Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[P:11]([Cl:15])(Cl)(Cl)=[O:12].[Cl-].[NH4+]>>[P:11]([Cl:15])(=[O:12])([O:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)[O:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: CC(C)c1ccc(O)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)c1ccc(OP(=O)(Cl)Oc2ccc(C(C)C)cc2)cc1
Temperature: 135 °C
Reaction time: 8 h

Procedure:
Following the procedure of U.S. Patent No. 3,773,866, 54.0 g (0.4 mole) of 4-isopropylphenol was added to 73.4 g (0.47 moles) of phosphorus oxychloride and 0.6 g of ammonium chloride at 105° C. over a 1.5 hour period. After heating an additional 1.5 hour the temperature was raised to 135° C. and a second 54 g portion of 4-isopropylphenol was added. The mixture was stirred at 168° C. overnight, and purified by fractional distillation. The fraction which distilled at 258° C. (0.5 torr) was identified as 97% pure by glc.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[H-].[Na+].Br[CH2:15][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([O:21][CH3:22])=[O:20]>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[O:8][CH2:15][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(COc2ccc([N+](=O)[O-])c(F)c2)c1
Reaction time: 3 h

Procedure:
2-Fluoro-4-hydroxynitrobenzene (3 g) is added portionwise to a stirred suspension of sodium hydride (0.9 g, 60% dispersion in mineral oil) in dry dimethylformamide (50 mL) under nitrogen. After stirring for 20 minutes methyl 3-bromomethylbenzoate is added in one portion and stirring continued for 3 hours. The reaction mixture is evaporated to dryness and the residue partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase is washed three times with water (50 mL),dried over magnesium sulphate and evaporated to give a yellow solid which is crystallised from a mixture of ethyl acetate and cyclohexane (1:3 v/v) to give methyl 3-(3-fluoro-4-nitrophenoxymethyl]benzoate (4.95 g) as a white solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8]([OH:10])=O)(=[O:3])[CH3:2].Cl.[CH3:17][O:18][C:19]([C:21]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.O>CN(C=O)C>[CH3:17][O:18][C:19]([C:21]1([NH:28][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)=[O:20]
Reactant: COc1ccc(C(=O)O)cc1OC(C)=O
Reactant: COC(=O)C1(N)CCCCCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(OC(C)=O)c2)CCCCCC1
Reaction time: 1 h
Yield: 73.5 %

Procedure:
3-Acetoxy-4-methoxy-benzoic acid (7.10 g, 33.8 mmol) was dissolved in DMF (70 ml). The solution was cooled in an ice bath and 1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride (7.72 g, 37.2 mmol), EDIA (24.4 ml, 135 mmol) and TOTU (16.6 g, 50.7 mmol) were added sequentially. Stirring was continued at room temperature for 1 h. Water was added and stirring was continued for 1 h. The solid material which formed was collected by filtration, washed with water and dried in vacuo. The obtained material was stirred with a diethyl ether/HEP mixture, filtered and dried in vacuo to yield the title compound (9.03 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([CH2:13][NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([CH2:13][NH:14][C:15](=[O:20])[C:16]([CH3:18])([CH3:17])[CH3:19])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(CNC(=O)C(C)(C)C)c(F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1cc(C(=O)O)c(Cl)cc1F
Yield: 83.8 %

Procedure:
The title compound was prepared following the procedure described in step-3 of Intermediate-2 using methyl 2-chloro-4-fluoro-5-(pivalamidomethyl)benzoate (250 mg, 0.83 mmol) in THF:MeOH:H2O (3:2:1; 6 mL) and NaOH (66 mg, 1.66 mmol) to afford 200 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.17-8.14 (t, J=6.0 Hz, 1H), 7.76-7.73 (d, J=8.4 Hz, 1H), 7.53-7.50 (d, J=9.9 Hz, 1H), 4.26 (d, J=5.7 Hz, 2H), 1.12 (s, 9H).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:8]=[N:9][N:10]2[CH2:15][CH2:14][CH2:13][NH:12][C:11]=12.C(N(C(C)C)C(C)C)C.[C:25]([O:29][C:30]([NH:32][C:33]([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=NS(C(F)(F)F)(=O)=O)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[C:46]([O:45][C:43]([N:42]=[C:33]([NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[NH:6][C:7]1[CH:8]=[N:9][N:10]2[CH2:15][CH2:14][CH2:13][NH:12][C:11]=12)=[O:44])([CH3:49])([CH3:48])[CH3:47]
Reactant: Nc1cnn2c1NCCC2
Reactant: CC(C)(C)OC(=O)NC(=NS(=O)(=O)C(F)(F)F)NC(=O)OC(C)(C)C
Agent: O=S(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1cnn2c1NCCC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89.5 %

Procedure:
To a solution of 3-amino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine sulfuric acid salt (2.96 g) and N-ethyldiisopropylamine (3.88 g) in methylene chloride (70 ml) was added 1,3-bis(tert-butoxycarbonyl)-2-(trifluoromethanesulfonyl)guanidine (3.91 g). The mixture was stirred at room temperature for 150 minutes. There action mixture was washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 2% methanol/chloroform to give 3-[2,3-bis(tert-butoxycarbonyl)guanidino]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (3.4 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:31])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11][C:10]([C:21]3[C:22]([O:29][CH3:30])=[N:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=3)=[N:9]2)=[CH:4][CH:3]=1.[C:32](Cl)(Cl)=[O:33].[CH3:36][S:37]([CH2:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:39])=[O:38]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:31])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:32]([N:46]3[CH2:45][CH2:44][N:43]([CH2:42][CH2:41][CH2:40][S:37]([CH3:36])(=[O:38])=[O:39])[CH2:48][CH2:47]3)=[O:33])[C:10]([C:21]3[C:22]([O:29][CH3:30])=[N:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: COc1ncc(C2=N[C@@](C)(c3ccc(Cl)cc3)[C@@](C)(c3ccc(Cl)cc3)N2)c(OC)n1
Reactant: CS(=O)(=O)CCCN1CCNCC1
Solvent: CCN(CC)CC
Product: COc1ncc(C2=N[C@@](C)(c3ccc(Cl)cc3)[C@@](C)(c3ccc(Cl)cc3)N2C(=O)N2CCN(CCCS(C)(=O)=O)CC2)c(OC)n1

Procedure:
rac-5-[(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-2,4-dimethoxy-pyrimidine was converted to the corresponding carbonyl chloride using phosgene and triethylamine in a manner similar to example 2. The carbonyl chloride was then reacted with 4-[3-(methylsulfonyl)propyl]-piperazine (prepared as described in Fotouhi, N. et al. WO 2005110996) following the synthetic procedure as described in example 3 to give the title compound. HR-MS (ES, m/z) calculated for C32H38N6O5SCl2 [(M+H)+] 689.2074, observed 689.2072.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1
Reactant: Oc1ccccc1
Reactant: COC(=O)c1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(F)cc1Oc1ccccc1

Procedure:
Methyl 2-bromo-4-fluorobenzoate (1 g), phenol (0.565 g), cesium carbonate (1.96 g), copper(I) triflate toluene complex (0.087 g), and ethyl acetate (0.034 mL) in toluene (12 mL) was stirred at 110° C. for 24 hours. The reaction was cooled and chromatographed on silica gel with 5% ethyl acetate/hexanes.
Reaction SMILES: ClC1C=[C:4]([CH3:8])[N:5]=[N:6]C=1.[C:9]([N:16]1CCC(N)C[CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[CH3:23][CH2:24][N:25]([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])C>CN1C(=O)CCC1>[CH3:8][C:4]1[N:5]=[N:6][CH:30]=[C:29]([N:25]2[CH2:24][CH2:23][CH:17]([NH:16][C:9](=[O:10])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:28][CH2:26]2)[CH:31]=1
Reactant: Cc1cc(Cl)cnn1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CN1CCCC1=O
Product: Cc1cc(N2CCC(NC(=O)OC(C)(C)C)CC2)cnn1
Yield: 73.8 %

Procedure:
To a mixture of 5-chloro-3-methylpyridazine (1.3 g, 10.1 mmol) and Boc-4-aminopiperidine (2.63 g, 13.1 mmol) in NMP (13 mL) was added DIPEA (2.47 mL, 14.2 mmol). Argon was bubbled through the cloudy solution for 5 minutes before the reaction mixture was heated in the microwave for 30 minutes to 150° C. The mixture was then poured into water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica gel, 50 g, 50 to 100% ethyl acetate in heptane) afforded the title compound (2.18 g, 74%) as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][C:24]([F:32])=[C:25]([NH:30][CH3:31])[CH:26]=4)[C:21]3=[O:33])=[CH:16][CH:15]=2)=[O:12])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[B-](F)(F)(F)[F:35].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][C:24]([F:32])=[C:25]([NH:30][CH3:31])[C:26]=4[F:35])[C:21]3=[O:33])=[CH:18][CH:19]=2)=[O:12])(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: F[B-](F)(F)F
Reactant: CNc1cc2c(cc1F)C(=O)N(c1ccc(NC(=O)NS(=O)(=O)c3ccc(Cl)s3)cc1)CC2
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CN(C)C=O
Product: CNc1c(F)cc2c(c1F)CCN(c1ccc(NC(=O)NS(=O)(=O)c3ccc(Cl)s3)cc1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.8 %

Procedure:
To a solution of 1-(5-chlorothiophen-2-ylsulfonyl)-3-(4-(7-fluoro-6-(methylamino)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)phenyl)urea (17 mg, 0.033 mmol) in DMF (2 mL) at room temperature, selectFluor (1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate), 32 mg, 0.090 mmol) was added. After being stirred at room temperature for 1 h, the reaction mixture was concentrated in vacuo. The residue was purified by RP-HPLC to give the titled compound as a powder (1 mg). ES-MS (M+H)+=527, 529 (Cl pattern).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li][CH2:12]CCC.IC>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([CH3:12])[S:10][C:3]=12
Reactant: [Li]CCCC
Reactant: Clc1ccnc2ccsc12
Solvent: CI
Product: Cc1cc2nccc(Cl)c2s1
Yield: 81 %

Procedure:
This material was prepared from 7-chlorothieno[3,2-b]pyridine (1.69 g, 10 mmole) by treatment with n-BuLi and iodomethane (2 ml, 4.56 g, 32 mmole) in a manner as previously described for example 1b to give a pale yellow, low-melting solid (1.48 g, 81%). 1H NMR (DMSO-d6): δ8.56 (1H, d, J=5.1 Hz), 7.48 (1H, d, J=5.1 Hz), 7.38 (1H, s), 2.65 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([OH:11])[CH:5]=[C:14]2[C:15]([OH:17])=[O:16]
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: O=C(O)CC(=O)O
Solvent: C1CCOC1
Product: O=C(O)c1cc(O)nc2ccc(Br)cc12
Reaction time: 12 h

Procedure:
5-bromoindoline-2,3-dione (0.250 g) was dissolved in THF (3 ml) in a round-bottomed flask and malonic acid (2 eq) was added. The vessel was connected to a reflux condenser and heated to reflux overnight by conventional heating. After 12 hours, solid precipitate was observed. Suspension was concentrated under reduced pressure to remove solvent, water was added, and the suspension was refluxed for 4 hours. The suspension was then filtered to provide 6-bromo-2-hydroxyquinoline-4-carboxylic acid (0.150 g) as a solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[N:25]=[CH:26][S:27][CH:28]=3)=[C:18]([Cl:29])[CH:17]=1)=[N:8][CH:9]=[N:10]2.[OH:30][C@H:31]1[CH2:36][CH2:35][O:34][C:32]1=[O:33]>>[Cl:29][C:18]1[CH:17]=[C:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[CH:14][C:5]=3[O:4][CH2:3][CH2:2][NH:1][C:32](=[O:33])[C@@H:31]([OH:30])[CH2:36][CH2:35][OH:34])[N:10]=[CH:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[N:25]=[CH:26][S:27][CH:28]=1
Reactant: NCCOc1cccc2ncnc(Nc3ccc(OCc4cscn4)c(Cl)c3)c12
Reactant: O=C1OCC[C@@H]1O
Product: O=C(NCCOc1cccc2ncnc(Nc3ccc(OCc4cscn4)c(Cl)c3)c12)[C@@H](O)CCO
Yield: 66 %

Procedure:
The procedure described in Example 63 was repeated using 5-(2-aminoethoxy)-N-[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 71, preparation of starting materials) and (S)-(−)-α-hydroxy-γ-butyrolactone to give the title compound in 66% yield; NMR spectrum (DMSO-d6 400 MHz) 1.44-1.55 (m, 1H), 1.73-1.85 (m, 1H), 3.41-3.52 (m, 2H), 3.65-3.77 (m, 2H), 3.93-4.02 (m, 1H), 4.31-4.48 (m, 3H), 5.38 (s, 2H), 5.50 (d, 1H), 7.17 (d, 1H), 7.33 (t, 2H), (7.60 (dd, 1H), 7.74 (t, 1H), 7.83 (s, 1H), 8.02 (s, 1H), 8.20 (t, 1H), 8.48 (s, 1H), 9.17 (s, 1H), 9.85 (s, 1H); Mass spectrum MH+ 529.9.
Reaction SMILES: ClC1C=CC([C@@H](C2C=CN(C)N=2)N)=CC=1F.[F:17][C:18]1[CH:19]=[C:20]([C@@H:26]([C:28]2[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=2)[NH2:27])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].[F:34][C:35]1[CH:44]=[C:43]([C:45](O)=[O:46])[CH:42]=[C:41]2[C:36]=1[CH:37]=[N:38][C:39]([NH:48][C@@H:49]1[CH2:53][CH2:52][O:51][CH2:50]1)=[N:40]2>>[F:34][C:35]1[CH:44]=[C:43]([C:45]([NH:27][C@@H:26]([C:20]2[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([F:17])[CH:19]=2)[C:28]2[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=2)=[O:46])[CH:42]=[C:41]2[C:36]=1[CH:37]=[N:38][C:39]([NH:48][C@@H:49]1[CH2:53][CH2:52][O:51][CH2:50]1)=[N:40]2
Reactant: O=C(O)c1cc(F)c2cnc(N[C@@H]3CCOC3)nc2c1
Reactant: COc1ccc([C@H](N)c2cnn(C)c2)cc1F
Agent: Cn1ccc([C@@H](N)c2ccc(Cl)c(F)c2)n1
Product: COc1ccc([C@H](NC(=O)c2cc(F)c3cnc(N[C@@H]4CCOC4)nc3c2)c2cnn(C)c2)cc1F

Procedure:
5-Fluoro-N-((S)-(3-fluoro-4-methoxyphenyl)(1-methyl-1H-pyrazol-4-yl)methyl)-2-((R)-tetrahydrofuran-3-ylamino)quinazoline-7-carboxamide (I-61) was prepared analogously except 32b was replaced with 40f and 84b was replaced with 87d.
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[CH2:18]O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BrH:22].[C:23]1([P:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(#N)C>[Br-:22].[C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[CH2:18][P+:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(COc2ccc(F)cc2CO)cc1
Reactant: Br
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)(C)c1ccc(COc2ccc(F)cc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Br-]

Procedure:
5.80 g (20 mmol) of [2-(4-tert-butylbenzyloxy)-5-fluorophenyl]methanol are dissolved in 70 ml of acetonitrile, 6.56 g (19.5 mmol) of triphenylphosphine hydrobromide are added, and the suspension is stirred under reflux for 24 h. The solvent is mostly distilled out in vacuo, and the crystals which have separated out are stirred with diethyl ether, filtered off with suction, washed with petroleum ether and dried on a clay dish. The resulting crude product is purified by preparative HPLC. 2.64 g (4.3 mmol, 21% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[C:4]([CH3:10])[C:3]=1[OH:11].[Br:12]Br>C(O)(=O)C>[Br:12][C:6]1[C:5]([CH3:9])=[C:4]([CH3:10])[C:3]([OH:11])=[C:2]([CH3:1])[C:7]=1[CH3:8]
Reactant: Cc1cc(C)c(C)c(O)c1C
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1c(C)c(Br)c(C)c(C)c1O
Reaction time: 5 h
Yield: 65.5 %

Procedure:
To a suspension of 2,3,5,6-tetramethylphenol (5.10 g, 34.0 mmol) in acetic acid (90 ml) was added dropwise a solution of bromine (1.98 mL, 38.6 mmol) in acetic acid (30 mL) at room temperature, and the mixture was stirred for 5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, and washed successively with aqueous sodium thiosulfate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitated crystals were washed with petroleum ether to give the title compound (5.10 g, yield 66%) as pale-yellow crystals. The mother solution was concentrated under reduced pressure, and washed with petroleum ether to give second crop (1.38 g, yield 18%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]([C:15](=[O:32])[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=1)[CH3:14].Br[C:35]1[CH:36]=[CH:37][C:38]([Cl:41])=[N:39][CH:40]=1.[C:42]([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]([C:15](=[O:32])[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:35]2[CH:40]=[N:39][C:38]([Cl:41])=[CH:37][C:36]=2[CH3:42])[CH:17]=1)[CH3:14]
Reactant: Clc1ccc(Br)cn1
Reactant: COC(=O)CCCc1ccccc1N(C)C(=O)c1ccc(Cl)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)CCCc1ccccc1N(C)C(=O)c1ccc(Cl)c(-c2cnc(Cl)cc2C)c1
Temperature: 100 °C

Procedure:
A mixture of 4-(2-{[4-chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoyl]-methyl-amino}-phenyl)-butyric acid methyl ester (50 mg, 0.11 mmol), 5-bromo-2-chloro-pyridine (26 mg, 0.13 mmol), Pd(PPh3)4 (6 mg, 0.005 mmol), K2CO3 (36 mg, 0.18 mmol) in dioxane (0.6 mL), was heated at 100° C. for 12 hrs. The mixture was purified after a filtration by prep. LCMS to yield 4-(2-{[4-chloro-3-(6-chloro-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenyl)-butyric acid methyl ester 13-1. MS [M+H]+: 470.9; tR=8.41 min. (method 2).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C(N(CC)CC)C.C(Cl)Cl.[CH3:27][OH:28].CN([CH:32]=[O:33])C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:27][O:28][C:32]([C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:33]
Reactant: CO
Reactant: O=c1c2ccccc2oc2cc(Br)ccc12
Reactant: CN(C)C=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc2c(=O)c3ccccc3oc2c1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
A sample of Compound 3a (20 g, 72.2 mmol) was dissolved in a 2:1 MeOH/DMF solution (600 mL). To this solution was added triethylamine (40 mL, 290 mmol) and the solution was degassed with Argon. To this was added dichlorobis(triphenylphosphine)palladium (II) (2.0 g, 2.85 mmol), and the reaction was transferred to a bomb and charged with 150 psi of CO (g). The reaction was stirred at 90° C. for 24 h. Upon completion, the reaction was cooled to 40° C. and CH2Cl2 was added. The reaction was filtered while warm and evaporated to provide the crude product. Recrystallization from ethanol gave 16.62 g (65.4 mmol) of Compound 4a. MS m/z (MH+) 255.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH:23]([CH3:29])[C:24]([O:26]CC)=[O:25])=[N:13]2)=[O:10])=[CH:4][CH:3]=1.CO.[OH-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH:23]([CH3:29])[C:24]([OH:26])=[O:25])=[N:13]2)=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)c1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C(=O)O)c1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product from Example 109C (1.4 g, 3.4 mmol) in THF (8 mL), water (4 mL), and MeOH (8 mL) was added 5M NaOH (3.4 mL, 17 mmol). After stirring at room temperature for 16 hours, the reaction mixture was concentrated to half the volume, diluted to 10 mL (water), washed with DCM, acidified to pH˜2 with aq 3N HCl, and filtered to obtain the precipitated product: 1H NMR (300 MHz, DMSO-d6) δ 12.72 (s, 1H), 11.60 (s, 1H), 8.33 (d, J=7.7, 1H), 8.03-7.97 (m, 2H), 7.91 (ddd, J=8.2, 6.7, 4.0, 1H), 7.41 (s, 4H), 4.40 (q, J=7.1, 1H), 3.69 (s, 2H), 1.45 (d, J=7.1, 3H); MS (ESI+) M/Z 386 (M+H)+.
Reaction SMILES: [ClH:1].Cl.Cl.[NH:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][C:19](C4C=NC=CC=4)=[CH:20][C:15]=3[CH2:14][N:13](C(=O)C(F)(F)F)[CH:12]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:11]2)[N:6]=[CH:5]1.[C:40](C1C=CC2NC[C@@H](CC3C=CC=CC=3)N(C(=O)CC3C=CC=CC=3)CC=2C=1)#N.[C:69]1([S:75]([Cl:78])(=[O:77])=[O:76])[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1.[H-]>>[ClH:78].[Cl:1][C:19]1[CH:18]=[CH:17][C:16]2[N:10]([CH2:9][C:7]3[N:6]([CH3:40])[CH:5]=[N:4][CH:8]=3)[CH2:11][C@@H:12]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:13]([S:75]([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)(=[O:77])=[O:76])[CH2:14][C:15]=2[CH:20]=1
Reactant: N#Cc1ccc2c(c1)CN(C(=O)Cc1ccccc1)[C@H](Cc1ccccc1)CN2
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(N1Cc2cc(-c3cccnc3)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1)C(F)(F)F
Agent: Cl
Agent: [H-]
Product: Cn1cncc1CN1C[C@@H](Cc2ccccc2)N(S(=O)(=O)c2ccccc2)Cc2cc(Cl)ccc21
Reaction time: 48 h

Procedure:
Example 249 was prepared as a light yellow solid from Compound B of Example 247 by the following sequence: Compound C of Example 247, with benzenesulfonyl chloride, with stirring at rt for 3 hours and chromatography on silica with 7/3 hexanes/EtOAc (57 %); Compound D of Example 247, with stirring at rt for 12 hours and with stirring for 2 days following addition of another equivalent of hydride and aldehyde, and with purification by reverse phase HPLC (gradient of aqueous methanol with 0.1% TFA; 52%). MS (M+H)+ =507.