22][CH3:21])[C:29]=1[OH:30])(=[O:32])[CH3:33]
Reactant: COC(=O)C(C)(C)CCCCBr
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCCc1c(OCCCCC(C)(C)C(=O)OC)ccc(C(C)=O)c1O

Procedure:
Following the procedure of Example 15, 2.5 g. of methyl 6-bromo-2,2-dimethylhexanoate, 1.46 g. of potassium carbonate, a catalytic amount of potassium iodide, and 2.14 g. of 2,4-dihydroxy-3-propylacetophenone were reacted to give 2.96 g. of the title product as a brown oil. IR, NMR.
Reaction SMILES: [CH3:1][N:2]1[CH:7]([C:8]([OH:10])=O)[C:6](=[O:11])[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[S:3]1(=[O:17])=[O:16].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C(OC(N1C2C(=CC=CC=2)C=CC1OCC)=O)C>O1CCCC1>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[NH:18][C:8]([CH:7]1[C:6](=[O:11])[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[S:3](=[O:17])(=[O:16])[N:2]1[CH3:1])=[O:10]
Reactant: CN1C(C(=O)O)C(=O)c2ccccc2S1(=O)=O
Reactant: Nc1ccccn1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: C1CCOC1
Product: CN1C(C(=O)Nc2ccccn2)C(=O)c2ccccc2S1(=O)=O

Procedure:
To a solution of 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid-1,1-dioxide (127 mg.) and 2-aminopyridine (52 mg.) in tetrahydrofuran (5 ml.) is added, with stirring, a solution of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (148 mg.) in tetrahydrofuran (1 ml.). The mixture is stirred at room temperature (23°-25° C.) for four hours and is then concentrated under reduced pressure to an oil. Thin layer chromatography on silica gel plates in the system - benzene:acetic acid (95:5) and visualization of the plate under a 366 mμ lamp showed, by comparison with an authentic sample, the title compound is present.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:32][N:33]([CH:41]=[O:42])[O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[C:8]([N:10]2[CH:14]([C:15]([NH:17][C:18]3[N:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][N:11]2C(OCC=C)=O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1CCOCC1>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([CH2:6][C@H:7]([CH2:32][N:33]([CH:41]=[O:42])[O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[N:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][NH:11]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C=CCOC(=O)N1CCC(C(=O)Nc2ncc(OC)cn2)N1C(=O)[C@H](CC1CCCC1)CN(C=O)OC1CCCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1COCCN1
Product: COc1cnc(NC(=O)[C@@H]2CCNN2C(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.2 %

Procedure:
Pd(Ph3P)4 (23.77 mg, 0.021 mmol) was added to a solution of 2-propen-1-yl 2-((2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoyl)-3-({[5-(methyloxy)-2-pyrimidinyl]amino}carbonyl)-1-pyrazolidinecarboxylate (173 mg, 0.294 mmol) and morpholine (81 μl, 0.935 mmol) in dichloromethane (DCM) (4.1 ml). The mixture was stirred at ambient temperature for 30 min. The solvent was removed under reduced pressure to give a crude product which was purified by RP-HPLC to give (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoyl)-N-[5-(methyloxy)-2-pyrimidinyl]-3-pyrazolidine carboxamide (67 mg, 0.133 mmol, 45% yield). MS (ES+) m/z 505.2 (MH+).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])[CH:6]=[CH:7][CH:8]=1.[CH2:17]([O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1Br)[CH3:18].CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH2:17]([O:19][C:20](=[O:28])[C:21]1[CH:22]=[CH:23][N:24]=[CH:25][C:26]=1[N:11]1[CH2:12][CH2:13][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)[C:10]1=[O:14])[CH3:18]
Reactant: O=C1NCCN1c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1ccncc1Br
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)c1ccncc1N1CCN(c2cccc(C(F)(F)F)c2)C1=O
Yield: 84.9 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(3-trifluoromethyl-phenyl)-imidazolidin-2-one (I-36b: 200 mg, 0.869 mmol) was reacted with 3-bromo-isonicotinic acid ethyl ester (239 mg, 1.042 mmol), copper iodide (16.5 mg, 0.869 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (37.01 mg, 0.26 mmol), potassium phosphate (460.5 mg, 2.172 mmol) and 1,4-dioxane (5 mL) to afford crude product. Purification by column chromatography on silica gel (60% ethyl acetate in hexane) afforded 280 mg of pure product (85% yield).
Reaction SMILES: [CH3:1]O.S(Cl)(Cl)=O.[I:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:19]([CH3:20])=[CH:18][C:17](=[O:21])[C:16]([C:22]([OH:24])=[O:23])=[N:15]2)=[CH:10][CH:9]=1.O>C(Cl)(Cl)Cl>[I:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:19]([CH3:20])=[CH:18][C:17](=[O:21])[C:16]([C:22]([O:24][CH3:1])=[O:23])=[N:15]2)=[CH:10][CH:9]=1
Reactant: CO
Reactant: Cc1cc(=O)c(C(=O)O)nn1-c1ccc(I)cc1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1nn(-c2ccc(I)cc2)c(C)cc1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 47 %

Procedure:
To 50 ml of methanol, cooled to -5°, there is added dropwise 2.62 g (0.022 mol) of thionyl chloride (pot temperature maintained between -5° C. and 0° C.). The solution is stirred at 0° C. for 15 min and to it there is added 7.12 g (0.02 mol) of 1-(4-iodophenyl)-1,4-dihydro-4-oxo-6-methylpyridazine-3-carboxylic acid. (See Example 3). The suspension formed is stirred at room temperature for 3 days and to it there is added 200 ml of water. The suspension that forms is stirred at room temperature for 2 days and is vacuum filtered. The filter cake is air dried to afford 4 g of crude product. The crude product is suspended in 25 ml of chloroform and filtered. The filtrate is concentrated in vacuo to afford 3.5 g (47% yield) of product, mp 185°-187° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]2[CH:12]=[N:13][NH:14][C:6]=12.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CO>O>[C:15]([O:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]2[CH:12]=[N:13][NH:14][C:6]=12)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cc(NCCO)c2[nH]ncc2n1
Reactant: O=C(Cl)c1ccccc1
Solvent: CO
Solvent: O
Product: Cc1cc(NCCOC(=O)c2ccccc2)c2[nH]ncc2n1

Procedure:
The title compound was prepared from 7-(2-hydroxyethyl-amino)-5-methyl-1H-pyrazolo[4,3-b]pyridine (2 g) and benzoyl chloride by the general method of Example 4 without the addition of methanol. The crude reaction mixture was poured into a large excess of water and extracted with ethyl acetate (×3). The combined organic layers were washed with water (×2), dried with anhydrous sodium sulphate, filtered and evaporated to dryness. The resulting intermediate dibenzoylated compound was recrystallized from carbon tetrachloride/60°-80° C. petrol to give a pale yellow solid, m.p. 136°-138° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:14]=[C:13]([OH:15])[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].CI.[CH3:23]N(P(N(C)C)(N(C)C)=O)C>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:3][C:4]1[CH:14]=[C:13]([O:15][CH3:23])[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)c1cc(O)cc(C)c1C(=O)OCC
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)c1cc(OC)cc(C)c1C(=O)OCC
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (380 mg. 50% oil) was added portionwise to a solution of diethyl 3-methyl-5-hydroxyphthalate (2 gm) in dry tetrahydrofuran (50 ml). The solution was stirred for 30 minutes. Methyl iodide (2 ml), tetra-n-butylammonium iodide (45 mg) and HMPA (5 ml) was added. The solution was stirred at room temperature for 21/2 hours at refluxed at 60° C. for 1 hour. The solvent was removed under reduced pressure. The oil was partitioned between ethyl acetate and 5% hydrochloric acid solution. The ethyl acetate layer was washed with brine solution and dried over magnesium sulphate. Solvent evaporation gave an oil which was chromatographed (20% ethyl acetate:petroleum ether) to give diethyl 3-methyl-5-methoxy-phthalate.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[S:20][C:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][CH2:12][C:6]=2[CH:5]=1.[S-:21][C:22]#[N:23].[K+].BrBr>>[NH2:23][C:22]1[S:21][C:5]2[C:6]3[CH2:12][CH2:11][N:10]([CH2:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:9][CH2:8][C:7]=3[S:20][C:4]=2[N:3]=1
Reactant: N#C[S-]
Reactant: Nc1cc2c(s1)CCN(Cc1ccccc1)CC2
Agent: BrBr
Agent: Cl
Agent: [K+]
Product: Nc1nc2sc3c(c2s1)CCN(Cc1ccccc1)CC3

Procedure:
This compound was prepared from 2-amino-6-benzyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine dihydrochloride, potassium thiocyanate and bromine analogous to Example 1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][CH:9]=O)=[C:6]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:5]=[C:4]([S:18][CH3:19])[N:3]=1.C([O-])=O.[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:18][CH3:19])[N:5]=[C:6]2[C:7]=1[N:8]=[CH:9][N:11]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CSc1nc(N)c(NC=O)c(NC2CCCCC2)n1
Agent: O=C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1nc(N)c2ncn(C3CCCCC3)c2n1

Procedure:
A solution of 4-amino-6-(cyclohexylamino)-5-(formylamino)-2-(methylthio)pyrimidine (25.0 g., 0.088 mole) or a mole equivalent of the formate salt thereof in 125 ml. ethanol and 500 ml. 1 N sodium hydroxide is refluxed for a 4 hr. period, cooled in an ice-bath, and then filtered affording 14.1 g. (61%) of yellow material. Crystallization from ethanol gives 6-amino-9-cyclohexyl-2-(methylthio)purine as off-white crystals, m.p. 222°-224°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16].I[CH2:33]CC>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH2:29][CH3:33])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCCI
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting 1-iodopropane and making non-critical variations provided the title compound as a light yellow syrup. IR (liq.) 3446, 2967, 2935, 2875, 1564, 1552, 1497, 1470, 1392, 1206, 1184, 1101, 1091, 1082, 748 cm−1; OAMS supporting ions at: ESI+ 469.9; MS (EI) m/z 469 (M+); [α]25D=−98 (c 0.91, methylene chloride); Anal. Calcd for C26H29Cl2N3O: C, 66.38; H, 6.21; N, 8.93. Found: C, 66.53; H, 6.15; N, 9.05.
Reaction SMILES: CS(C)=O.[OH-:5].[K+].[CH2:7]([O:14][C:15]1[CH:20]=[C:19](F)[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O>[CH2:7]([O:14][C:15]1[CH:20]=[C:19]([O:5][C:19]2[CH:18]=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[C:15]([O:14][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:20]=2)[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)cc1OCc1ccccc1
Temperature: 100 °C

Procedure:
400 g of dimethyl sulfoxide and a solution of 37 g of potassium hydroxide (0.66 mol) in 400 ml:of water are warmed to 100° C. in a three-neck flask fitted with reflux condenser and stirrer. 163 g of the 5-fluoro-2-nitrophenyl benzyl ether prepared as described in Example 1 (0.66 mol) are then added in portions, and the mixture is then heated at 100° C. for 8 hours. After the mixture has been cooled to room temperature, a colorless reaction product precipitates; this is filtered off, washed with water and dried. The reaction product is then recrystallized from ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([CH3:15])=[N:13][N:14]=[C:7]1[N:6]=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH4-].[Na+].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([CH3:15])=[N:13][N:14]=[C:7]1[NH:6][CH:5]2[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1nnc2nc(-c3ccccc3)c3cc(Cl)ccc3n12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)N2
Temperature: 0 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
To a suspension of 1.3 g of 7-chloro-1-methyl-5-phenyl-s-triazolo[4,3-a]quinazoline in 70 ml of dimethylformamide was added 0.5 g of sodium borohydride. The mixture was heated with stirring at 75°-80° C. for 2 hours and then poured into ice-water. The resulting mixture was neutralized with dilute hydrochloric acid, and the precipitate formed was collected by filtration and washed with water. The solid was then suspended in a mixture of 40 ml of methanol and 5 ml of concentrated hydrochloric acid, and the mixture was stirred at room temperature for 2 hours. After neutralization with ammonia water, the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was recrystallized from dimethylformamideethanol to give 0.75 g of 7-chloro-4,5-dihydro-1-methyl-5-phenyl-s-triazolo[4,3-a]quinazoline as colorless needles, m.p. 262°-265° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1.[N:22]1[CH:27]=[CH:26][C:25]([CH:28]([NH2:30])[CH3:29])=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>[Cl-].[Na+].O.CN(C=O)C>[N:22]1[CH:27]=[CH:26][C:25]([CH:28]([NH:30][C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Br:1])[N:3]=3)[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=2)=[O:13])[CH3:29])=[CH:24][CH:23]=1
Reactant: CC(N)c1ccncc1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Br)cnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
2-Bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (320 mg, 0.86 mmol), 1-(pyridin-4-yl)ethanamine (105 mg, 0.86 mmol) and DIPEA (449 mg, 2.58 mmol) were combined with DMF (5 mL) to give a yellow solution. HATU (327 mg, 0.86 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with brine and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water and brine then dried with MgSO4, filtered and concentrated in vacuo to afford 380 mg (93%) of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-pyridin-4-yl-ethyl)-amide as a red oil. MS: (M+H)+=477.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:49][CH:50]1[C@H:54]2[C@H:55](OC3CCCCO3)[N:56](C(OC(C)(C)C)=O)[C:57]3[CH:64]=[CH:63][C:62]([O:65][CH3:66])=[CH:61][C:58]=3[C:59](=[O:60])[N:53]2[CH2:52][CH2:51]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH:18]1[C@H:22]2[C@H:23](OC3CCCCO3)[N:24](C(OC(C)(C)C)=O)[C:25]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:26]=3[C:27](=[O:28])[N:21]2[CH2:20][CH2:19]1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:16]([O:17][CH:18]1[C@@H:22]2[CH:23]=[N:24][C:25]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:26]=3[C:27](=[O:28])[N:21]2[CH2:20][CH2:19]1)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:49][CH:50]1[C@@H:54]2[CH:55]=[N:56][C:57]3[CH:64]=[CH:63][C:62]([O:65][CH3:66])=[CH:61][C:58]=3[C:59](=[O:60])[N:53]2[CH2:52][CH2:51]1
Reactant: COc1ccc2c(c1)C(=O)N1CCC(OCCCCCCCCCOC3CCN4C(=O)c5cc(OC)ccc5N(C(=O)OC(C)(C)C)[C@@H](OC5CCCCO5)[C@H]34)[C@H]1[C@H](OC1CCCCO1)N2C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1ccc2c(c1)C(=O)N1CCC(OCCCCCCCCCOC3CCN4C(=O)c5cc(OC)ccc5N=C[C@@H]34)[C@@H]1C=N2
Reaction time: 1 h
Yield: 78.9 %

Procedure:
95% TFA (3 mL) was added drop-wise to dimer compound 15g (200 mg, 0.19 mmol) at 0° C. This was then stirred for 1 hr and the mixture was poured into saturated NaHCO3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3×20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO4) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 16g (98 mg, 0.15 mmol, 83%) as a solid: [α]20D=+864° (c=0.14, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.32-1.52 (m, 10H, 14-H, 14′-H, 15-H, 15′-H, 16-H), 1.83-1.90 (m, 4H, 13-H, 13′-H), 2.02-2.09 (m, 4H, 2-H, 2′-H), 2.27-2.36 (m, 4H, 1-H, 1′-H), 3.54-3.64 (m, 2H, 3-H, 3′-H), 3.70-3.77 (m, 2H, 11a-H, 11a′-H), 3.78-3.88 (m, 2H, 3-H, 3′-H), 3.93 (s, 6H, 7-OMe, 7′-OMe), 3.99-4.15 (m, 4H, 12-H, 12′-H), 6.80 (s, 2H, 9-H, 9′-H), 7.51 (s, 2H, 6-H, 6′-H), 7.65 (d, 2H, J=4.4, 11-H, 11′-H); 13C NMR (CDCl3, 400 MHz): δ 24.1, 25.8, 28.8, 29.2, 29.3, 29.6, 46.6, 53.7, 56.1, 69.0, 110.4, 111.6, 120.0, 140.6, 147.8, 150.9, 162.8, 164.6; IR (neat): 2934, 1622, 1599, 1557, 1505, 1455, 1429, 1382, 1339, 1260, 1216, 1092, 1020 cm−1; MS (FAB) m/z (relative intensity) 681 ([M+2×MeOH]+., 6), 649 ([M+MeOH]+., 12), 617 (M+., 100).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH2:33][CH2:32][CH2:31][C@@H:30]1[C:34](Cl)=[O:35]>C1COCC1>[CH3:28][N:29]1[CH2:33][CH2:32][CH2:31][C@@H:30]1[C:34]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:6][CH:7]=1)=[O:35]
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1
Reactant: CN1CCC[C@@H]1C(=O)Cl
Solvent: C1CCOC1
Product: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NC(=O)[C@H]3CCCN3C)cc2)c2ccccc2N1

Procedure:
The title compound was synthesized using (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one and (R)-1-methylpyrrolidine-2-carbonyl chloride in THF according to the procedure described in the synthesis of Example 26. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.71 (t, J=7.33 Hz, 3H) 1.30-1.40 (m, J=7.45, 7.45, 7.45, 7.45 Hz, 2H) 1.94-2.04 (m, 2H) 2.10-2.23 (m, 3H) 2.60-2.63 (m, 1H) 2.91 (s, 3H) 3.24-3.27 (m, 1H) 4.21-4.30 (m, 1H) 6.79 (s, 1H) 7.57 (t, J=7.71 Hz, 1H) 7.75-7.83 (m, 3H) 7.85-7.90 (m, 3H) 8.09 (d, J=8.08 Hz, 1H) 9.87 (s, 1H) 11.01 (s, 1H); ESI-MS: m/z calc'd for C27H29N5O2S 487.62. found 488.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)O)=[C:9]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[O:8][C:7]=2[CH:29]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCCC1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH2:11][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[C:9]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[O:8][C:7]=2[CH:29]=1
Reactant: COc1ccc(-c2oc3cc(OC)ccc3c2C(O)c2ccc(OC)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCCc1ccccc1
Product: COc1ccc(Cc2c(-c3ccc(OC)cc3)oc3cc(OC)ccc23)cc1

Procedure:
A solution of 400 mg (1.02 mmol) of [6-Methoxy-2-(4-methoxyphenyl)benzo[b]furan-3-yl][4-methoxyphenyl]methanol was dissolved in 10 mL of n-propylbenzene and 200 mg (5.25 mmol) of LiAlH4 was added. The reaction mixture was heated to reflux under a nitrogen atmoshere for 45 minutes. After sixteen hours, the reaction was quenched by the addition of 5 mL of water. To this suspension was added 3 mL of 15%(W/N)NaOH and an additional 3 mL of water. This suspension was filtered. The resulting filterate separated into two layers. The top (organic) layer was removed and evaporated to dryness. The crude product was chromatographed on silica eluted with 20% EtOAc in hexane. The final product was crystallized from ether. This yielded 100 mg of the title compound as a solid with a low melting point.
Reaction SMILES: CCN(CC)CC.[OH:8][C@@H:9]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=1)[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].[O:27](S(C(F)(F)F)(=O)=O)[S:28]([C:31]([F:34])([F:33])[F:32])(=O)=[O:29].O>C(Cl)Cl>[F:32][C:31]([F:34])([F:33])[S:28]([O:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C@H:9]([OH:8])[CH2:10][CH2:11][NH:12][C:13]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:19])[CH:21]=1)(=[O:29])=[O:27]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OS(=O)(=O)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Et3N (1.5 mL, 10.76 mmol) was added to a suspension of Intermediate I (1.00 g, 3.74 mmol) in anhydrous CH2Cl2 (20 mL), and a clear solution resulted. The reaction mixture was cooled to 0° C. under N2 and Tf2O (0.7 mL, 4.14 mmol) was added slowly via syringe. The reaction mixture was stirred for 2 h, water was added and the mixture was extracted with CH2Cl2 twice. Combined organic layers were washed with brine and concentrated under reduced pressure. Purification by flash chromatography (10%-50% EtOAc-hexanes gradient) gave (R)-3-(3-((tert-butoxycarbonyl)amino)-1-hydroxypropyl)phenyl trifluoromethanesulfonate as a colorless oil. Yield (1.10 g, 74%); 1H NMR (400 MHz, DMSO-d6); δ 7.45-7.52 (m, 1H), 7.39-7.43 (m, 1H), 7.33-7.38 (m, 1H), 7.27-7.32 (m, 1H), 6.72 (br. t, 1H), 5.45 (d, J=4.7 Hz, 1H), 4.56-4.66 (m, 1H), 2.86-3.2 (m, 2H), 1.60-1.70 (m, 2H), 1.33 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[C:5]([F:20])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:21][C:22]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:23]=1[NH2:24]>>[CH3:21][C:22]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:23]=1[NH:24][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[C:5]([F:20])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CN(c1ccccc1)c1nc(Cl)nc2c(F)cccc12
Reactant: Cc1cc(F)ccc1N
Product: Cc1cc(F)ccc1Nc1nc(N(C)c2ccccc2)c2cccc(F)c2n1

Procedure:
In a procedure analogous to that of Example 41 2-chloro-4-(N-methylphenylamino)-8-fluoroquinazoline and 2-methyl-4-fluoroaniline are reacted together to give the title compound.