Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[C:8]=1[CH3:14].Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>C1COCC1.[Cl-].[Cl-].[Zn+2].Cl[Pd]Cl>[Br:13][C:9]1[C:8]([CH3:14])=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Brc1ccccn1
Reactant: Cc1c(Br)cccc1Br
Agent: Cl[Pd]Cl
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1-c1ccccn1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
A solution of i-PrMgCl (27.49 mL, 2M in THF, 55 mmol.) was added dropwise to commercially available 1,3-dibromo-2-methyl-benzene (12.5 g, 50 mmol) at RT under argon and then heated at 65° C. for 1.5 h. The mixture was added via syringe to a suspension of dry ZnCl2 (6.83 g, 50 mmol.) in dry THF (20 ml) and cooled to 0° C. under argon. The resulting suspension was stirred at RT for 30 min. Then 2-bromo-pyridine (4.78 ml, 50 mmol.) and PdCl2*dppf (2.03 g) were added and the mixture was refluxed for 2 h. The reaction mixture was then quenched by the addition of a 5% solution of citric acid (200 ml) and extracted with ethyl acetate (2×250 ml). The combined organic layers were consecutively washed with a 5% solution of citric acid (150 ml) and brine (150 ml), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude material was chromatographed on silica gel. Yield: 7.7 g, 78%.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[NH:8])[CH3:2].[Cl:9][C:10]1[CH:11]=[C:12]([N:16]=[C:17]=[O:18])[CH:13]=[CH:14][CH:15]=1>C1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]([N:8]=[C:4]2[CH2:5][CH2:6][CH2:7][N:3]2[CH2:1][CH3:2])=[O:18])[CH:13]=[CH:14][CH:15]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: CCN1CCCC1=N
Solvent: c1ccccc1
Product: CCN1CCCC1=NC(=O)Nc1cccc(Cl)c1
Temperature: 25 °C

Procedure:
The hydrochloride salt of 1-ethyl-2-iminopyrrolidine (7.43 g.; 0.05 mole) is converted to free base (5.6 g.; 0.05 mole) by adding 7 ml. of 50% NaOH to an aqueous slurry (minimal amount of water) of the salt and benzene extraction. After drying over K2CO3, the benzene solution is stirred at room temperature and 7.68 g. (0.05 mole) of m-chlorophenylisocyanate, dissolved in anhydrous benzene, is added. The reaction mixture is stirred for 13/4 hours and the solvent is then evaporated in vacuo leaving a solid residue, 1-m-chlorophenyl-3-(1-ethyl-2-pyrrolidylidene)urea. Recrystallizations from ethyl acetate yields the pure product, m.p. = 122°-124° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][NH2:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH3:15][NH:16][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (0.50 g, 2.5 mmol, Aldrich) and 2.0 M methylamine in Tetrahydrofuran (10. mL, 20. mmol, Aldrich) was added sodium triacetoxyborohydride (1.3 g, 6.3 mmol). After stirring of the suspension overnight, the reaction was quenched with water and stirred for 1 hour. Brine was added and the product was extracted with two portions of DCM. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The product was used without further purification in Step 2. LCMS (M+H)+: 215.2.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][CH:11]=[C:12]([C:14]([NH:16][C:17]2[C:18]([C:29](=[O:31])[NH2:30])=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)=O)[N:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+]>CO>[C:1]([NH:5][S:6]([C:9]1[S:10][CH:11]=[C:12]([C:14]2[N:30]=[C:29]([OH:31])[C:18]3[C:17](=[CH:22][CH:21]=[CH:20][C:19]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:16]=2)[N:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)c1nc(C(=O)Nc2cccc(-c3ccccc3)c2C(N)=O)cs1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)NS(=O)(=O)c1nc(-c2nc(O)c3c(-c4ccccc4)cccc3n2)cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.6 %

Procedure:
To a solution 2-(N-tert-butylsulfamoyl)-N-(2-carbamoylbiphenyl-3-yl)thiazole-4-carboxamide (0.11 g, 0.24 mmol) in methanol (10 mL) was added NaOMe (0.25 ml, 25% in MeOH, 1.2 mmol). The resulting mixture was stirred at RT for 16 h. After this time, the reaction mixture was concentrated, diluted with ethyl acetate and washed with water. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (40% EtOAc in hexane) to provide (N-tert-butyl-4-(4-hydroxy-5-phenylquinazolin-2-yl)thiazole-2-sulfonamide (0.10 g, 100% yield) as a white solid. LCMS Method V: retention time 2.01 min; [M+1]=441.2.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>CN(C=O)C.O>[CH2:20]([O:12][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([OH:13])[C:2]=1[Br:1])[C:6]([O:8][CH3:9])=[O:7])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(O)c(Br)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(O)c(Br)c(OCc2ccccc2)c1
Reaction time: 8 h
Yield: 52 %

Procedure:
To a mixture of methyl 4-bromo-3,5-dihydroxybenzoate (18.8 g, 76 mmol) and potassium carbonate (5.26 g, 38.1 mmol) in DMF (190 mL) was added benzyl bromide (3.17 mL, 26.6 mmol). The mixture was stirred overnight, diluted with 200 mL water and acidified to pH 1 by slow addition of concentrated hydrochloric acid. The solution was extracted with 1:1 ethyl acetate/ether (6×) and the combined extracts were washed with water (8×), saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated to an orange solid. The solids were suspended in DCM (200 mL) and stirred overnight. The solids (primarily unreacted 4-bromo-3,5-dihydroxybenzoate) were removed by filtration and the filtrate was concentrated to an orange oil which was purified by column chromatography (80 g silica gel, 2:1 DCM in heptane elution, followed by DCM elution) to provide methyl 3-(benzyloxy)-4-bromo-5-hydroxybenzoate (4.66 g). MS (M+1)=337.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.32-7.57 (m, 6H), 7.26 (d, J=1.52 Hz, 1H), 5.77 (s, 1H), 5.22 (s, 2H), 3.93 (s, 3H) as well as the di-benzylated methyl 3,5-bis(benzyloxy)-4-bromobenzoate (1.8 g).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:7]([CH2:11]O)=[C:8](Cl)[N:9]=1)[CH2:2][CH2:3][CH3:4].[CH3:21][O:22][C:23](=[O:35])[C@:24]([CH2:33][CH3:34])([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH2:25]>>[CH3:21][O:22][C:23](=[O:35])[C@:24]([CH2:33][CH3:34])([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH:25][CH2:11][C:7]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9][CH:8]=1
Reactant: CC[C@](N)(Cc1ccccc1)C(=O)OC
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccccc1Cl
Product: CCCCc1ncc(CN[C@@](CC)(Cc2ccccc2)C(=O)OC)n1Cc1ccccc1Cl

Procedure:
The procedure of Example 4 (i), Method A, was followed using a-ethylphenylalanine methyl ester in place of α-methyl-phenylalanine methyl ester to give N-[{1-(2-chlorophenyl)methyl-2-n butyl-1H-imidazol-5-yl}methyl-α-ethylphenylalanine methyl ester. Hydrolysis of the ester using the procedure of Example 2 (ii), followed by treatment with hydrochloric acid, gave the title compound as the dihydrochloride salt; mp 209°-211° C.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1>>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][N:24]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)[CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccccc2)C1
Reactant: Clc1ccccn1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCN(c3ccccn3)CC2)[C@H](c2ccccc2)C1

Procedure:
The title compound, MS: m/e=563.3 (M+H+), was prepared in accordance with the general method of example 59 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-(3-phenyl-4-piperazin-1-yl-piperidin-1-yl)-methanone and 2-chloropyridine.
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[CH:19]=[CH:18][C:15](CBr)=[CH:14][CH:13]=1>C1COCC1>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[CH:13]=[C:14]([CH:15]=[CH:18][CH:19]=1)[CH2:4][O:3][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:6]1
Reactant: BrCc1ccc(-c2nc3ccccc3o2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1cc(COC2CCCCC2)cc(-c2nc3ccccc3o2)c1
Reaction time: 5 h

Procedure:
A mixture of 2-cyclohexan-1-ol (0.63 ml; 6.4 mmol) and sodium hydride (60%; 384 g; 9.6 mmol) in 30 ml dry THF is refluxed overnight. The solution is cooled and 4-(benzoxazol-2-yl)benzyl bromide (1.95 g; 6.75 mmol) is added in one portion and refluxing continued for 5 hrs. The solution is quenched with the addition of 2 ml H2O, concentrated in vacuo poured into H2O and extracted with 2×100 ml CH2Cl2, dried (Na2SO4), concentrated in vacuo and flash chromatographed using 9:1 6:1; hexane:EtOAc to obtain 3-[3-(benzoxazol-2-yl)benzyloxy]cyclohexane which is used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]2)[CH:5]=[C:4]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([OH:32])[CH:30]=3)[N:25]([S:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:24]=2)[CH:3]=1.[CH2:42](O)[C:43]#[CH:44].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOC(C)=O.ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:10]2)[CH:5]=[C:4]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([O:32][CH2:44][C:43]#[CH:42])[CH:30]=3)[N:25]([S:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:24]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2cc(-c3cn(S(=O)(=O)c4ccccc4)c4ncc(O)cc34)cc(Cl)n2)CC1
Reactant: C#CCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: C#CCOc1cnc2c(c1)c(-c1cc(Cl)nc(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c1)cn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of Example 224a (0.075 g, 0.125 mmol), propargyl alcohol (0.018 mL, 0.313 mmol), di-tert-butyl azodicarboxylate (0.072 g, 0.313 mmol), and triphenylphosphine (3 mmol/1 g)-polymer supported (0.105 g, 0.4 mmol) in THF (3.0 mL) was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and dichloromethane, filtered through celite, concentrated and purified on 12 g column, using Analogix System, eluted with 0-30% EtOAc in hexanes to give 56.0 mg (70%) of the title compound.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21](=[O:26])(=[O:25])[N:22]([CH3:24])[CH3:23])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1>>[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:33][C:4]([C:6]2[N:7]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21](=[O:26])(=[O:25])[N:22]([CH3:23])[CH3:24])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=2[OH:12])=[O:5])=[CH:30][CH:29]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1nc(-c2ccccc2S(=O)(=O)N(C)C)n(C)c(=O)c1O
Product: CN(C)S(=O)(=O)c1ccccc1-c1nc(C(=O)NCc2ccc(F)cc2)c(O)c(=O)n1C

Procedure:
Prepared according to the procedure described for example 2 from 2-(2-dimethylsulfamoyl-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.076 g, 0.2mmol), and 4-fluorobenzylamine (0.11 mL, 1.0 mmol). The title product was obtained as white needles (0.0549 g, 60% yield). 1HNMR (500 MHz, CDCl3) δ: 12.08 (1H, s), 7.91 (1H, d, J=7.33 Hz), 7.71–7.66 (3H, m), 7.37 (1H, dd, J=7.32, 1.83 Hz), 7.22 (2H, q, J=5.50 Hz), 7.00 (2H, t, J=8.55 Hz), 4.62 (1H, dd, J=15.26, 7.02 Hz), 4.40 (1H, dd, J=14.64, 5.49 Hz), 3.23 (3H, s), 2.64 (6H, s). HRMS (ESI) calcd for C21H22FSN4O5 (M+H): 461.1295; found: 461.1300.
Reaction SMILES: [CH:1]1C2C(=O)NC3C=CC=CC=3NC=2C=CC=1.Cl.CC1C=C(C=CN=1)C(Cl)=O.[CH3:28][C:29]1[CH:34]=[C:33]([C:35]([N:37]2[C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[C:41](=[O:48])[NH:40][C:39]3[CH:49]=[CH:50][CH:51]=[CH:52][C:38]2=3)=[O:36])[CH:32]=[CH:31][N:30]=1>>[CH3:1][N:30]1[CH:29]([CH3:28])[CH2:34][C:33]([C:35]([N:37]2[C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[C:41](=[O:48])[NH:40][C:39]3[CH:49]=[CH:50][CH:51]=[CH:52][C:38]2=3)=[O:36])=[CH:32][CH2:31]1
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Reactant: Cc1cc(C(=O)N2c3ccccc3NC(=O)c3ccccc32)ccn1
Agent: Cc1cc(C(=O)Cl)ccn1
Agent: Cl
Product: CC1CC(C(=O)N2c3ccccc3NC(=O)c3ccccc32)=CCN1C

Procedure:
From 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 2-methylisonicotinic acid chloride hydrochloride via 5,10-dihydro-5-[(2-methyl-4-pyridinyl)carbonyl]-11H-dibenzo[b,e][1,4]diazepin-11-one and 5,10-dihydro-5-[(2-methyl-4-pyridinyl)carbonyl]-11H-dibenzo[b,e][1,4]-diazepin-11-one methoiodide.
Reaction SMILES: CC1C=CC(C([O:8][CH2:9][C@@H:10]2[CH:14]([O:15]C(C3C=CC(C)=CC=3)=O)[CH2:13][C@H:12]([N:25]3[C:29]4=[N:30][C:31]([NH2:36])=[N:32][C:33]([O:34][CH3:35])=[C:28]4[C:27]([I:37])=[N:26]3)[O:11]2)=O)=CC=1.C[O-].[Na+].C(O)(=O)C>CO>[NH2:36][C:31]1[N:30]=[C:29]2[N:25]([C@@H:12]3[O:11][C@H:10]([CH2:9][OH:8])[CH:14]([OH:15])[CH2:13]3)[N:26]=[C:27]([I:37])[C:28]2=[C:33]([O:34][CH3:35])[N:32]=1
Reactant: COc1nc(N)nc2c1c(I)nn2[C@H]1CC(OC(=O)c2ccc(C)cc2)[C@@H](COC(=O)c2ccc(C)cc2)O1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1nc(N)nc2c1c(I)nn2[C@H]1CC(O)[C@@H](CO)O1
Temperature: -10 °C

Procedure:
To a suspension of 15 (32.4 g, 50.40 mmol) in 600 mL of methanol was added 12.5 mL of 1M sodium methoxide in methanol. The reaction mixture was stirred at reflux for 18 h. and then cooled in a freezer (−10° C.). The crystals of 3 that formed were filtered and rinsed with ice-cold methanol: 10.95 g yield. Acetic acid (12.5 mL) was added to the filtrate and the volume was reduced to about 300 mL. The solution was allowed to sit in the freezer overnight and another crop of crystals (3.95 g) was collected. The filtrate was evaporated to dryness and the residual oil was triturated in ether. The solid that formed was filtered, dried and recrystallized from boiling water: 2.03 g. Total yield=16.93 g (83%); TLC (10% methanol in ethyl acetate), Rf=0.23; 1H NMR (DMSO-d6) δ 7.02 (2H, br s, 6-amino), 6.33 (1H, t, J=6.1 Hz), 5.24 (1H, d, J=4.4 Hz, 3′-OH), 4.73 (1H, t, J=5.6 Hz, 5′-OH), 4.36 (1H, m, 3′-H), 3.99 (3H, s, 4-methoxy), 3.75 (1H, m, 4′-H), 3.51-3.32 (2H, m, 5′-Hs), 2.79 and 2.17 (2H, 2×m, 2′-Hs). Anal. Calcd. For C11H14IN5O4.0.3H2O; C, 32.02; H, 3.57; N, 16.98. Found C, 32.13; H, 3.35; N, 16.77.
Reaction SMILES: C[O:2][C:3]([CH:5]([O:28][C:29]1[N:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([CH3:37])[N:30]=1)[C:6]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:7][CH2:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12]C)=[O:11])=[O:4].[OH-].[Na+]>O1CCOCC1.O>[C:3]([CH:5]([O:28][C:29]1[N:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([CH3:37])[N:30]=1)[C:6]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[O:7][CH2:8][C:9]([CH3:15])([CH3:14])[C:10]([OH:12])=[O:11])([OH:4])=[O:2]
Reactant: COC(=O)C(Oc1nc(C)cc(OC)n1)C(OCC(C)(C)C(=O)OC)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C)nc(OC(C(=O)O)C(OCC(C)(C)C(=O)O)(c2ccccc2)c2ccccc2)n1
Yield: 42.7 %

Procedure:
10.1 g (20 mmol) of methyl 3-[2-methoxycarbonyl-2-(4-methoxy-6-methyl-2-pyrimidinyloxy)-1,1-diphenylethoxy]-2,2-di-methylpropionate were dissolved in 50 ml of dioxane and 50 ml of 2N NaOH solution and stirred at 80° C. for 4 h. The solution was diluted with 300 ml of H2O and extracted with 100 ml of ethyl acetate. The aqueous phase was neutralized with 1N HCl and extracted with ethyl acetate, and the organic phase was dried over MgSO4, filtered and concentrated. The oily residue was crystallized from diethyl ether/hexane to result in 4.1 g (42%) of colorless crystals.
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:27])[NH:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])(C)(C)C>O1CCOCC1.ClCCl>[ClH:1].[ClH:1].[CH3:26][N:24]([CH3:25])[CH2:23][CH2:22][CH2:21][NH:20][C:19](=[O:27])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH2:8]
Reactant: CN(C)CCCNC(=O)CCCCCCCCCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN(C)CCCNC(=O)CCCCCCCCCCN
Temperature: 0 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
A solution of 4.0 M hydrochloric acid in dioxane (1 mL) was added dropwise to a solution of amide 4 (154 mg, 0.40 mmol) in dichloromethane (3 mL) which was pre-cooled to 0° C. After this time, the reaction was then allowed to warm to ambient temperature and stirred for an additional 2 hours. After this time, the solvent was removed under vacuum to give salt 5 (124 mg, 86%) as a white solid: 1H NMR (300 MHz, CD3OD) δ 1.34 (s, 12H), 1.53-1.66 (m, 6H), 1.87-1.98 (m, 2H), 2.19-2.37 (m, 3H), 2.88-2.97 (m, 8H), 3.20-3.28 (m, 2H), 3.28-3.33 (m, 2H); m/z (ESI) 286 [C16H35N3O+H]+.
Reaction SMILES: CSC.B.[F:5][C:6]1[C:11]([F:12])=[C:10]([OH:13])[CH:9]=[CH:8][C:7]=1[CH2:14][C:15](O)=[O:16]>O1CCCC1>[F:12][C:11]1[C:6]([F:5])=[C:7]([CH2:14][CH2:15][OH:16])[CH:8]=[CH:9][C:10]=1[OH:13]
Reactant: O=C(O)Cc1ccc(O)c(F)c1F
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: OCCc1ccc(O)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of borane dimethylsulfide complex (2M in THF, 14.4 mL) was added dropwise to a solution of 2-(2,3-difluoro-4-hydroxyphenyl)acetic acid (example 77, step a) (1.08 g) in tetrahydrofuran (25 mL) at 0° C. and the resulting mixture was allowed to warm to RT and stirred overnight. The reaction was quenched with methanol and when bubbling had ceased the solvent evaporated. The residue was purified by silica gel chromatography eluting with 4:1 isohexane:ethyl acetate to ethyl acetate gradient. The fractions containing product were combined and evaporated to give the subtitled compound as white solid. Yield 0.95 g.
Reaction SMILES: OO.[OH:3][O:4]S([O-])=O.[K+].C(OO)=O.NC(N)=O.[C:17]1(=[O:27])[O:22][C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12>>[CH:24]1[CH:23]=[C:19]([C:20]([OH:22])=[O:21])[C:18]([C:17]([O:4][OH:3])=[O:27])=[CH:26][CH:25]=1
Reactant: O=S([O-])OO
Reactant: O=C1OC(=O)c2ccccc21
Agent: NC(N)=O
Agent: O=COO
Agent: OO
Product: O=C(O)c1ccccc1C(=O)OO

Procedure:
Selective oxidation of the sulfide into sulfone in (e) may be performed under known reaction conditions, including using hydrogen peroxide (H2O2) in the presence of any metal oxide catalyst, or using oxone, peroxycarboxylic acid, etc. Preferably, hydrogen peroxide is adsorbed to urea and then reacted with phthalic anhydride to give mono-perphthalic acid that is then reacted in the presence of an acetonitrile solvent.
Reaction SMILES: [Cl:1][C:2](Cl)([F:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][Cl:9].[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[Cl:1][C:2]([F:10])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][Cl:9]
Reactant: FC(Cl)(Cl)CCCCCCCl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: FC(Cl)=CCCCCCCl
Temperature: 100 °C
Yield: 44.7 %

Procedure:
35.9 g of 1,1,7-trichloro-1-fluoroheptane were added to 32.5 ml of NaOH at 50% concentration and 0.65 g of triethylbenzylammonium chloride. Under vigorous stirring, the reaction mixture was heated at 100° C for 20 hours; it was then cooled down and extracted with ethyl ether. The ether solution was neutralized with diluted hydrochloric acid, repeatedly washed with water, dried and finally evaporated. From the distillation of the residue there were obtained 13.4 g of 1,7-dichloro-1-fluoro-1-heptene (1:1 mixture of cis- and trans- isomers) boiling at 40° C/0.2 mm Hg.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:19][C:20](=[O:22])[CH3:21])[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.C[Si](C)(C)[C:25]1[S:26][C:27]([Sn](C)(C)C)=[CH:28][N:29]=1>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.O1CCOCC1>[S:26]1[C:27]([C:2]2[CH:3]=[C:4]([NH:19][C:20](=[O:22])[CH3:21])[CH:5]=[C:6]([NH:8][C:9]3[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=3)[CH:7]=2)=[CH:28][N:29]=[CH:25]1
Reactant: C[Si](C)(C)c1ncc([Sn](C)(C)C)s1
Reactant: CC(=O)Nc1cc(Br)cc(Nc2nccc(C(F)(F)F)n2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Temperature: 90 °C
Yield: 85.8 %

Procedure:
N-(3-bromo-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)acetamide (150 mg, 0.400 mmol), 2-(trimethylsilyl)-5-(trimethylstannanyl)-1,3-thiazole (141 mg, 0.440 mmol) (prepared using literature procedure: Dondoni, A.; Mastellari, A. R.; Medici, A.; Negrini, E.; Pedrini, P. Synthesis 1986, 9, 757-760) and Pd(Ph3P)4 (46.2 mg, 0.040 mmol) were placed in a nitrogen purged microwave vial. Dioxane (2 mL) was added and the resultant solution was purged for 10 minutes with nitrogen gas. The reaction mixture was heated to 90° C. for 15 h. Note: Under the reaction conditions the TMS group is removed. The reaction mixture was concentrated and directly purified by column chromatography to yield 130 mg of N-[3-(1,3-thiazol-5-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]acetamide (0.343 mmol, 86%) as a yellow powder.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11]2[C:16]([NH:17][CH:18]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:3][CH2:2]1.[H-].[Na+].[C:33](O)(=O)C>CN(C=O)C.CI.C(OCC)(=O)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11]2[C:16]([N:17]([CH:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[CH3:33])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:3][CH2:2]1
Reactant: c1cncc(C(Nc2cccnc2N2CCOc3ccccc32)c2cccnc2)c1
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CN(c1cccnc1N1CCOc2ccccc21)C(c1cccnc1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-(dipyridin-3-ylmethyl)pyridine-3-amine (82 mg, 0.207 mmol) in dry DMF (1.5 mL) was added 60% sodium hydride/mineral oil (16 mg, 0.40 mmol) and let stir at ambient temperature for 15 minutes. Over a one hour period methyl iodide (3 drops) was added. The reaction was diluted with ethyl acetate, neutralized with acetic acid, and washed with water (3×). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent evaporated. The residue was purified by chromatography on silica gel eluting with a 20-90% acetone/hexane gradient to give the title compound as a white solid. 1H-NMR (500 MHz, CDCl3): δ 8.50 (2H, d, J=4.6 Hz), 8.19 (2H, s), 8.16 (1H, d, J=4.4 Hz), 7.25 (2H, d, J=6.4 Hz), 7.15-7.17 (2H, m), 7.01 (21H, m), 6.75-6.84 (4H, m), 6.57 (1H, d, J=7.8 Hz), 6.01 (1H, s), 4.16 (2H, t, J=4.4 Hz), 3.86 (2H, t, J=4.4 Hz), 2.53 (3H, s). m/e (m+1): 410.2