Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([Cl:27])[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3scc(C)c23)cc1Cl
Reactant: c1cn[nH]c1
Product: COc1ccc(CNc2nc(-n3cccn3)nc3scc(C)c23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C1([O:6][C:7]2[C:12]([O:13][CH:14]([F:16])[F:15])=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:17]=[CH:18]/[C:19]2[N:20]=[C:21]3[N:25]([C:26]=2[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:24]=[CH:23][S:22]3)CCCC1.C1(OC2C(OC(F)F)=CC=CC=2/C=C/C2N=C3N(C=2C(O)=O)C=CS3)CCCC1.C(O)(=O)C.C([O-])(O)=O.[Na+]>Br>[F:16][CH:14]([F:15])[O:13][C:12]1[C:7]([OH:6])=[C:8](/[CH:17]=[CH:18]/[C:19]2[N:20]=[C:21]3[N:25]([C:26]=2[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:24]=[CH:23][S:22]3)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1c(/C=C/c2cccc(OC(F)F)c2OC2CCCC2)nc2sccn12
Agent: Br
Agent: O=C(O)c1c(/C=C/c2cccc(OC(F)F)c2OC2CCCC2)nc2sccn12
Agent: O=C([O-])O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(/C=C/c2cccc(OC(F)F)c2O)nc2sccn12
Temperature: 60 °C
Yield: 86.2 %

Procedure:
A solution of Ethyl 6-{(E)-2-[2-(cyclopentyloxy)-3-(difluoromethoxy)phenyl]vinyl}imidazo[2,1-b][1,3]thiazole-5-carboxylate (4.10 g, 9.149 mmol) from Intermediate 5, Step 1 in a mixture of 48% hydrobromic acid (20 mL) and glacial acetic acid (20 mL) was heated at 60° C. for 2 h. The reaction mixture was cooled to room temperature and neutralized with saturated solution of NaHCO3. The mixture was extracted with ethyl acetate (2×100 mL) and the combined organic layers were washed with water (2×100 mL), dried over anhydrous Na2SO4. The residue obtained after the evaporation of the solvent was purified by silica gel column chromatography using 2% ethyl acetate in petroleum ether to obtain 3.0 g of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.40 (t, J=6.3 Hz, 3H), 4.34-4.43 (m, 2H), 6.80-6.90 (m, 1H), 7.05-7.10 (m, 1H), 7.12 (t, J=69.0 Hz, 1H), 7.40-7.48 (m, 2H), 7.78 (d, J=16.2 Hz, 1H), 7.87 (d, J=16.2 Hz, 1H), 8.10-8.16 (m, 1H), 9.79 (br s, 1H); APCI-MS (m/z) 381.15 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[C:14]1[C:15]2[NH:22][C:21]([CH3:23])=[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:16]=2[N:17]=[CH:18][N:19]=1)[CH3:2].Cl[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:12])([F:13])[F:11])=[CH:6][C:5]=1[C:14]1[C:15]2[N:22]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:21]([CH3:23])=[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:16]=2[N:17]=[CH:18][N:19]=1)[CH3:2]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC)ncnc12
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(C(F)(F)F)ccc3OCC)ncnc12

Procedure:
Starting from ethyl 4-[2-ethoxy-5-(trifluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example D.a9) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is obtained as yellow viscous oil.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:5][CH:6]1[CH2:11][CH:10]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:9][CH2:8][C:7]1=[O:17])[CH3:4].Br[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1>>[ClH:1].[CH3:4][N:3]([CH2:5][CH:6]1[CH2:11][CH:10]([O:12][CH2:13][CH:14]([CH3:15])[CH3:16])[CH2:9][CH2:8][C:7]1([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)[OH:17])[CH3:2]
Reactant: CC(C)COC1CCC(=O)C(CN(C)C)C1
Reactant: COc1cccc(Br)c1
Agent: Cl
Product: COc1cccc(C2(O)CCC(OCC(C)C)CC2CN(C)C)c1
Yield: 38 %

Procedure:
The base of compound (22) was reacted with 1-bromo-3-methoxy-benzene corresponding to the conditions described in Example 1. The base obtained was purified with 1:1 ethyl acetate/methanol via a silica gel column, and was taken up in ether. After adding trimethylchlorosilane/water, compound (20) was obtained in a yield of 38% theoretical.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[CH2:19]([OH:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:27][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:3]=1
Reactant: OCCc1ccccc1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCCc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, phenethyl alcohol and DBU in DME. EI-MS m/e (%): 306 (M+, 4), 202 ([M—C6H5CH═CH2]+, 48), 104 (21).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1.FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[CH:11][N:10]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][O:13]3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: C1=COCCC1
Reactant: Brc1ccc(-c2cc[nH]n2)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc(-c2ccn(C3CCCCO3)n2)cc1
Yield: 94 %

Procedure:
To a heated (80° C.) solution of 3-(4-bromophenyl)-1H-pyrazole (1.0 g, 4.5 mmol) and trifluoroacetic acid (0.02 mL, 0.23 mmol) in toluene (5 mL) was added 3,4-dihydro-2H-pyran (0.43 mL, 4.7 mol) over 1 hour. The reaction mixture was stirred for an additional hour and was then concentrated and dried to provide 3-(4-bromophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (1.3 g, 94% yield). MS (EI) for C14H15BrN2O: 308 (MH+).
Reaction SMILES: N([O-])=O.[Na+].[C:5]1([C:11]2([OH:30])[CH2:16][CH2:15][N:14]([CH2:17][CH:18]3[CH2:27][CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23](N)[CH:24]=4)[C:19]3=[O:29])[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.C(=O)([O-])[O-:33].[K+].[K+]>C(Cl)(Cl)Cl.O>[C:5]1([C:11]2([OH:30])[CH2:16][CH2:15][N:14]([CH2:17][CH:18]3[CH2:27][CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23]([OH:33])[CH:24]=4)[C:19]3=[O:29])[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc2c(c1)CCC(CN1CCC(O)(c3ccccc3)CC1)C2=O
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C1c2ccc(O)cc2CCC1CN1CCC(O)(c2ccccc2)CC1

Procedure:
A solution of 0.7 g. of NaNO2 in 3 ml. of water is added dropwise to a stirred solution of 3.5 g. of 2-(4-phenyl-4-hydroxypiperidinomethyl)-6-amino-1-tetralone in 10 ml. of 4 N hydrochloric acid. The mixture is warmed until nitrogen evolution has ceased. It is cooled, neutralized with potassium carbonate and worked up with chloroform in the customary manner. 2-(4-Phenyl-4-hydroxypiperdinomethyl)-6-hydroxy-1-tetralone is obtained. EXAMPLE 5
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].O.[OH-].[Li+].Cl>O1CCOCC1.CO.O>[C:14]([O:13][C:11]([N:8]1[CH2:7][CH2:6][C:5]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)C1(Cc2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(Cl)cc2)(C(=O)O)CC1
Temperature: 50 °C
Reaction time: 48 h
Yield: 100.2 %

Procedure:
To a solution of 4-(4-chlorobenzyl)piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (1.515 g, 4.117 mmol) in dioxane (20 ml), methanol (10 ml) and water (10 ml) at room temperature was added lithium hydroxide monohydrate (3.455 g, 82.341 mmol). After stirring at 50° C. for 2 days the solution was acidified to pH 6 with 2M HCl and the resulting white precipitate was extracted with diethyl ether (2×100 ml). The organic phases were combined, dried over sodium sulphate and concentrated to dryness, to give the acid as a white solid (1.460 g, 100%). LC-MS (LCT) m/z 376 [M+Na+], Rt 7.62 min.
Reaction SMILES: [C:1]([CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[C:7]([O:18][CH3:19])[CH:6]=[CH:5][C:4]1=2)#[N:2].Cl.[CH2:21](N)[CH2:22][NH2:23].N>CO.CO.C(Cl)(Cl)Cl>[NH:2]1[CH2:21][CH2:22][N:23]=[C:1]1[CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[C:7]([O:18][CH3:19])[CH:6]=[CH:5][C:4]1=2
Reactant: NCCN
Reactant: COc1ccc2c(c1NS(C)(=O)=O)CCCC2C#N
Agent: Cl
Agent: N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1NS(C)(=O)=O)CCCC2C1=NCCN1
Temperature: 0 °C
Reaction time: 12 h
Yield: 74.4 %

Procedure:
N-(5-Cyano-2-methoxy-5,6,7,8-tetrahydronaphthalen-1-yl)methane-sulfonamide (1.5 g, 5.4 mmol) was dissolved in 200 ml of MeOH and cooled to 0° C. The solution was then treated with dry HCl gas for 2 h, sealed tightly and stored for 12 h at 25° C. The solvent was removed and the residue was redissolved in 100 ml of MeOH, followed by addition of ethylenediamine (0.67 ml, 10 mmol). The resulting solution was stirred at reflux for 12 h. The reaction mixture was concentrated in vacuo, yielding an oily residue which was subjected to column chromatography (25% NH3 sat'd MeOH-CHCl3) to provide 1.3 g (76%) of the desired product. 1H NMR (300 MHz, CD3OD): δ 1.78 (m, 2H), 1.96 (m, 1H), 2.12 (m, 1H), 2.95 (broad t, 2H), 2.98 (s, 3H), 3.82 (s, 3H), 3.90 (broad s, 4H), 4.11 (t, 1H, J=6.3 Hz), 6.96 (t, 1H, J=8.9 Hz), 7.05 (t, 1H, J=8.9 Hz).
Reaction SMILES: [CH:1]1([N:4]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:31][CH:30]=1>CN(C=O)C>[CH:1]1([N:4]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[CH:31][CH:30]=3)[CH2:16][CH2:15]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Reactant: O=S(=O)(c1ccccc1)N(C1CCNCC1)C1CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1)N(C1CC1)C1CCN(Cc2ccc(-c3ccccc3)cc2)CC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 18.4 %

Procedure:
N-Cyclopropyl-N-piperidin-4-yl-benzenesulfonamide (56 mg, 0.2 mmol) was dissolved in DMF (2.5 ml) and triethylamine (75 μL, 54 mg, 0.54 mmol) added, followed by 4-chloromethyl-biphenyl (81 mg, 0.4 mmol). The reaction mixture was stirred for 12 hours at 80° C. and the solvent was evaporated. The residue was purified by flash chromatography to give 16.4 mg of the desired product N-cyclopropyl-N-[1-(4-phenylbenzyl)piperidin-4-yl]benzenesulfonamide (16). 1H NMR (CDCl3): δ 7.92-7.85 (m, 1H), 7.63-7.31 (m, 9H), 7.30-7.25 (m, 4H), 3.93-3.83 (m, 1H), 3.54 (s, 2H), 3.00-2.89 (m, 2H), 2.14-1.89 (m, 5H), 1.66-1.49 (m, 2H+H2O), 1.04-0.97 (m, 2H), 0.81-0.72 (m, 2H). LC: 98%. MS (EI): m/z 447 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.FC(F)(F)S(O[C@@H:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.C(OC)(C)(C)C>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([C@H:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:6]=1
Reactant: Clc1cn[nH]c1
Reactant: COC(=O)[C@H](C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COC(C)(C)C
Product: COC(=O)[C@@H](C)n1cc(Cl)cn1
Temperature: 25 °C
Yield: 83.1 %

Procedure:
4-Chloro-1H-pyrazole (668 mg, 6.51 mmol) was dissolved in ethyl acetate and (S)-methyl 2-(trifluoromethylsulfonyloxy)propanoate (1.538 g, 6.51 mmol) was added followed by potassium carbonate (2.70 g, 19.5 mmol) while stirring at room temperature. The reaction mixture was stirred for 18 h. The mixture was diluted with methyl tert-butyl ether (15 mL), filtered through Celite, and washed with a mixture of ethyl acetate:methyl tert-butyl ether (1:1, 15 mL×4). The filtrate was reduced in volume by approximately 30-40 mL then was washed with aqueous hydrochloric acid (0.1 M, 25 mL), water and brine (15 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated to afford (R)-methyl 2-(4-chloro-1H-pyrazol-1-yl)propanoate as an oil (1.02 g). 1H NMR (500 MHz, CDCl3) δ 1.77 (d, 3H), 3.76 (s, 3H), 5.05 (q, 1H), 7.46 (s, 1H), 7.54 (s, 1H); MS (EI+) (M+) 188; Chiral HPLC retention time: 3.11 min (Method: Chiralpak AD-H 0.46×25 cm, Mobile Phase: 95/5 CO2/methanol; Flow: 2.5 mL/min); 73.3% ee.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[S:11](=[O:22])(=[O:21])[NH:12][C:13]2[C:18]([C:19]=1[OH:20])=[N:17][CH:16]=[CH:15][N:14]=2.N1C=CC=CC=1.[CH3:29][C:30]([CH3:35])([CH3:34])[C:31](Cl)=[O:32]>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[S:11](=[O:21])(=[O:22])[NH:12][C:13]2[C:18]([C:19]=1[O:20][C:31](=[O:32])[C:30]([CH3:35])([CH3:34])[CH3:29])=[N:17][CH:16]=[CH:15][N:14]=2
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=S1(=O)Nc2nccnc2C(O)=C1c1c(F)ccc(F)c1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)OC1=C(c2c(F)ccc(F)c2Cl)S(=O)(=O)Nc2nccnc21
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a suspension of Compound No. A2 (Example 3.1) in dichloromethane (10 ml) was added pyridine (0.205 ml) followed by 2,2-dimethylpropionyl chloride (0.15 ml). The reaction mixture was heated to 40° C. for 4 hours and then stored at ambient temperature of 16 hours. The reaction mixture was partition between dichloromethane (30 ml) and aqueous hydrochloric acid (2M) (30 ml). The phases were separated. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were concentrated. The residue was triturated with iso-hexane and dried under vacuum to give Compound No. B3 of Table B (408 mg) as a yellow solid.
Reaction SMILES: C([NH:9][C:10]([NH:21][CH2:22][CH2:23][CH2:24][C:25]1[N:26]=[CH:27][NH:28][CH:29]=1)=[N:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)C1C=CC=CC=1>Cl>[NH:28]1[CH:29]=[C:25]([CH2:24][CH2:23][CH2:22][NH:21][C:10]([NH:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[NH:9])[N:26]=[CH:27]1
Reactant: O=C(NC(=NCCCc1ccccc1)NCCCc1c[nH]cn1)c1ccccc1
Agent: Cl
Product: N=C(NCCCc1ccccc1)NCCCc1c[nH]cn1

Procedure:
0.73 g (1.9 mmol) of N-benzoyl-N'-[(3-imidazol-4-yl) propyl]-N"-(3-phenylpropyl)-guanidine are heated under reflux in 45 ml of 20% hydrochloric acid for 7 hours. The method of working up is analogous to that of Example 58.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([O:27][C:28]([NH:30][C@@H:31]([C@H:47]([O:56][Si:57]([C:60]([CH3:63])([CH3:62])[CH3:61])([CH3:59])[CH3:58])[CH2:48][O:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH2:32][CH2:33][CH:34]([OH:46])[CH2:35][C:36]1[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[C:23]([O:27][C:28]([NH:30][C@@H:31]([C@H:47]([O:56][Si:57]([C:60]([CH3:63])([CH3:62])[CH3:61])([CH3:58])[CH3:59])[CH2:48][O:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH2:32][CH2:33][C:34](=[O:46])[CH2:35][C:36]1[CH:37]=[CH:38][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:44][CH:45]=1)=[O:29])([CH3:25])([CH3:24])[CH3:26]
Reactant: COC(=O)c1ccc(CC(O)CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](COc2ccccc2)O[Si](C)(C)C(C)(C)C)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC(=O)c1ccc(CC(=O)CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](COc2ccccc2)O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.7 %

Procedure:
Dess-martin reagent (390 mg, 0.92 mM) was placed in a 100 ml round bottom flask and 5 ml of methylene chloride was added, 5 min later, methyl 4-{(5R,6S)-5-[(tert-butoxycarbonyl)amino]-6-{[tert-butyl(dimethyl)silyl]oxy}-2-hydroxy-7-phenoxyheptyl}benzoate from step E (360 mg, 0.61 mM) in 5 ml of methylene chloride was added, and the resulting mixture was stirred for 3 h at RT. The mixture was then filtered and the filtrate was washed by saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated to dryness. The residue was then loaded onto a Biotage column (40 S) and eluted with hexane/ethyl acetate (0-30% EA, 500 ml; 30-50% EA, 300 ml) to afford 139 mg of the title compound. LC-MS: m/z (ES) 608.24 (M=23).
Reaction SMILES: [Cl-].[S:2]([C:6]1[CH:15]=[C:14]([S:16]([OH:19])(=[O:18])=[O:17])[CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([NH2+:20]N)=[CH:11]2)([OH:5])(=[O:4])=[O:3].[CH3:22][CH:23]([C:32](=O)[CH3:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30]>C(O)(=O)C>[CH3:22][C:23]1([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C:11]2[C:12]3[CH:13]=[C:14]([S:16]([OH:19])(=[O:18])=[O:17])[CH:15]=[C:6]([S:2]([OH:5])(=[O:4])=[O:3])[C:7]=3[CH:8]=[CH:9][C:10]=2[N:20]=[C:32]1[CH3:33]
Reactant: CC(=O)C(C)CCCCCC(=O)O
Reactant: N[NH2+]c1ccc2c(S(=O)(=O)O)cc(S(=O)(=O)O)cc2c1
Agent: [Cl-]
Solvent: CC(=O)O
Product: CC1=Nc2ccc3c(S(=O)(=O)O)cc(S(=O)(=O)O)cc3c2C1(C)CCCCCC(=O)O

Procedure:
(5,7-Disulfo-2-naphthyl)hydrazinium chloride (2.0 g), 7-methyl-8-oxononanoic acid (1.5 g) and acetic acid (15 ml) were heated from 80-140° C. for a total of 24 hrs. After evaporation of the solvent under vacuum, the residue was triturated with 2-propanol to give a pink solid. This solid was collected by filtration, washed with 2-propanol, then excess diethyl ether and dried under vacuum over phosphorus pentoxide. Yield of crude product=1.96 g. This was purified as required by preparative HPLC (RPC18. Water/MeCN/TFA) to give pure product. 1H-nmr (D2O) δ 0.25-0.4 (1H, broad m), 0.5-0.65 (1H, broad m), 1.00 (2H, m), 1.25 (2H, m), 1.78 (3H, s), 2.06 (2H, t), 2.35-2.5 (1H, broad m), 2.65-2.8 (1H, broad m), 2.90 (3H, s), 8.05 (1H, d), 8.58 (1H, d), 8.70 (1H, d) and (8.97 (1H, d). MS (LCMS) MH+ 470. Acc. Mass: MH+ 470.0931 (−2.6 ppm for C20H24NO8S2).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([C:14]1[C:15](/[N:23]=[CH:24]/[N:25]([CH3:27])C)=[N:16][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:18][CH:19]=1)#N.O>C(O)(=O)C>[CH:20]([C:17]1[CH:18]=[CH:19][C:14]2[C:27]([NH:1][C:2]3[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[N:25][CH:24]=[N:23][C:15]=2[N:16]=1)([CH3:21])[CH3:22]
Reactant: COC(=O)c1cccc(N)c1
Reactant: CC(C)c1ccc(C#N)c(/N=C/N(C)C)n1
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cccc(Nc2ncnc3nc(C(C)C)ccc23)c1
Temperature: 120 °C
Reaction time: 0.42 h
Yield: 98.4 %

Procedure:
To methyl 3-aminobenzoate (0.50 g, 3.31 mmol) in acetic acid (10 mL) was added (E)-N′-(3-cyano-6-isopropylpyridin-2-yl)-N,N-dimethylformimidamide (0.71 g, 3.31 mmol) and the mixture was stirred at 120° C. for 25 minutes. Reaction mixture was cooled to room temperature and a solid formed. Water was added and solid was collected by filtration. Purification by chromatography on silica gel eluting with 0-30% methanol in dichloromethane gave the title compound (1.05 g, 98% yield).
Reaction SMILES: [C:1]([O:6][CH:7](OCC=C)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:19]([O:22]C1C=CC(CCO)=CC=1)[CH:20]=[CH2:21].C(Br)C=C>>[C:1]([O:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:22][CH2:19][CH:20]=[CH2:21])=[CH:13][CH:14]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=CCOC(Cc1ccccc1)OC(=O)C(=C)C
Reactant: C=CCOc1ccc(CCO)cc1
Solvent: C=CCBr
Product: C=CCOc1ccc(CCOC(=O)C(=C)C)cc1

Procedure:
Allyloxyphenethyl methacrylate, 82% purity, was prepared in the manner of Example 3 from 2-(4-allyloxyphenyl)ethyl alcohol. The starting 2-(4-allyloxyphenyl)ethyl alcohol was prepared by alkylation of the corresponding phenolic alcohol with allyl bromide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[C:5]([F:17])=[CH:4][C:3]=1[C:18](=[O:20])[CH3:19].Br[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.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]>[F:1][C:2]1[CH:7]=[C:6]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=2)[C:5]([F:17])=[CH:4][C:3]=1[C:18](=[O:20])[CH3:19]
Reactant: CC(=O)c1cc(F)c(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: Fc1ccc(Br)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1cc(F)c(-c2ccc(F)cn2)cc1F
Temperature: 80 °C

Procedure:
Pd(dppf)Cl2 (579 mg, 0.7 mmol) was added to a degassed, ambient temperature solution of 1-[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanone (2 g, 7.1 mmol), 2-bromo-5-fluoropyridine (2.5 g, 14 mmol) and sodium carbonate (2.26 g, 21 mmol) in N,N-dimethyformamide (20 mL) and water (10 mL). After heating at 80° C. overnight, the reaction mixture was poured into water and extracted with diethyl ether. The combined organic phases were dried (magnesium sulfate), filtered and concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=O)=[CH:5][CH:4]=1.[NH2:21][C:22]1[C:30]([NH2:31])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[N:21][C:22]3[C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=[CH:29][C:30]=3[N:31]=2)=[CH:5][CH:4]=1
Reactant: Nc1cccc(C(=O)O)c1N
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Solvent: CC(=O)O
Product: COc1ccc(-c2nc3cccc(C(=O)O)c3nc2-c2ccc(OC)cc2)cc1
Yield: 25.9 %

Procedure:
A solution of 1,2-bis(4-methoxyphenyl)ethane-1,2-dione (270 mg, 1.00 mmol, 1.00 equiv) and 2,3-diaminobenzoic acid (152 mg, 1.00 mmol, 1.00 equiv) in acetic acid (10 mL) was heated under reflux for 3 h. The reaction was quenched by the addition of 20 mL of ice/water. The solids were collected by filtration and purified by re-crystallization from methanol, affording 100 mg (26%) of 2,3-bis(4-methoxyphenyl)quinoxaline-5-carboxylic acid as a yellow solid.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[NH2:5][C:6]([CH:34]1[CH2:36][CH2:35]1)([CH:31]1[CH2:33][CH2:32]1)[C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]([NH:20][C:21]3[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=3)[CH:16]=[C:17]([CH3:19])[CH:18]=2)=[CH:9][CH:8]=1.C1COCC1.C(O)(=O)C>C([O-])(O)=O.[Na+].O>[CH:31]1([C:6]([CH:34]2[CH2:36][CH2:35]2)([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH:14]=[C:15]([NH:20][C:21]4[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][N:22]=4)[CH:16]=[C:17]([CH3:19])[CH:18]=3)=[CH:11][N:12]=2)[NH:5][C:2]([NH2:3])=[O:1])[CH2:33][CH2:32]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(C(N)(C3CC3)C3CC3)nc2)c1
Reactant: N#C[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(C(NC(N)=O)(C3CC3)C3CC3)nc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium cyanate (71.1 mg, 0.876 mmol) was added to a mixture of N-(3-{6-[amino(dicyclopropyl)methyl]pyridin-3-yl}-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine (257 mg, 0.584 mmol), THF (4.00 mL), acetic acid (0.050 ml, 0.876 mmol), and water (2.00 mL) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with saturated aqueous NaHCO3 (20.0 mL) and extracted with ethyl acetate (50.0 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% methanol in ethyl acetate) and the isolated material was then triturated with ethyl acetate (4.00 mL) and methanol (0.50 mL) to yield 1-{dicyclopropyl[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]methyl}urea. MS APCI calc'd for C25H26F3N6O [M+H]+ 483. found 483. 1H NMR (500 MHz, CD3OD) δ11.08 (s, 1H), 9.65 (d, J=5.3 Hz, 1H), 9.49 (d, 1H), 8.74 (s, 1H), 8.68 (d, J=11.2 Hz, 1H), 8.47-8.19 (m, 2H), 8.08 (d, J=5.2 Hz, 1H), 7.98 (s, 1H), 6.87 (s, 1H), 6.24 (s, 2H), 3.16 (s, 4H), 2.26 (s, 2H), 1.26 (d, J=25.7 Hz, 3H), 1.10 (d, J=6.0 Hz, 4H).