Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([OH:14])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:4]([CH3:15])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C(Br)C=C.[CH2:26]([O:29]CC=C)[CH:27]=[CH2:28].C(C1C=CC=C(C2C=CC(Cl)=CC=2C)C=1O)C=C.ClC1C=C(C=CC=1)C(OO)=O>C1(C)C=C(C)C=C(C)C=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[O:14][CH:27]([CH2:26][OH:29])[CH2:28][C:10]=3[CH:11]=[CH:12][CH:13]=2)=[C:4]([CH3:15])[CH:3]=1
Reactant: C=CCOCC=C
Reactant: Cc1cc(Cl)ccc1-c1ccccc1O
Agent: C=CCc1cccc(-c2ccc(Cl)cc2C)c1O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Solvent: Cc1cc(C)cc(C)c1
Solvent: C=CCBr
Product: Cc1cc(Cl)ccc1-c1cccc2c1OC(CO)C2
Yield: 61 %

Procedure:
Treatment of 4′-chloro-2′-methyl-1,1′-biphenyl-2-ol (4.54 g, 20.78 mmol) with potassium carbonate (11.47 g, 83.04 mmol) and allyl bromide (3.01 g, 24.91 mol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-4′-chloro-2′-methyl-1,1′-biphenyl-2-ol. Treatment of 3-allyl-4′-chloro-2′-methyl-1,1′-biphenyl-2-ol (4.5 g, 17.39 mmol) with 3-chloroperoxybenzoic acid (12.0 g, 69.57 mmol, 77%) followed by potassium carbonate (6.0 g, 43.48 mmol) generally according to the procedure described for Intermediate 9 afforded 2.9 g (61%) of (±)-[7-(4-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol as a colorless oil. Anal. calcd. for C16H15ClO2: C, 69.95; H, 5.5. Found: C, 69.23; H, 5.42.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH2:15][CH3:16])[CH2:12][OH:13])=[N:8][C:7]([S:17]CC3C=CC=CC=3)=[N:6][C:5]=2[N:25]=1.[Na]>N>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH2:15][CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:17])=[N:6][C:5]=2[N:25]=1
Reactant: CCC[C@H](CO)Nc1nc(SCc2ccccc2)nc2nc(N)sc12
Agent: N
Agent: [Na]
Product: CCC[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Temperature: -33 °C
Reaction time: 0.01 h
Yield: 80.3 %

Procedure:
A round-bottomed flask was equipped with a dry ice-ethanol condenser and immersed in a dry ice-ethanol cooling bath. Ammonia (250 mL) was condensed into the flask followed by addition of (2R)-2-{[2-amino-5-(benzylthio)[1,3]thiazolo[4,5-d]pyrimidin-7-yl]amino}pentan-1-ol (6.8 g, 18.1 mmol). The resulting mixture was allowed to warm to −33° C. and sodium metal was added in small pieces until a blue colour appeared and persisted for 30 seconds. The reaction was then quenched by addition of a spoonful of solid ammonium chloride. The ammonia was evaporated off and water (250 mL) was added to the residue. The resulting mixture was neutralized with 1M hydrochloric acid (aq). The precipitated product was collected by filtration, washed with water and dried in vacuo to yield 4.15 g (80% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Br[CH2:15][CH2:16]Br>CN(C)C=O>[N+:9]([C:7]1[CH:6]=[CH:5][C:3]2[NH:4][CH2:15][CH2:16][O:1][C:2]=2[CH:8]=1)([O-:11])=[O:10]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(c1)OCCN2

Procedure:
Following Intermediate Method 4, the reaction of 2-hydroxy-4-nitroaniline with sodium hydride and 1,2-dibromoethane in N,N-dimethylformamide produces 2,3-dihydro-7-nitro-1,4-benzoxazine, (XIX). The reaction of (XIX) with sodium hydride and 2-iodopropane in N,N-dimethylformamide yields 2,3-dihydro-4-(1-methylethyl)-7-nitro-1,4-benzoxazine, (XX). Hydrogenation of (XX) with platinum oxide yielded (XXI). ##STR31##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:39][CH2:40][CH3:41])=[C:24]([NH:27][C:28](=[O:38])[CH2:29]P(OCC)(OCC)=O)[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:42]#[N:43])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C)C=CC=CC=1.[CH3:61][N:62]1[CH2:67][CH2:66][CH2:65][CH2:64][CH:63]1[CH:68]=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:39][CH2:40][CH3:41])=[C:24]([NH:27][C:28](=[O:38])/[CH:29]=[CH:68]/[CH:63]4[CH2:64][CH2:65][CH2:66][CH2:67][N:62]4[CH3:61])[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:42]#[N:43])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)CP(=O)(OCC)OCC
Reactant: CN1CCCCC1C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)/C=C/C1CCCCN1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 4.9 %

Procedure:
N-[4-[[3-Chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-2-diethoxyphosphoryl-acetamide 1d (300 mg, 0.48 mmol) was dissolved in 10 mL of tetrahydrofuran in a dry ice bath, followed by dropwise addition of a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (530 μL, 0.53 mmol). After stirring for 30 minutes, a solution of 1-methylpiperidine-2-carbaldehyde 6b (120 mg, 0.96 mmol) in 5 mL of tetrahydrofuran was added dropwise. The reaction mixture was stirred for another 30 minutes, then warmed up to room temperature and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-3-(1-methyl-2-piperidyl)prop-2-enamide 6 (14 mg, yield 4.9%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][CH2:14][OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][C:19](C)([O-])[CH3:20].[K+].C(Br)C=C>CS(C)=O>[CH2:20]([O:15][CH2:14][CH2:13][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:16]=1)[CH:19]=[CH2:18]
Reactant: CC(C)(C)[O-]
Reactant: OCCc1ccc(OCc2ccccc2)cc1
Agent: [K+]
Solvent: C=CCBr
Solvent: CS(C)=O
Product: C=CCOCCc1ccc(OCc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A reaction flask was charged with 4-benzyloxy phenethyl alcohol of formula (6), (12 g, 0.052 mol), potassium tert-butoxide (8.842 g, 0.079 ml) and 50 ml and DMSO. The mixture was stirred under nitrogen at 50° C. for 30 minutes. A solution of allyl bromide (6.8 ml, 0.079 mol) was added drop wise to the reaction mixture with cooling about 20–25° C. The mixture was then stirred at 50° C. for 2 h. and cooled to room temperature. The reaction mixture was subsequently quenched with 150 ml of water. The desired product was extracted from neutralized aqueous mixture with toluene. The toluene extract was then washed with water and concentrated under vacuum to afford the title compound of formula (7), 13.9 g, (98%).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:17]=[CH:18][N:19]=[C:4]2[N:3]=1.C(N(CC)CC)C.[F:27][C:28]([F:37])([F:36])[C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32]>C(O)CCC>[CH2:15]([N:14]1[C:10]2[N:9]=[CH:8][C:7]3[C:2]([NH:32][C:31]4[CH:33]=[CH:34][CH:35]=[C:29]([C:28]([F:27])([F:36])[F:37])[CH:30]=4)=[N:3][C:4]4[N:5]([N:17]=[CH:18][N:19]=4)[C:6]=3[C:11]=2[CH:12]=[N:13]1)[CH3:16]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CCn1ncc2c1ncc1c(Cl)nc3ncnn3c12
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CCn1ncc2c1ncc1c(Nc3cccc(C(F)(F)F)c3)nc3ncnn3c12

Procedure:
5.8 g. of 5-chloro-8-ethyl-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine (0.02 mol.), 3 g. of triethylamine and 3.3 g. of 3-trifluoromethylaniline are refluxed in butyl alcohol for 24 hours with stirring. The solvent is removed in vacuo and the residue treated with 20 ml. of water and filtered off. Recrystallization from alcohol yields 8-ethyl-N-[3-(trifluoromethyl)phenyl]-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5-amine.
Reaction SMILES: [N-]=[N+]=[N-].[Na+].[N:5]([CH2:8][CH:9]1[CH2:13][C:12]2[CH:14]=[C:15]([F:28])[CH:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])[C:11]=2[O:10]1)=[N+]=[N-].[N-]=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[F:28][C:15]1[CH:16]=[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([F:27])([F:25])[F:26])[C:11]2[O:10][CH:9]([CH2:8][NH2:5])[CH2:13][C:12]=2[CH:14]=1
Reactant: [N-]=[N+]=NCC1Cc2cc(F)cc(-c3ccccc3C(F)(F)F)c2O1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: NCC1Cc2cc(F)cc(-c3ccccc3C(F)(F)F)c2O1
Yield: 89 %

Procedure:
Treatment of (±)-{5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl)}methyl 4-methylbenzenesulfonate (5.34 g, 0.011 mol) with sodium azide (2.60 g, 0.04 mol) generally according to the procedure described for Intermediate 98 provided (±)-2-(azidomethyl)-5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran. Treatment of the azide with triphenylphosphine (2.89 g, 0.011 mol) generally according to the procedure described for Example 21 afforded 3.25 g (89%) of (±)-1-{5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine as a white solid, hydrochloride salt. mp 196-198° C. (dec); Anal. calcd. for C16H13F4NOHCl: C, 55.26; H, 4.06; N, 4.03. Found: C, 55.88; H, 4.26; N, 3.77.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[C:9]2[CH:10]=[C:11]([NH2:16])[C:12]([NH2:15])=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.O=[C:23]([CH3:29])[C:24](OCC)=[O:25]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[C:9]2[CH:10]=[C:11]3[C:12](=[CH:13][CH:14]=2)[NH:15][C:24](=[O:25])[C:23]([CH3:29])=[N:16]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(c2cccc(Cl)c2)n2ccnc2)cc1N
Reactant: CCOC(=O)C(C)=O
Solvent: CO
Product: Cc1nc2cc(C(c3cccc(Cl)c3)n3ccnc3)ccc2[nH]c1=O
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
A mixture of 9.1 parts of 4-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-1,2-benzenediamine, 3.7 parts of ethyl 2-oxopropanoate and 160 parts of methanol was stirred for 30 minutes at reflux temperature. The reaction mixture was evaporated to dry. The residue was crystallized from a mixture of 36 parts of 2-propanone and 4 parts of methanol. After stirring for 30 minutes at room temperature, the precipitated product was filtered off (the filtrate was set aside) and recrystallized from a mixture of methanol and dichloromethane. The product was filtered off and dried, yielding 3 parts (28.1%) of 6-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-3-methyl-2(1H)-quinoxalinone; mp. 270.9° C. (comp. 73). The filtrate (see above) was evaporated and the residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was taken up in a mixture of 2-butanone and 2-propanone and the whole was allowed to stand for a few days. The precipitated product was filtered off and dried, yielding 1.4 parts (11.5%) of 7-[(3-chlorophenyl) (1H-imidazol-1-yl)methyl]-3-methyl-2(1H)-quinoxalinone hemihydrate; mp. 201.9° C. (comp. 81).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)=[C:6]([CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[CH:7]=1.Cl.O.C(=O)(O)[O-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:32][CH:33]=3)=[CH:24][CH:23]=2)=[C:6]([CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:7]=1
Reactant: CCOC(=O)CCCCNCCc1cc(F)ccc1OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCCNCCc1cc(F)ccc1OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 100 °C

Procedure:
A solution of 4.5 g (6.93 mmol) of ethyl 5-{[2-(5-fluoro-2-{[4′-(trifluoromethyl)biphenyl-4-yl]-methoxy}phenyl)ethyl]amino}pentanoate in 90 ml of THF is mixed with 18 ml of half-concentrated hydrochloric acid and heated at 100° C. for 20 min. After cooling, the mixture is added to water and neutralized with saturated sodium bicarbonate solution. It is extracted with ethyl acetate, the organic phase is dried over sodium sulfate and the solvent is removed in vacuo. The residue is crystallized from ethyl acetate/diethyl ether (1:1). The resulting crystals are filtered off with suction and dried under high vacuum. 2.4 g (4.9 mmol, 71% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)([OH:27])[CH3:26])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[H-].[Na+].I[CH3:46]>O1CCCC1>[F:40][C:37]([F:38])([F:39])[C:35]1[CH:34]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:41])[F:42])[CH:36]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)([O:27][CH3:46])[CH3:26])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(C)(O)C2CCCCC2)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
To a solution of 1-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)-1-cyclohexylethanol (26 mg; 0.043 mmol) in tetrahydrofuran (0.7 mL) was added sodium hydride (11 mg; 0.275 mmol; 60% dispersion in mineral oil). After stirring for 30 minutes at room temperature, iodomethane (30 uL; 0.485 mmol) was added. The reaction was stirred for 16 hours. More sodium hydride (12 mg; 0.3 mmol; 60% dispersion in mineral oil) and iodomethane (30 uL; 0.485 mmol) were added. After 1 hour more sodium hydride (12 mg; 0.3 mmol; 60% dispersion in mineral oil) was added. After 30 minutes, iodomethane (30 uL; 0.485 mmol) was added. The reaction was stirred for 2 hours. The reaction was quenched with aqueous 2N hydrochloric acid (6 drops). The mixture was diluted with ethyl acetate and filtered over sodium sulfate/silica plug. Then the solution was concentrated. The residue was purified by 4 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 5-25% ethyl acetate in heptane) to give 19 mg (71% yield) of a colorless gum. MS (ES+): Calc: 623.5, Found: 592.5 (M-OCH3). 1H NMR (400 MHz, CDCl3) δ ppm 7.78 (s, 1H), 7.73 (s, 2H), 7.46 (s, 1H), 7.45 (d, J=7.47 Hz, 1H), 7.27 (d, J=8.30 Hz, 1H), 5.25 (d, J=17.43 Hz, 1H), 5.07 (d, J=17.43 Hz, 1H), 4.79 (q, J=16.60, 16.18 Hz, 2H), 4.19 (s, 3H), 3.02 (s, 3H), 2.01 (d, J=11.2 Hz, 1H), 1.78-1.67 (m, 2H), 1.66-1.55 (m, 2H), 1.53 (s, 3H), 1.11-0.83 (m, 6H).
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:41]=[C:40]([NH:42][C:43](=[O:45])[CH3:44])[CH:39]=[CH:38][CH:37]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Cl.N1C=CC=CC=1>>[OH:1][C:2]([C:30]1[CH:31]=[CH:32][C:33]([C:36]2[N:41]=[C:40]([NH:42][C:43](=[O:45])[CH3:44])[CH:39]=[CH:38][CH:37]=2)=[CH:34][CH:35]=1)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:4])[CH3:5]
Reactant: CC(=O)Nc1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)n1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(-c2ccc(C(O)(c3c[nH]cn3)C(C)C)cc2)n1
Yield: 59.4 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using N-(6-(4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenyl}-2-pyridyl)acetamide (1.48 g) and pyridine hydrochloride (520 mg), the title compound (520 mg) was obtained as colorless powder crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5](F)=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[F:18])[NH2:14]>>[Cl:10][C:11]1[CH:12]=[C:13]([NH:14][C:2]2[N:7]=[C:6]([NH:14][C:13]3[CH:15]=[CH:16][C:17]([F:18])=[C:11]([Cl:10])[CH:12]=3)[CH:5]=[CH:4][N:3]=2)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc(F)c(Cl)c1
Product: Fc1ccc(Nc2ccnc(Nc3ccc(F)c(Cl)c3)n2)cc1Cl

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-fluoroaniline were reacted to produce N2,N4-bis(3-chloro-4-fluorophenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.58 (s, 1H), 9.48 (s, 1H), 8.17 (d, 1H, J=4.1 Hz), 7.94-7.90 (m, 2H), 7.73-7.67 (m, 1H), 7.51-7.45 (m, 1H), 7.38 (t, 1H, J=8.8 Hz), 7.26 (t, 1H, J=8.8 Hz); LCMS: ret. time: 27.83 min.; purity: 99%; MS (m/e): 386 (MH+).
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[CH3:5][C:6]([CH3:11])([CH2:9][OH:10])[CH2:7][OH:8]>ClCCl>[CH3:5][C:6]1([CH3:11])[CH2:9][O:10][S:1](=[O:2])[O:8][CH2:7]1
Reactant: CC(C)(CO)CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC1(C)COS(=O)OC1
Temperature: 40 °C

Procedure:
Thionylchloride (735 mL) is added to a solution of 2,2-dimethylpropane-1,3-diol (1 g) in dichloromethane (10 mL) chilled in an ice bath. The mixture is heated to 40° C. for 3 hours and partitioned between saturated aqueous NaHCO3 solution and dichloromethane. The organic phase is washed with brine, dried (MgSO4) and concentrated to give the title compound. Yield: 535 mg; TLC: rf=0.65 (silicagel, cyclohexane/ethyl acetate 3:1).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:13]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][C:18]=1[Cl:27])(=[O:15])[CH3:14]>>[C:13]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:25])=[O:24])=[CH:19][C:18]=1[Cl:27])(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1Cl
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(NC(C)=O)c(Cl)c2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-acetamido-3-chlorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (16.1 mg) with purity >90%. MS (pos) m/z 418.2, 420.2.
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH2:24][CH2:23]1)[CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:11]([OH:13])=[O:12])=O)(C)(C)C.Cl>C(Cl)Cl>[ClH:20].[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C@@H:10]([CH2:9][NH:8][CH2:21][CH:22]2[CH2:24][CH2:23]2)[C:11]([OH:13])=[O:12])=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N(CC1CC1)C[C@@H](C(=O)O)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Product: O=C(O)[C@H](CNCC1CC1)c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 190.9 %

Procedure:
Crude (S)-3-(tert-butoxycarbonyl(cyclopropylmethyl)amino)-2-(4-chlorophenyl)propanoic acid (4.6 g, 13 mmol) was dissolved into DCM (130 mL) and excess 4N HCl was added. The reaction was allowed to stir overnight, after which it was concentrated. The resulting white solid was taken up into EtOAC and filtered. The resulting solid was washed with EtOAc (4×) to give pure (S)-2-(4-chlorophenyl)-3-(cyclopropylmethylamino)propanoic acid hydrochloride (3.60 g, 95%). This (S)-2-(4-chlorophenyl)-3-(cyclopropylmethylamino)propanoic acid (0.57 g, 2.24 mmol) was dissolved into 10:1 CH3CN:H2O (50 mL) and tetramethylammonium hydroxide pentahydrate (1.00 g) was added followed by Boc2O (0.73 g, 3.36 mmol). The reaction mixture was allowed to stir at room temperature overnight, and the reaction was quenched by the addition of 1N HCl. The reaction was concentrated, and the residue was diluted with EtOAc. The organics were separated, and the aqueous portion was extracted with EtOAc. The combined organics were dried with MgSO4, filtered and concentrated. The crude residue was purified by silica plug eluting Hex to 1:1 Hex/EtOAc to give (S)-3-(tert-butoxycarbonyl(cyclopropylmethyl)amino)-2-(4-chlorophenyl)propanoic acid (0.58 g, 73%) as a clear oil. (LCMS (APCI+) [M−Boc+H]+ 254.0)
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:3]=1.[CH:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([O:28][CH:29]([CH3:31])[CH3:30])[CH:27]=1)=[O:21].CN(C)C=O.C(=O)(O)[O-].[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:29]([O:28][C:26]1[CH:27]=[C:22]([CH:23]=[C:24]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[N:4]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:3]=2)[CH:25]=1)[CH:20]=[O:21])([CH3:31])[CH3:30]
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2cccnc21
Reactant: CC(C)Oc1cc(C=O)cc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC(C)Oc1cc(C=O)cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)c1
Yield: 71.9 %

Procedure:
3-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (750 mg, 0.0022 mol) and 3-formyl-5-isopropoxyphenylboronic acid (510 mg, 0.0024 mol) were dissolved in N,N-Dimethylformamide (10 mL, 0.2 mol) and then added 1.2 M of Sodium bicarbonate in water (6 mL) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (20 mg, 0.00002 mol). Flushed with nitrogen and The reaction was microwaved on 50 watts, 120° C. for 15 minutes. LC-MS showed complete reaction (1.99 min, ES+/421.07) Worked up with DCM and water. Dried over MgSO4. Purified on silica gel column with 0-100% EtOAc to give the desired product as a yellow syrup (665 mg, 71%) MS (ES+) m/z 421.07 (M+1). 1H NMR (CDCl3, 400 MHz): ™10.03 (s, 1H), 8.50 (d, 1H), 8.26 (d, 2H), 8.13 (d, 1H), 7.97 (s, 1H), 7.66 (s, 1H), 7.60 (t, 1H), 7.51 (t, 2H), 7.38 (s, 2H) 7.26 (dd, 1H), 4.72 (qd, 1H), 1.41 (d, 6H)
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][F:12])(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].O[C:21]1[N:22]=[CH:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[N:25][CH:26]=1.O>CN(C=O)C>[F:12][CH2:11][O:10][C:21]1[N:22]=[CH:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[N:25][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)OCF)cc1
Reactant: COC(=O)c1cnc(O)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnc(OCF)cn1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 11.5 %

Procedure:
Fluoromethyl toluene-4-sulfonate (Journal of Labelled Compounds & Radiopharmaceuticals, 46 (6), 555-566; 2003) (344 mg) and cesium carbonate (824 mg) were added to a solution of methyl 5-hydroxypyrazine-2-carboxylate (130 mg) in DMF (2.0 mL). The reaction solution was stirred at 70° C. for 5 h and 30 min and then cooled to RT. Water was added to the reaction solution, followed by extraction with EtOAc. The organic layer was concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (18.0 mg). 1H-NMR (400 MHz, CDCl3) δ (ppm): 4.03 (s, 3H), 6.14 (d, J=51.2 Hz, 2H), 8.42 (d, J=1.2 Hz, 1H), 8.94 (d, J=1.2 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[Si:11](OS(C(F)(F)F)(=O)=O)([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13].CCN(C(C)C)C(C)C.O1CCOCC1>CCOC(C)=O>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1
Reactant: Brc1ccc2cc[nH]c2n1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(Br)nc21
Temperature: 55 °C
Reaction time: 16 h
Yield: 84.7 %

Procedure:
In a 25 mL round-bottomed flask, 6-bromo-1H-pyrrolo[2,3-b]pyridine (250 mg, 1.27 mmol, Eq: 1.00), TIPS-OTf (972 mg, 860 μl, 3.17 mmol, Eq: 2.5) and DIEA (492 mg, 665 μl, 3.81 mmol, Eq: 3) were combined with dioxane (6.25 ml) to give a light brown solution. The reaction mixture was heated to 55° C. and stirred for 16 h. The reaction mixture was poured into 20 mL EtOAc and extracted with sat NaHCO3 (3×10 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 5% to 10% EtOAc in hexanes) to give 6-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (380 mg, 85%) of colorless oil.