Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[C:12](OCC)(=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].N12CCCN=C1CCCCC2>>[CH2:16]([O:15][C:13](=[O:14])/[C:12](/[OH:18])=[CH:8]/[C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1)[CH3:17]
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)/C(O)=C/c1cc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 133.2 %

Procedure:
A mixture of 1.5 g (8.7 mmol) 2-chloro-4-methyl-5-nitropyridine (commercially available) in 5.88 mL (43.5 mmol) diethyl oxalate was treated with 2.34 ml (15.6 mmol) 1,8-diazabicylo[5.4.0]undec-7-ene and stirred for 4 h at room temperature. After evaporation of all volatiles the residue was acidified with 1N KHSO4 aq. and extracted with DCM. The combined organic layers were dried with MgSO4 and concentrated under reduced pressure to afford 3.16 g of the title compounds which was used without further purification in the next step.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]2[S:11][CH:12]=[C:13]([C:15]([NH:17][C:18]3[C:19]4[C:23]([CH:24]=[C:25]([C:27]5[CH:28]=[N:29][C:30]([O:39][CH3:40])=[C:31]([NH:33][S:34]([CH:37]=[CH2:38])(=[O:36])=[O:35])[CH:32]=5)[CH:26]=3)=[N:22][N:21](C3CCCCO3)[CH:20]=4)=[O:16])[N:14]=2)[CH2:3]1.[CH3:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1>C(#N)C>[CH3:8][C@H:6]1[O:7][C@@H:2]([CH3:1])[CH2:3][N:4]([CH2:9][C:10]2[S:11][CH:12]=[C:13]([C:15]([NH:17][C:18]3[CH:26]=[C:25]([C:27]4[CH:28]=[N:29][C:30]([O:39][CH3:40])=[C:31]([NH:33][S:34]([CH2:37][CH2:38][N:51]5[CH2:52][CH2:53][N:48]([CH3:47])[CH2:49][CH2:50]5)(=[O:35])=[O:36])[CH:32]=4)[CH:24]=[C:23]4[C:19]=3[CH:20]=[N:21][NH:22]4)=[O:16])[N:14]=2)[CH2:5]1
Reactant: CN1CCNCC1
Reactant: C=CS(=O)(=O)Nc1cc(-c2cc(NC(=O)c3csc(CN4C[C@@H](C)O[C@@H](C)C4)n3)c3cn(C4CCCCO4)nc3c2)cnc1OC
Solvent: CC#N
Product: COc1ncc(-c2cc(NC(=O)c3csc(CN4C[C@@H](C)O[C@@H](C)C4)n3)c3cn[nH]c3c2)cc1NS(=O)(=O)CCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Acetonitrile (10 ml) was added to 2-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-N-[6-[5-[(ethenylsulfonyl)amino]-6-(methyloxy)-3-pyridinyl]-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl]-1,3-thiazole-4-carboxamide (250 mg) followed by 1-methylpiperazine (0.33 ml). The reaction was stirred at RT for 3 hours. The reaction was evaporated to dryness and the residue was separated between DCM and water. The DCM was passed through a hydrophobic frit then evaporated to dryness. The residue was dissolved in DMSO:methanol (1:1, v/v, 2 ml) and purified by MDAP (method E). Pure fractions were combined and evaporated to dryness. Analysis showed complete deprotection on dry-down to give title compound (116 mg).
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][C:9]1[C:10]([CH:26]([CH3:28])[CH3:27])=[N:11][C:12]([O:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:13][C:14]=1[CH:15]([CH3:17])[CH3:16])=S)([CH3:4])([CH3:3])[CH3:2].[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>C(#N)C>[C:1]([N:5]=[C:6]=[N:8][C:9]1[C:10]([CH:26]([CH3:28])[CH3:27])=[N:11][C:12]([O:18][C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[CH:13][C:14]=1[CH:15]([CH3:17])[CH3:16])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)c1cc(Oc2ccc(Cl)cc2)nc(C(C)C)c1NC(=S)NC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)c1cc(Oc2ccc(Cl)cc2)nc(C(C)C)c1N=C=NC(C)(C)C
Reaction time: 1 h

Procedure:
3.0 g of 1-tert.-butyl-3-[2,4-diisopropyl-6-(4-chlorophenoxy)-pyrid-3-yl]-thiourea and 2.1 g of 2-chloro-1-methylpyridinium iodide are placed in 20 ml of acetonitrile and, at room temperature, a solution of 1.6 g of triethylamine in 7 ml of acetonitrile is added. The reaction mixture is then stirred for 1 hour at approximately +65° C. After evaporation of the solvent, the residue is taken up in hexane/water. The organic phase is dried over magnesium sulfate and the solvent is removed in vacuo. The crude product is purified by column chromatography on silica gel (eluant: ethyl acetate/hexane 1:5). 1-tert.-Butyl-3-[2,4-diisopropyl-6-(4-chlorophenoxy)-pyrid-3-yl]-carbodiimide is obtained in the form of a colourless oil which solidifies after a few hours. M.p. 46°-55° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[F:24][C:25]1[CH:26]=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[CH3:31]>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:32][C:27]2[CH:28]=[CH:29][C:30]([CH3:31])=[C:25]([F:24])[CH:26]=2)=[N:3][CH:4]=1
Reactant: Cc1ccc(O)cc1F
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2ccc(C)c(F)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 3-fluoro-4-methylphenol: 1H-NMR (CDCl3) δ 8.54 (1H, d, J=2.8 Hz), 8.14 (1H, d, J=2.8 Hz), 8.07 (1H, d, J=7.7 Hz), 8.00 (2H, d, J=8.4 Hz), 7.41 (2H, d, J=8.4 Hz), 7.26 (1H, m), 6.25 (2H, m), 5.36 (1H, m), 3.91 (3H, s), 2.30 (3H, s), 1.59 (3H, d, J=7.0 Hz); MS (ESI) m/z 443 (M+H)+, 441 (M−H)−.
Reaction SMILES: [CH3:1][C:2]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15](=[O:32])[NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:21][CH:20]=2)=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].C(OC(=O)C(OC1C=CC([F:61])=CC=1)(C)CC1C=CC(O)=CC=1)C>>[F:61][C:37]1[CH:36]=[CH:35][C:34]([O:33][C:2]([CH3:1])([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15](=[O:32])[NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:21][CH:20]=3)=[CH:11][CH:12]=2)[C:3]([OH:5])=[O:4])=[CH:39][CH:38]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(F)cc1
Reactant: CC(Cc1ccc(OCC(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)(Oc1ccccc1)C(=O)O
Product: CC(Cc1ccc(OCC(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)(Oc1ccc(F)cc1)C(=O)O

Procedure:
The title compound was prepared using same method for 2-Methyl-2-phenoxy-3-(4-{[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-methoxy}-phenyl)-propionic acid from 2-(4-Fluoro-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:8]([OH:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1.COC1C(C=O)=CC=C2C=1[CH:24]=[N:25][N:26]2[CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38]>>[CH3:19][O:18][C:5]1[C:6]([CH:8]([OH:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:2]=[C:3]2[C:4]=1[CH:24]=[N:25][N:26]2[CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38]
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Reactant: COc1c(C=O)ccc2c1cnn2COCC[Si](C)(C)C
Product: COc1c(C(O)C#Cc2ccccc2)ccc2c1cnn2COCC[Si](C)(C)C
Yield: 98 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 4-methoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole-5-carbaldehyde was reacted to give the title compound as a colourless oil (100 mg, 98%). LCMS (Method B): RT=4.84 min, [M+Na]+=431.
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][CH:8]([OH:39])[CH2:9][CH:10]([OH:38])[CH2:11][CH2:12][C:13]1[N:14]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[N:15]=[C:16]([C:21](=[O:30])[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:17]=1[CH:18]([CH3:20])[CH3:19])(C)(C)C.[OH-].[Na+:42]>CO>[Na+:42].[CH2:23]([NH:22][C:21]([C:16]1[C:17]([CH:18]([CH3:20])[CH3:19])=[C:13]([CH2:12][CH2:11][C@@H:10]([OH:38])[CH2:9][C@@H:8]([OH:39])[CH2:7][C:6]([O-:40])=[O:5])[N:14]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[N:15]=1)=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)c1c(C(=O)NCc2ccccc2)nn(-c2ccc(F)cc2)c1CCC(O)CC(O)CC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1c(C(=O)NCc2ccccc2)nn(-c2ccc(F)cc2)c1CC[C@@H](O)C[C@@H](O)CC(=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 94 %

Procedure:
To a solution of 7-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid tert-butyl ester (0.103 g, 0.186 mmol) in MeOH (5 mL) was added 1.0 N NaOH (0.190 mL, 0.195 mmol; commercially available from Sigma Aldrich) and the reaction was stirred at 25° C. for 48 hr after which time the reaction was solvent was removed under reduced pressure. The resulting solid was then azeotroped toluene (3×100 mL) and triturated with diethyl ether to provide a light yellow solid that was dried under vacuum at 60° C. to afford (3R,5R)-7-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt (0.091 g, 94%): MS(APCI+): m/z498.2 (M+H); H-NMR (DMSO-d6) δ 8.55 (t, 1 H), 7.53-7.49 (m, 2 H), 7.33-7.13 (m, 7 H), 4.70 (bs, 1 H), 4.34 (d, 2 H), 3.63-3.57 (m, 1 H), 3.45-3.42 (m, 1 H), 2.74-2.66 (m, 1 H), 2.58-2.50 (m, 1 H), 1.95-1.90 (m, 1 H), 1.75-1.69 (m, 1 H), 1.40-1.10 (m, 10 H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]([Cl:24])=[CH:4][N:3]=1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]2[CH2:35][CH2:34][CH2:33][C:32](=[O:36])[NH:31][C:30]=2[CH:37]=1.C(O)(C)C.Cl>O1CCOCC1.C(N(CC)CC)C>[Cl:24][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:7][C:2]([NH:25][C:26]2[CH:27]=[CH:28][C:29]3[CH2:35][CH2:34][CH2:33][C:32](=[O:36])[NH:31][C:30]=3[CH:37]=2)=[N:3][CH:4]=1
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Reactant: Clc1ncc(Cl)c(Nc2ccccc2OCCN2CCOCC2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=C1CCCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4OCCN4CCOCC4)n3)cc2N1
Temperature: 120 °C

Procedure:
Into a microwave vial, (2,5-dichloro-pyrimidin-4-yl)-[2-(2-morpholin-4-yl-ethoxy)-phenyl]-amine (100.0 mg, 0.2708 mmol), 8-amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (61.2 mg, 0.348 mmole), isopropyl alcohol (2.00 mL, 26.1 mmol) and 4 M of hydrogen chloride in 1,4-dioxane (0.20 mL) were added, respectively. The reaction was heated in the microwave on 300 watts, 120° C. for 20 minutes. Triethylamine (0.2 mL) was added. The reaction was concentrated to dryness. The desired product was isolated via ISCO column chromatography with DCM and methanol as eluant (10% methanol). The resulting solid was triturated with diethyl ether to afford 8-{5-Chloro-4-[2-(2-morpholin-4-yl-ethoxy)-phenylamino]-pyrimidin-2-ylamino}-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as a white solid (42 mg, 30%). 1H-NMR (DMSO-D6, 400 MHz): δ 9.42 (s, 1H), 9.32 (s, 1H), 8.25 (s, 1H), 8.18 (s, 1H), 8.10 (bs, 1H), 7.35 (d, 1H), 7.27 (s, 1H), 7.12 (s, 2H), 7.0 (d, 1H), 6.85-6.95 (m, 1H), 4.16 (t, 2H), 3.50 (t, 4H), 2.55-2.70 (m, 4H), 2.40 (s, 4H), 2.00-2.20 (m, 4H). LC/MS (ESI+) 509 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[N+:10]([O-])=O.[OH-].[Na+]>CO.Cl.[Fe]>[NH2:10][C:3]1[CH:4]=[C:5]([CH2:8][OH:9])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=[N+]([O-])c1cc(CO)ccc1Cl
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Nc1cc(CO)ccc1Cl
Temperature: 65 °C

Procedure:
To a solution of (4-chloro-3-nitro-phenyl)-methanol (4.96 g, 26.4 mmol) in MeOH (60 mL) and conc HCl (22 ml) was added iron powder (4.43 g, 3 eq) in portions. The mixture was then heated at reflux (65° C.) for 6 h, cooled and poured on ice water. The solution was neutralised with dilute NaOH and filtered. The filtrate was extracted with EA several times. The combined organic layers were washed with brine, dried over MgSO4 and concentrated. The product was recovered as a greyish solid (3.8 g, 92%).
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH2:7]1)=[O:5].[CH3:23][Mg]Br>C1COCC1>[C:4]([CH:6]1[CH2:7][N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)[C:9](=[O:11])[CH2:10]1)(=[O:5])[CH3:23]
Reactant: CON(C)C(=O)C1CC(=O)N(c2cccc(C(F)(F)F)c2)C1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)C1CC(=O)N(c2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.5 %

Procedure:
To a stirred solution of 5-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidine-3-carboxylic acid methoxy-methyl-amide (0.6 g, 1.89 mmol) in THF (6 mL) was added methylmagnesium bromide (1.6 ml, 4.74 mmol, 3.0M in ether) drop wise over a period of 10 min at 0° C. The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was quenched with saturated ammonium chloride solution (2 ml) and extracted with ethyl acetate (2×15 ml). The combined organic layer was washed with saturated brine solution (25 ml). The organic layer was dried over Na2SO4, evaporated to obtain 4-Acetyl-1-(3-trifluoromethyl-phenyl)-pyrrolidin-2-one as a brown oil (0.5 g, 97%).
Reaction SMILES: CN1CCN([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:20]=[C:19]([C:21]4[C:22]([C:26]5[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=5)=[N:23][NH:24][CH:25]=4)[CH:18]=[CH:17][N:16]=3)=[CH:10][CH:9]=2)CC1.NC1C=CC([S:40]([NH2:43])(=[O:42])=[O:41])=CC=1>>[C:29]1([CH3:32])[CH:30]=[CH:31][C:26]([C:22]2[C:21]([C:19]3[CH:18]=[CH:17][N:16]=[C:15]([NH:14][C:11]4[CH:12]=[CH:13][C:8]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:9][CH:10]=4)[N:20]=3)=[CH:25][NH:24][N:23]=2)=[CH:27][CH:28]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1ccc(-c2n[nH]cc2-c2ccnc(Nc3ccc(N4CCN(C)CC4)cc3)n2)cc1
Product: Cc1ccc(-c2n[nH]cc2-c2ccnc(Nc3ccc(S(N)(=O)=O)cc3)n2)cc1

Procedure:
The title compound is prepared as described in Example 1 using ethyl-4-methylbenzoate (see Example 25) and 4-amino-benzenesulfonamide.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[C:11]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]1[CH:24]=[CH:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:29]=1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:50][CH2:51][CH2:52][CH2:53]Br>CN(C=O)C>[CH2:17]([O:16][CH:11]1[CH:12]=[C:13]([O:15][CH2:53][CH2:52][CH2:51][Br:50])[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]1[CH:24]=[CH:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:29]=1)=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCCCBr
Reactant: COc1ccc(C(=O)C=CC2C(OCc3ccccc3)=CC(O)=CC2OCc2ccccc2)cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)C=CC2C(OCc3ccccc3)=CC(OCCCBr)=CC2OCc2ccccc2)cc1OCc1ccccc1
Yield: 83.7 %

Procedure:
A mixture of 2.37 g (5 mmol) of 2,3',6-tris(benzyloxy)-4-hydroxy-4'-methoxydihydrochalcone, 1.38 g (10 mmol) of K2CO3, and 70.1 g (50 mmol) of 1,3-dibromopropane in 75 mL of DMF was reacted for 48 hours, after which standard workup yielded 2.91 g (84%) of 2,3',6-tris(benzyloxy)-4-(3-bromopropoxy)-4'-methoxydihydrochalcone as a white solid. The resulting intermediate bromide (2.91 g, 4.18 mmol) was dissolved in 50 mL of P(OCH3)3 and refluxed for 39 hours. After all solvent was removed in vacuo, standard workup, followed by column chromatography over 200 g of silica gel (CHCl3 --CH3OH), yielded 1.93 g (64%) of 2.3',6-tris(benzyloxy)-4-(dimethyl-3-phosphopropoxy)-4'-methoxydihydrochalcone as an oil, which crystallized on standing. Crystallization from hexane-EtOAc yielded colorless clusters: mp 92°-95.5° C.; IR (film) 5.88 (C=O) μm; UV (MeOH)λmax 278 nm (ε 7600); NMR (CDCl3)δ 2.90 (m, 4H, ArCOCH2CH2Ar'), 3.64 [s, 6H, PO(OCH3)2 ], 3.77 (s, 3H, Ar'OCH3), 3.94 (t, 2H, J=6 Hz, ArOCH2), 5.03 (s, 6H, PhCH2O), 6.17 (s, 2H, ArH), 7.37 (s, 15H, PhH). Anal (C42H45O9P) C, H.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[C:6]([SH:10])[CH:7]=[CH:8][CH:9]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH2:25][CH3:26])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>C1COCC1>[CH2:25]([O:24][C:18]1[CH:17]=[C:16]2[C:21]([C:12]([S:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[NH2:3])=[N:13][CH:14]=[N:15]2)=[CH:20][C:19]=1[O:22][CH3:23])[CH3:26]
Reactant: CCOc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1cccc(S)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
To a stirred slurry of sodium hydride (350 mg of a 60% dispersion in mineral oil, 8.80 mmol) in anhydrous THF (50 mL) at rt, was added 3-aminobenzenethiol (1.00 g, 9.17 mmol). After stirring for 30 mins, 4-chloro-7-ethoxy-6-methoxyquinazoline (prepared as described in Example 6A Steps 1 through 5) (1.91 g, 8.03 mmol) was added and the reaction mixture was stirred at rt for a further 4 h. The mixture was concentrated under reduced pressure and the resulting solid was washed with water (three times) then ethyl acetate (three times) to afford 3-(7-ethoxy-6-methoxyquinazolin-4-ylthio)aniline (2.36 g, 90%) as yellow solid. 1H NMR (400 MHz; DMSO-d6) δ 8.69 (s, 1H), 7.30-7.31 (m, 2H), 7.13 (m, 1H), 6.80 (s, 1H), 6.72-6.74 (m, 2H), 5.31 (brs, 2H), 4.25 (q, J=7 Hz, 2H), 3.97 (s, 3H), 1.43 (t, J=7 Hz, 3H); LC-MS (ESI) m/z 328 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:10]2[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[F:28][CH2:29][CH2:30][CH2:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:13]([CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([CH2:2][NH:1][S:32]([CH2:31][CH2:30][CH2:29][F:28])(=[O:34])=[O:33])[CH:12]=2)[CH2:7][CH2:8][CH:9]1[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(CN)cc2C1Cc1ccccc1
Reactant: O=S(=O)(Cl)CCCF
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCc2ccc(CNS(=O)(=O)CCCF)cc2C1Cc1ccccc1
Temperature: 25 °C

Procedure:
Tert-butyl [7-(aminomethyl)-1-benzyl-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate (32 mg, 0.87 mmol) was dissolved in dichloromethane (15 mL) and 4-dimethylaminopyridine (12 mg, 0.096 mmol) and 3-fluoropropane-1-sulfonyl chloride (14 mg, 0.087 mmol) were added. The reaction mixture was stirred at room temperature over night. The dichloromethane solution of the crude product was washed successively with 1N aqueous hydrochloric acid and aqueous NaHCO3 solution, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography (dichloromethane, methanol, silica gel). Yield: 9.3 mg (0.019 mmol, 22%).
Reaction SMILES: [I:1][C:2]1[NH:6][C:5]([CH3:7])=[N:4][CH:3]=1.S(O[CH2:13][C:14]([F:17])([F:16])[F:15])(=O)(=O)C>>[I:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([CH2:13][C:14]([F:17])([F:16])[F:15])[CH:3]=1
Reactant: Cc1ncc(I)[nH]1
Reactant: CS(=O)(=O)OCC(F)(F)F
Product: Cc1nc(I)cn1CC(F)(F)F

Procedure:
The title compound, MS: m/e=291.0 (M+H+), was prepared in accordance with the general method of example 1 from 5-iodo-2-methyl-1H-imidazole and 2,2,2-trifluoroethyl mesylate.
Reaction SMILES: [Br-].[CH:2]1([CH2:5][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:4][CH2:3]1.C([Li])CCC.Cl[C:31]1[C:32]2[N:33]([CH:37]=[C:38]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=3[F:47])[N:39]=2)[CH:34]=[CH:35][N:36]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[CH:2]1([CH2:5][C:31]2[C:32]3[N:33]([CH:37]=[C:38]([C:40]4[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=4[F:47])[N:39]=3)[CH:34]=[CH:35][N:36]=2)[CH2:4][CH2:3]1
Reactant: Fc1ccc(-c2cn3ccnc(Cl)c3n2)c(F)c1
Reactant: c1ccc([P+](CC2CC2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Li]CCCC
Solvent: COCCOC
Solvent: O
Product: Fc1ccc(-c2cn3ccnc(CC4CC4)c3n2)c(F)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 11 %

Procedure:
To a suspension of (cyclopropylmethyl)triphenylphosphonium bromide (Alfa Aesar, 10.2 g, 25.7 mmol) in dry DME (60 mL) kept between about −30° C. and 40° C. was added a 2.5M solution of n-butyllithium in hexanes (10.2 mL, 25.7 mmol) over about 5 min. After stirring between about −30° C. and −40° C. for about 45 min, 8-chloro-2-(2,4-difluorophenyl)imidazo[1,2-a]pyrazine (Example #13, Step A, 5.74 g, 23.2 mmol) was added. The mixture was warmed to ambient temperature, then stirred at about 85° C. for about 3.5 h, at which point a solution of Na2CO3 (1.364 g, 12.9 mmol) in water (50 mL) was added and heating was continued overnight. After cooling to ambient temperature, the mixture was partitioned between 1 N HCl and CHCl3 and the organic phase extracted five more times with 1 N HCl. The combined aqueous phase was rendered alkaline with NaOH and extracted with Et2O. After drying over Na2SO4 and concentration, the crude material was purified by silica gel chromatography with heptane/EtOAc (gradient 10-100% EtOAc). After concentration, the residue was three times re-dissolved in DCM and re-concentrated to give 0.728 g (22%) of the title compound as an orange solid: LC/MS (Table 1, Method g) Rt=3.08 min; MS m/z: 286.1 (M+H)+.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([C:17]2[S:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.O>ClCCl>[C:22]1([C:19]2[S:18][C:17]([C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:16]=[C:7]([OH:6])[CH:8]=3)=[CH:21][CH:20]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1cc(-c2ccc(-c3ccccc3)s2)c2ccccc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1cc(-c2ccc(-c3ccccc3)s2)c2ccccc2c1
Reaction time: 20 h
Yield: 90.4 %

Procedure:
Boron tribromide (1.04 ml, 10.76 mmol) was added slowly to a solution of 3-methoxy-1-(5-phenyl-2-thienyl)naphthalene (1.7 g, 5.38 mmol) in dichloromethane (50 ml) at 0° C. under nitrogen. After the addition was complete, the solution was allowed to stir for 20 h. The mixture was then poured into water (200 ml), extracted with Et2O (2×100 ml), washed with water (100 ml), dried (Na2SO4) and the solvent removed under reduced pressure. The resulting solid was washed with hexane and filtered to afford the title compound (1.47 g, 91%) as a red solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH:20]=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)([OH:24])N.[O-]Cl=O.[Na+]>O1CCOCC1.O.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([OH:24])=[O:21])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2C=O)CC1
Reactant: NS(=O)(=O)O
Agent: [Cl-]
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2C(=O)O)CC1
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
An alternative method for preparing this intermediate is as follows. 4-(2-Formyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.50 g, 1.72 mmol) is dissolved in 80 mL of dioxane and 20 mL of H2O. The mixture is cooled to 4° C. To this is added sulfamic acid (1.36 g, 14.00 mmol) in one portion. The mixture is stirred for an additional 30 min. To this is added 3 mL of a solution of NaClO2 (0.343 g, 3.80 mmol) in a dropwise manner. The reaction is quenched reaction with addition of 50 mL of H2O and 50 mL of brine. The mixture is extracted with 3×100 mL of CH2Cl2. The organic phase is washed with 2×50 mL of brine, dried (MgSO4), filtered and concentrated to give 500 mg of 4-(2-carboxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester, 95% yield.