Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][CH2:3][S:4][C:5]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:6]=1[NH2:7].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[N+:12]([C:9]1[CH:10]=[CH:11][C:5]2[S:4][CH2:3][CH2:2][NH:7][C:6]=2[CH:8]=1)([O-:14])=[O:13]
Reactant: Nc1cc([N+](=O)[O-])ccc1SCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(c1)NCCS2
Temperature: 90 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a stirred solution of 2-(2-iodoethylthio)-5-nitroaniline (1.18 g, 3.64 mmol) in DMF (10 mL) was added potassium carbonate (1.006 g, 7.28 mmol). The resulting mixture was then stirred at 90° C. for 1 hour. The mixture was then cooled to room temperature and diluted with water (40 mL). The resulting red precipitate was collected by vacuum filtration, giving the title compound (625 mg, 87%). 1H NMR (DMSO-d6) δ 7.38 (s, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.12 (d, J=8.7 Hz, 6.78 (brs, 1H), 3.56-3.49 (m, 2H), 3.08-3.03 (m, 2H); ELMS (m/z, %): 196 (M+, 100), 181 (45), 122 (73).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([C:23]3[CH:31]=[CH:30][C:26]4[O:27][CH2:28][O:29][C:25]=4[CH:24]=3)[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:39]([O:41][C:42](=[O:67])[CH2:43][CH2:44][CH2:45][O:46][C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58]Br)[C:48]=1[CH2:60][CH2:61][C:62]([O:64][CH2:65][CH3:66])=[O:63])[CH3:40]>CC(C)=O.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[O:32])[C:16]2[CH:21]=[C:20]([O:22][CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][C:49]3[CH:50]=[CH:51][CH:52]=[C:47]([O:46][CH2:45][CH2:44][CH2:43][C:42]([O:41][CH2:39][CH3:40])=[O:67])[C:48]=3[CH2:60][CH2:61][C:62]([O:64][CH2:65][CH3:66])=[O:63])[CH:19]=[C:18]([C:23]3[CH:31]=[CH:30][C:26]4[O:27][CH2:28][O:29][C:25]=4[CH:24]=3)[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)c2cc(O)cc(-c3ccc4c(c3)OCO4)c2)CC1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC
Temperature: 75 °C
Reaction time: 48 h

Procedure:
To a solution of 4-(3-benzo[1,3]dioxol-5-yl-5-hydroxy-benzoyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (400 mg) in a mixture of acetone and DMF (2:1, 3 mL) were added potassium carbonate (10 eq.) and 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (1.1 eq). The resulting mixture was stirred at 75° C. for 2 days. Then the insoluble material was filtered out and the filtrate was diluted with ethyl acetate and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate and hexanes to yield 4-(3-benzo[1,3]dioxol-5-yl-5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-benzoyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (556 mg). The total amount of material from the previous step was dissolved in EtOH (3 mL), followed by addition of 10 M NaOH solution (10 eq.). The resulting reaction mixture was stirred at room temperature for 3 h. Then it was neutralized with 3 N HCl and extracted into ethyl acetate. The organic extract was washed with water and brine and dried over anhydrous sodium sulfate. The crude material was concentrated under reduced pressure and redissolved in a mixture of TFA and dichloromethane (1:1, 2 mL) and stirred at room temperature for 2 h. The solvents were removed under reduced pressure and the crude material was purified on reverse-phase HPLC to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]=O)=[C:5]([CH3:9])[N:4]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[N:20]=[C:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:22][C:23]=3[CH3:24])=[CH:13][CH:12]=2)[N:3]=1.C(OP([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])(OCC)=O)C.[H-].[Na+].O>CN(C)C=O>[CH3:1][C:2]1[C:6](/[CH:7]=[CH:39]/[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:5]([CH3:9])[N:4]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]3[N:20]=[C:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:22][C:23]=3[CH3:24])=[CH:15][CH:16]=2)[N:3]=1
Reactant: Cc1nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c(C)c1C=O
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1c(C)nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
To a solution of 3,5-dimethyl-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-carbaldehyde (900 mg) and ethyl diethylphosphonoacetate (1.10 g) in N,N-dimethylformamide (20 ml), sodium hydride (60%, oily, 200 mg) was added at 0, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The obtained crystals were collected by filtration, and ethyl(E)-3-[3,5-dimethyl-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propenoate (740 mg) was obtained. After the mother liquor was concentrated, the residue was subjected to silica gel column chromatography, and 150 mg of crystals were additionally obtained from the fraction eluted with ethyl acetate-hexane (2:3, volume ratio). The total was 890 mg (yield: 87%). This was recrystallized from ethyl acetate-isopropyl ether. Melting point: 98–99° C.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([CH3:9])[N:4]=[C:3]1[NH:10][NH2:11].[CH:12](OCC)(OCC)OCC>C(O)CCC>[NH2:11][N:10]1[C:3]2=[N:4][C:5]([CH3:9])=[CH:6][C:7](=[O:8])[N:2]2[N:1]=[CH:12]1
Reactant: Cc1cc(=O)n(N)c(NN)n1
Reactant: CCOC(OCC)OCC
Solvent: CCCCO
Product: Cc1cc(=O)n2ncn(N)c2n1

Procedure:
A 2.4 g portion of 3-amino-2-hydrazino-6-methyl-4(3H)-pyrimidinone was dissolved in 100 ml of n-butanol by heating to the boiling point. A 20 ml portion of triethyl orthoformate was added and the solution was refluxed for 45 minutes. The solid was collected while the solution was hot, washed with ether and dried, giving 1.45 g of the desired intermediate, mp 202°-204°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[CH:5]=O.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][N:9]=1
Reactant: O=Cc1ccnc(Br)c1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Brc1cc(CN2CCCC2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromoisonicotinaldehyde (400 mg) and pyrrolidine (0.197 mL) in acetonitrile (16 mL) was added sodium triacetoxyborohydride (547 mg) at room temperature, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (445 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C([Mg]Cl)(C)C.[CH:15]([N:28]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:31](=[O:32])[C:29]1=[O:30])([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>O1CCCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:31]2([OH:32])[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:28]([CH:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:29]2=[O:30])=[C:4]([OH:9])[CH:3]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: Oc1ccc(F)c(F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc(F)c(F)cc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
To a solution of 3,4-difluorophenol (10.33 g, 79.4 mmol) in anhydrous tetrahydrofuran (60 mL) at 0° C. under nitrogen was added isopropyl magnesium chloride (39.7 mL, 79.4 mmol), and the solution was stirred at ambient temperature for 3 h. Tetrahydrofuran was removed by rotary evaporation, and the residue was redissolved in anhydrous dichloromethane (140 mL). The solution was cooled to 0° C. under nitrogen, then N-benzhydryl isatin (13.77 g, 43.9 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. After 3 days, the reaction was quenched with aqueous saturated ammonium chloride (60 mL) and concentrated in vacuo. The residue was re-dissolved in ethyl acetate (150 mL) and washed with water (2×100 mL) and brine (100 mL), dried over sodium sulfate, filtered, and concentrated. The residue was precipitated from diethyl ether to yield 3-(4,5-difluoro-2-hydroxyphenyl)-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one (12.08 g, 61%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 9.23 (br s, 1H), 7.47-7.44 (m, 1H), 7.35-7.21 (m, 9H), 7.18-7.11 (m, 2H), 6.90 (s, 1H), 6.83 (dd, J=11.2, 6.9 Hz, 1H), 6.67 (dd, J=11.2, 8.7 Hz, 1H), 6.56-6.51 (m, 1H), 4.13 (br s, 1H); MS (ES+) m/z 426.2 (M−17).
Reaction SMILES: [Na].[C:2]([O:8][CH3:9])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].[CH2:10]([C:15]1[C:16](=[O:20])[CH2:17][CH2:18][CH:19]=1)[CH2:11][CH2:12][CH2:13][CH3:14].[Cl-].[Na+]>C(O)(=O)C.CO>[CH2:10]([C:15]1([CH:3]([C:2]([O:8][CH3:9])=[O:7])[C:4](=[O:5])[CH3:6])[CH2:19][CH2:18][CH2:17][C:16]1=[O:20])[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCC1=CCCC1=O
Reactant: COC(=O)CC(C)=O
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCCC1(C(C(C)=O)C(=O)OC)CCCC1=O
Reaction time: 48 h
Yield: 70.5 %

Procedure:
750 ml of absolute methanol was introduced into a 2 liter flask. Then 17.3 g of sodium were added thereto, and 580 g of methyl acetoacetate were then added after which 456 g of 2-n-pentyl-cyclopent-2-en-1-one were added and the mixture was allowed to stand for 48 hours at the ambient temperature. The reaction product was neutralised with 45 g of acetic acid and then poured into 3 liters of a 10% aqueous sodium chloride solution. The product was then worked up as described in Example 1 (a). There were thus obtained 567 g (yield=70%) of 2-n-pentyl-(1-carbomethoxy-2-oxopropyl)-1-cyclopentanone having: nD20 =1.4702, d420 =1.0545.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:24])[CH2:7][C@H:8]([CH:21]([CH3:23])[CH3:22])[CH2:9][C@H:10]([OH:20])[C@@H:11]([NH2:19])[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:2][CH2:3][CH3:4].[NH:25]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C@H:26]([C:34]([NH:36][C@H:37]([C:44](O)=[O:45])[CH2:38][C:39]1[N:43]=[CH:42][NH:41][CH:40]=1)=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:1]([NH:5][C:6]([CH2:7][C@H:8]([CH:21]([CH3:23])[CH3:22])[CH2:9][C@H:10]([OH:20])[C@@H:11]([NH:19][C:44]([C@@H:37]([NH:36][C:34]([C@@H:26]([NH:25][C:47](=[O:48])[O:49][C:50]([CH3:52])([CH3:51])[CH3:53])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:35])[CH2:38][C:39]1[N:43]=[CH:42][NH:41][CH:40]=1)=[O:45])[CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: CCCCNC(=O)C[C@@H](C[C@H](O)[C@@H](N)CC1CCCCC1)C(C)C
Product: CCCCNC(=O)C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)C

Procedure:
In an analogous manner to that described in Example 9, by reacting (3R,5S,6S)-6-amino-7-cyclohexyl-5-hydroxy-3-isopropylheptanoic acid butylamide with Boc-Phe-His-OH there is obtained t-butyl [(S)-α-[[(S)-1-[[(1S,2S,4R)-4-[(butylcarbamoyl)methyl]-1-(cyclohexylmethyl)-2-hydroxy-5-methylhexyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate as an amorphous solid, MS: 725 (M+H)+.
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]C.C[C:22]1(C)[O:27][C:26](=[O:28])[CH2:25][C:24](=[O:29])O1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>C(Cl)Cl>[O:29]=[C:24]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH2:25][C:26]([O:27][CH3:22])=[O:28]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)CC(=O)OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Stearic acid (5.0 g, 17.6 mmoles) is suspended in methylene chloride (88 mL) and 2,2-dimethyl-1,3-dioxane-4,6-dione (2.7 g, 18.5 mmoles), triethylamine (6.7 mL, 48.0 mmoles) and diethyl cyanophosphonate (2.7 mL, 17.6 mmoles) are added. All solids dissolve quickly. The solution is stirred for 16 hours at ambient temperature. The reaction mixture is then diluted with methylene chloride (100 mL) and carefully washed three times with aqueous hydrochloric acid (3 M, 50 mL each), three times with water (50 mL each) and once with saturated aqueous sodium chloride (50 mL). The reaction mixture is then dried over anhydrous sodium sulfate, filtered and evaporated. The resulting syrup is dissolved in anhydrous methanol (100 mL) and heated to reflux for 16 hours. The methanol is evaporated and the crude product dissolved in hexanes with slight heating. The crude product was then loaded on silica gel (150 mL bed volume) eluting with hexanes (500 mL) then hexane:acetone (98:2 [v/v], 1000 mL). Fractions containing pure product by thin layer chromatography are pooled and evaporated to dryness. The resulting oil is dried well in vacuo. The yield is 5.2 g (87%).
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[Cl:5][C:6]1[C:7]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[C:8]2[C:13](=[CH:14][C:15]=1[Cl:16])[N:12]=[C:11]([O:17][CH3:18])[C:10]([O:19][CH3:20])=[N:9]2.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:5][C:6]1[C:7]([N:21]([CH2:2][C:3]#[N:4])[S:22]([CH3:25])(=[O:24])=[O:23])=[C:8]2[C:13](=[CH:14][C:15]=1[Cl:16])[N:12]=[C:11]([O:17][CH3:18])[C:10]([O:19][CH3:20])=[N:9]2
Reactant: N#CCCl
Reactant: COc1nc2cc(Cl)c(Cl)c(NS(C)(=O)=O)c2nc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1nc2cc(Cl)c(Cl)c(N(CC#N)S(C)(=O)=O)c2nc1OC
Yield: 54 %

Procedure:
Chloroacetonitrile (233 μl, 279 mg, 3,69 mmol) was added to a refluxing mixture of N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)methane-sulphonamide (from Preparation 3, 1.00 g, 2.84 mmol) and potassium carbonate (0.47 g, 3.41 mmol) in acetone (50 ml) under nitrogen. The mixture was refluxed for 18 h and was then allowed to cool, and was partitioned between ethyl acetate (500 ml) and water (500 ml). The organic phase was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with 0-100% ethyl acetate in hexane and then 5% methanol in dichloromethane) to give N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(cyanomethyl) methanesulphonamide as an off-white solid (600 mg, 54%).
Reaction SMILES: [H-].[Na+].C[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:20]=[C:19]([NH:21][CH2:22][C:23]2[O:24][C:25]([CH3:28])=[N:26][N:27]=2)[C:18]2[C:13](=[CH:14][C:15]([CH3:29])=[CH:16][CH:17]=2)[N:12]=1.[CH3:30]I>CN(C=O)C>[CH3:29][C:15]1[CH:14]=[C:13]2[C:18]([C:19]([N:21]([CH3:30])[CH2:22][C:23]3[O:24][C:25]([CH3:28])=[N:26][N:27]=3)=[N:20][C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[OH:4])=[N:12]2)=[CH:17][CH:16]=1
Reactant: COc1ccccc1-c1nc(NCc2nnc(C)o2)c2ccc(C)cc2n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(N(C)Cc3nnc(C)o3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
[2-(2-Methoxy-phenyl)-7-methyl-quinazolin-4-yl]-methyl-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-anine To a stirring suspension of freshly washed sodium hydride (42 mg, 1.04 mmol) in dry DMF at 0° C. under a nitrogen atmosphere was added the [2-(2-Methoxy-phenyl)-7-methyl-quinazolin-4-yl]-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amine (180 mg, 0.518 mmol, in 5 ml DMF). After 30 minutes at 0° C., MeI (74 μl, 1.19 mmol) was added and the reaction was allowed to warm to room temperature. After one hour the reaction was quenched with water and extracted 3 times with EtOAc. Organics were combined, dried over MgSO4, filtered and concentrated to a yellow oil. Purified by flash chromatography 50/50 EtOAc/hexanes to afford the desired product as a clear oil. 128 mg, 66% yield. LC/MS (10-99%) M/Z 376.1, retention time 2.06 minutes.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][S:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4([C:32]([OH:34])=O)[CH2:31][CH2:30]4)=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[O:4][N:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:47][S:48]([NH2:51])(=[O:50])=[O:49].CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:1][C:2]1[C:6]([CH2:7][S:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4([C:32]([NH:51][S:48]([CH3:47])(=[O:50])=[O:49])=[O:34])[CH2:30][CH2:31]4)=[CH:25][CH:24]=3)=[CH:21][CH:22]=2)[O:4][N:3]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CSCCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1CSCCc1ccccc1

Procedure:
1-[4′-(3-Methyl-4-phenethylsulfanylmethyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid (0.2 g, 0.43 mmol) was dissolved in dioxane along with carbonyldiimidazole (0.2 g, 1.23 mmol), methanesulfonamide (0.14 g, 1.47 mmol) and Hünig's base. The reaction was heated to reflux overnight then cooled and submitted to standard aqueous workup. The residue was purified via silica gel chromatography (0-60% EtOAc in hexanes) to give the title compound.
Reaction SMILES: Cl.[CH2:2]([O:6][C:7]1[CH:12]=[C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[N:10]=[CH:9][N:8]=1)[CH:3]([CH3:5])[CH3:4].[I:19][C:20]1[N:24]([CH3:25])[N:23]=[C:22]([C:26](O)=[O:27])[CH:21]=1>>[I:19][C:20]1[N:24]([CH3:25])[N:23]=[C:22]([C:26]([N:16]2[CH2:17][CH2:18][N:13]([C:11]3[CH:12]=[C:7]([O:6][CH2:2][CH:3]([CH3:5])[CH3:4])[N:8]=[CH:9][N:10]=3)[CH2:14][CH2:15]2)=[O:27])[CH:21]=1
Reactant: Cn1nc(C(=O)O)cc1I
Reactant: CC(C)COc1cc(N2CCNCC2)ncn1
Agent: Cl
Product: CC(C)COc1cc(N2CCN(C(=O)c3cc(I)n(C)n3)CC2)ncn1

Procedure:
The title compound was prepared according to the procedure described in Example 3 using 4-isobutoxy-6-(piperazin-1-yl)pyrimidine hydrochloride and 5-iodo-1-methyl-1H-pyrazole-3-carboxylic acid.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:12]([CH3:14])[CH3:13])=[C:7]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:6]=1)C.O.[OH-].[Na+].Cl>O1CCOCC1>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[CH2:17][CH2:16][O:15][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:4]([OH:26])=[O:3]
Reactant: CCOC(=O)c1ccc(OC(C)C)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Oc1ccc(C(=O)O)cc1OCCc1ccc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 16 h

Procedure:
0.75 g (1.89 mmol) of 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-isopropoxy-benzoic acid ethyl ester was dissolved in 15 ml of dioxan. 5 ml of water and 2N aqueous NaOH was added to the solution to give a pH of 13. The reaction solution was heated at 60° C. for 4 h and stirred at room temperature for 16 h. The reaction solution was cooled to 0° C. and concentrated hydrochloric acid was added to give a pH of 1-2, whereupon the product precipitated from solution. The suspension was stirred for 30 min, then the product was filtered off and dried under reduced pressure.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30](Br)=[C:29]4[C:25]=3[C:26](=[O:35])[N:27]([CH3:34])[CH2:28]4)[C:20]([C:36]([F:39])([F:38])[F:37])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Si]([O:47][CH2:48][CH2:49][N:50]1[CH:54]=[CH:53][C:52](B(O)O)=[N:51]1)(C(C)(C)C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[OH:47][CH2:48][CH2:49][N:50]1[CH:54]=[CH:53][C:52]([C:30]2[CH:31]=[CH:32][C:24]([NH:23][C:21]3[C:20]([C:36]([F:39])([F:38])[F:37])=[CH:19][N:18]=[C:17]([NH:16][C:13]4[CH:14]=[CH:15][C:10]([CH2:9][P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])=[CH:11][CH:12]=4)[N:22]=3)=[C:25]3[C:29]=2[CH2:28][N:27]([CH3:34])[C:26]3=[O:35])=[N:51]1
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(B(O)O)n1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)cc1)OCC
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4ccn(CCO)n4)c4c3C(=O)N(C)C4)n2)cc1)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared according to the procedure for Compound 97A diethyl[4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate (30.0 mg, 0.0477 mmol) and [1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1H-pyrazol-3-yl]boronic acid (Compound 142A, 46.7 mg, 0.173 mmol). The afforded intermediate, diethyl (4-{[4-({7-[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1H-pyrazol-3-yl]-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate, was purified using an ISCO Combiflash system (eluting with 0-100% EtOAc:CH2Cl2). The product thus obtained was dissolved in CH2Cl2 (2 mL), treated with 4.0 M of HCl in dioxane (0.5 mL) and stirred at rt for 2 h. The solid was filtered off and rinsed with a mixture of CH2Cl2/heptane, giving the title material as an off-white solid, 24.6 mg (77%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.89 (s, 1H), 10.03 (br s, 1H), 8.89 (br s, 1H), 8.49 (s, 1H), 7.91 (d, J=8.6 Hz, 1H), 7.81 (d, J=2.3 Hz, 1H), 7.57 (br s, 2H), 7.30 (br d, J=6.6 Hz, 2H), 6.93 (br s, 1H), 4.72 (s, 2H), 4.21 (t, J=5.6 Hz, 2H), 3.97 (quin, J=7.4 Hz, 4H), 3.81 (t, J=5.7 Hz, 2H), 3.25 (d, J=21.5 Hz, 2H), 3.13 (s, 3H), 1.16 (t, J=7.1 Hz, 6H). MS (ES+): m/z 660.22 (100) [MH+]. HPLC: tR=2.72 min (ZQ3, nonpolar—5 min).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH2:18][CH2:17][C:16](=O)[CH2:15][CH:14]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CC(O)=O.Cl.[CH3:25][NH2:26].[OH-].[Na+]>ClCCCl>[CH3:25][NH:26][CH:16]1[CH2:17][CH2:18][C:13]([C:8]2[C:7]3[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[NH:10][CH:9]=2)=[CH:14][CH2:15]1
Reactant: O=C1CC=C(c2c[nH]c3cc([N+](=O)[O-])ccc23)CC1
Reactant: CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CNC1CC=C(c2c[nH]c3cc([N+](=O)[O-])ccc23)CC1
Reaction time: 16 h
Yield: 88.8 %

Procedure:
A solution of compound 119 (0.5 g, 1.951 mmol) in 1,2-dichloroethane (10 mL) was treated with AcOH (0.11 mL, 1.951 mmol), methylamine hydrochloride (0.13 g, 1.951 mmol), NaBH(OAC)3 (0.62 g, 2.926 mmol) at room temperature and stirred for over night (16 h). The reaction was basified with 2 N NaOH (25 mL) and product was extracted into ethyl acetate (2×25 mL). The combined ethyl acetate layer washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2M NH3 in MeOH:CH2Cl2, 1:9) to obtain compound 120 (0.47 g, 89%) as a solid. mp 170-172° C.; 1H NMR (DMSO-d6) δ 1.37-1.50 (m, 1H), 1.90-1.99 (m, 2H), 2.33 (s, 3H), 2.43-2.64 (m, 4H), 6.14 (brs, 1H), 7.80 (s, 1H), 7.86-7.96 (m, 2H), 8.30 (d, 1H, J=2.1 Hz); ESI-MS (m/z, %): 272 (MH+, 100), 241 (43).