Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[N+:16]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:27]=1[NH:26][CH:25]=[C:24]2[CH:28]=O)([O-:18])=[O:17]>>[N+:16]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:27]=1[NH:26][CH:25]=[C:24]2/[CH:28]=[CH:14]/[C:13]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:15])([O-:18])=[O:17]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: O=Cc1c[nH]c2c([N+](=O)[O-])cccc12
Product: COc1cc(C(=O)/C=C/c2c[nH]c3c([N+](=O)[O-])cccc23)cc(OC)c1OC
Yield: 44.2 %

Procedure:
Substantially the same procedure as in Example 1 was repeated using 3',4',5'-trimethoxyacetophenone (630 mg) and 7-nitroindole-3-carboxaldehyde (552 mg) to give Compound 44 (491 mg).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[NH2:16])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CCOCC.[Cl:29][C:30]([Cl:35])([Cl:34])[C:31](Cl)=[O:32]>C(Cl)Cl>[CH:1]1([C:7]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[NH:16][C:31](=[O:32])[C:30]([Cl:35])([Cl:34])[Cl:29])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(Cl)cc1C(=O)C1CCCCC1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cc(Cl)ccc1NC(=O)C(Cl)(Cl)Cl)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
To a solution of 14.3 g of 2-amino-5-chlorophenyl cyclohexyl ketone and 6.0 g of triethylamine in the mixture of 100 ml of ether and 30 ml of methylene chloride was added dropwise with ice-cooling 11.0 g of trichloroacetyl chloride. After the mixture was stirred at room temperature for 2 hours, the organic layer was washed with water and dried over anhydrous sodium sulfate. Then the solvent was removed under reduced pressure to give oily residue. The residue was crystallized from ether to obtain 18.5 g of 2-trichloroacetamido-5-chlorophenyl cyclohexyl ketone as light yellow crystals, m.p. 93.0°-93.5°C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][C@H:16]([CH:29]([CH3:31])[CH3:30])[CH2:17][C@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=[O:20])[CH:13]=2)[CH:8]=[N:7]1.[CH2:32]([O:39][CH2:40][C@H:41]([CH:45]([CH3:47])[CH3:46])[CH2:42][Mg]Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[NH4+].[Cl-]>C1COCC1>[CH2:32]([O:39][CH2:40][C@H:41]([CH:45]([CH3:47])[CH3:46])[CH2:42][CH:19]([OH:20])[C@@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:17][C@H:16]([CH2:15][C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[N:7][N:6]2[CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:10][CH:11]=1)[CH:29]([CH3:31])[CH3:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COCCCn1ncc2ccc(C[C@@H](C[C@@H](C=O)NC(=O)OC(C)(C)C)C(C)C)cc21
Reactant: CC(C)[C@@H](COCc1ccccc1)C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCCn1ncc2ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(O)C[C@H](COCc3ccccc3)C(C)C)C(C)C)cc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
A 250-mL, three-neck, round-bottom flask equipped with a condenser under N2 was charged with Mg powder (1.36 g, 56.7 mmol). The mixture was warmed briefly with a heat gun and a solution (S)-((2-(bromomethyl)-3-methylbutoxy)methyl)benzene (10.5 g, 37.8 mmol) in anhydrous THF (100 mL) was added dropwise. When the reaction mixture reached reflux temperature the heat gun was stopped. The mixture was stirred for an additional 30 min to afford a solution of (S)-(2-(benzyloxymethyl)-3-methylbutyl)magnesium bromide. A second 250-mL, three-neck round-bottom flask was charged with a solution of tert-butyl (2S,4S)-4-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-5-methyl-1-oxohexan-2-ylcarbamate (2.7 g, 6.3 mmol) in anhydrous THF (50 mL) and cooled to −78° C. under N2 and the solution was stirred for 30 min. The freshly prepared solution of (S)-(2-(benzyloxymethyl)-3-methylbutyl)magnesium bromide prepared above was added dropwise and the mixture was warmed to rt and stirred overnight. 10% aq NH4Cl was added and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed brine, dried and evaporated. The residue was purified by flash chromatography on silica gel to afford the crude tert-butyl (3S,5S,8S)-8-(benzyloxymethyl)-6-hydroxy-3-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-2,9-dimethyldecan-5-ylcarbamate (1.3 g, 33% yield) as an 11:5 mixture of diastereomers at the alcohol center.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C@H:11]([NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([CH2:25][C:26]#[N:27])[CH:22]=[CH:21][C:19]=2[N:20]=1)([CH2:13][CH3:14])[CH3:12].[F:28][C:29]1[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=1[C:31](OC)=[O:32].Cl>C1COCC1>[C@H:11]([NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([CH:25]([C:31]([C:30]3[CH:35]=[CH:36][CH:37]=[CH:38][C:29]=3[F:28])=[O:32])[C:26]#[N:27])[CH:22]=[CH:21][C:19]=2[N:20]=1)([CH2:13][CH3:14])[CH3:12]
Reactant: CC[C@@H](C)Nc1nc2ccc(CC#N)cc2s1
Reactant: COC(=O)c1ccccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@@H](C)Nc1nc2ccc(C(C#N)C(=O)c3ccccc3F)cc2s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
To a solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 35.3 mL) in THF (60 mL) was added a solution of (R)-2-(2-(sec-butylamino)benzo[d]thiazol-6-yl)acetonitrile (3.74 g, 15.2 mmol) in THF (60 mL) at −78° C. over 40 min. The resulting solution was stirred at −78° C. for 10 min before a solution of methyl 2-fluorobenzoate (2.5 mL, 19.6 mmol) in THF (15 mL) was added over 5 min. The mixture was stirred at −78° C. for 1 hr and then at rt for 3 hr before it was poured into ice-cold water (100 mL). After its pH value was adjusted to 9 with 6 N HCl, the mixture was extracted with AcOEt (3×60 mL). The combined extract was washed with brine and dried over anhydrous MgSO4. The solution was concentrated under vacuum, and the residue was subjected to ISCO (2% MeOH/CH2Cl2) to give a mixture (4.09 g) of the title compound and the starting material in a ratio of 1:1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][Si](C)(C)C)[CH:5]=[CH:4][N:3]=1.I[C:15]1[N:16]=[C:17]([CH3:25])[N:18]([CH2:20][C:21]([F:24])([F:23])[F:22])[CH:19]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:15]2[N:16]=[C:17]([CH3:25])[N:18]([CH2:20][C:21]([F:23])([F:24])[F:22])[CH:19]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C[Si](C)(C)C#Cc1ccnc(Cl)c1
Reactant: Cc1nc(I)cn1CC(F)(F)F
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1CC(F)(F)F

Procedure:
The title compound, MS: m/e=300.0 (M+H+), was prepared in accordance with the general method of example A, step 2, from 2-chloro-4-trimethylsilanylethynyl-pyridine and 4-iodo-2-methyl-1-(2,2,2-trifluoro-ethyl)-1H-imidazole.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[NH2:6][CH:7]1[CH2:13][CH:12]2[N:14]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([C:25]#[N:26])=[CH:17][CH:16]=3)[CH:9]([CH2:10][CH2:11]2)[CH2:8]1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[C:25]([C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([N:14]2[CH:12]3[CH2:11][CH2:10][CH:9]2[CH2:8][CH:7]([NH:6][C:1](=[O:3])[CH3:2])[CH2:13]3)=[CH:16][CH:17]=1)#[N:26]
Reactant: N#Cc1ccc(N2C3CCC2CC(N)C3)c2ccccc12
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NC1CC2CCC(C1)N2c1ccc(C#N)c2ccccc12
Reaction time: 1 h
Yield: 54.8 %

Procedure:
To a −30° C. solution of acetyl chloride (15 μL, 0.21 mmol) in DMF (1.5 mL) was added dropwise a solution of 165RL21 (54 mg, 0.20 mmol) and DIPEA (37 μL, 0.21 mmol) in DMF (3.5 mL). After 1 hour of stirring the reaction mixture was brought to rt and allowed to react overnight. Water (20 mL) was then added and the mixture extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography on silica gel using ethyl acetate/MeOH (9:1) to give the desired compound (35 mg, 56%).
Reaction SMILES: [C:1]([C:4]1[S:5][C:6]([CH3:10])=[CH:7][C:8]=1[Cl:9])(O)=[O:2].C(Cl)(=O)C([Cl:14])=O.CN(C=O)C>C(Cl)Cl>[Cl:14][C:1]([C:4]1[S:5][C:6]([CH3:10])=[CH:7][C:8]=1[Cl:9])=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(Cl)c(C(=O)O)s1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(Cl)c(C(=O)Cl)s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 101 %

Procedure:
To a suspension of 2-carboxy-3-chloro-5-methylthiophene (1.2 g, 6.6 mmol) in methylene chloride (16 mL) at 0° C. were added oxalyl chloride (0.6 mL, 7.3 mmol) and a drop of DMF. The mixture was stirred at ambient temperature for 5 hours, then concentrated of all volatiles and dried in vacuo to afford 1.3 g (quantitative yield) of 2-chlorocarbonyl-3-chloro-5-methylthiophene as a pale yellow solid; NMR (DMSO-d6/TFA) 7.4 (s, 1), 2.5 (s, 3) ppm.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].[OH-].[NH4+:40]>O1CCOCC1>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14]([NH2:40])[N:13]=2)[CH2:6]1)(=[O:3])=[O:4]
Reactant: [NH4+]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Agent: [OH-]
Solvent: C1COCCO1
Product: CS(=O)(=O)N1CCC[C@H](Nc2nc(N)ncc2-c2cnc3[nH]ccc3n2)C1
Temperature: 90 °C

Procedure:
A suspension of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine from Example 84, step 1 in ammonium hydroxide in dioxane was heated at 90° C. for 6 hours. The reaction was concentrated and diluted with water and extracted with EtOAc (2×20 ml). The organic layers were dried over MgSO4 and concentrated in vacuo to give a yellow foaming solid. MS (ES+): 561. The de-protection step was similar to step 5 of Example 76 to give N*4*-((S)-1-methanesulfonyl-piperidin-3-yl)-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidine-2,4-diamine. MS (ES+): 389.
Reaction SMILES: [Cl:1][C:2]1[C:10](I)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1nn2ccccc2c1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Clc1nn2ccccc2c1-c1ccccc1
Temperature: 100 °C

Procedure:
A mixture 2-chloro-3-iodopyrazolo[1,5-a]pyridine (27-3; 0.8 g, 2.87 mmol), phenyl boronic acid (0.42 g, 3.44 mmol), and cesium carbonate (2.8 g, 8.61 mmol), in tetrahydrofuran (15.0 mL) was degassed for 10 min. Next, triphenylphosphine (0.15 g, 0.574 mmol) and palladium acetate (0.064 g, 0.287 mmol) were added and heated in a sealed tube at 100° C. for 18 h. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. Purification of the resulting residue by flash chromatography on silica gel (0-5% ethyl acetate in hexanes) provided 2-chloro-3-phenylpyrazolo[1,5-a]pyridine. 1H NMR (400 MHz, DMSO-d6) δ 8.70-8.68 (d, J=7.2 Hz, 1 H), 7.69-7.67 (d, J=8.8 Hz, 1 H), 7.57-7.55 (d, J=7.2 Hz, 2 H), 7.52-7.48 (t, J=7.6 Hz, 2 H), 7.39-7.34 (m, 2 H), 7.03-7.00 (m, 1 H). MS (M+1): 229.1.
Reaction SMILES: [CH3:1][C:2]1[C:3](O)=[N:4][C:5]([NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[N:6][C:7]=1[CH3:8].P(Cl)(Cl)([Cl:24])=O>>[CH3:1][C:2]1[C:3]([Cl:24])=[N:4][C:5]([NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(Nc2nc(-c3ccccc3)cs2)nc(O)c1C
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc(Nc2nc(-c3ccccc3)cs2)nc(Cl)c1C
Yield: 50 %

Procedure:
The same procedures as in Step 3 of Example 22 were repeated using 5,6-dimethyl-2-(4-phenylthiazol-2-yl)amino-4-hydroxypyrimidine (5.6 g, 18.77 mmol) and phosphorus oxychloride(7 ml) to afford 3.0 g of the titled compound. (Yield: 50%)
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:17]2[CH:16]=[C:15]([S:18]([NH:21][C@H:22]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=4)[C:31]([NH2:33])=[NH:32])[C:23]3=[O:37])(=[O:20])=[O:19])[S:14][C:13]=2[CH:12]=[C:11]([Cl:38])[CH:10]=1.CN1CCCCC1.Cl[C:47]([O:49][CH2:50][C:51]([Cl:54])([Cl:53])[Cl:52])=[O:48]>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[Cl:52][C:51]([Cl:54])([Cl:53])[CH2:50][O:49][C:47](=[O:48])[NH:32][C:31]([C:30]1[CH:34]=[CH:35][CH:36]=[C:28]([CH2:27][N:24]2[CH2:25][CH2:26][C@H:22]([NH:21][S:18]([C:15]3[S:14][C:13]4[CH:12]=[C:11]([Cl:38])[CH:10]=[C:9]([Cl:8])[C:17]=4[CH:16]=3)(=[O:19])=[O:20])[C:23]2=[O:37])[CH:29]=1)=[NH:33]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: N=C(N)c1cccc(CN2CC[C@H](NS(=O)(=O)c3cc4c(Cl)cc(Cl)cc4s3)C2=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCCCC1
Product: N=C(NC(=O)OCC(Cl)(Cl)Cl)c1cccc(CN2CC[C@H](NS(=O)(=O)c3cc4c(Cl)cc(Cl)cc4s3)C2=O)c1
Reaction time: 16 h
Yield: 75 %

Procedure:
To a solution of 3-[3-(S)-(4,6-dichlorobenzo[b]thiophene-2-sulfonylamino)-2-oxo-pyrrolidin-1-ylmethyl]-benzamidine trifluroacetate (0.25 g, 0.40 mmol), prepared as in EXAMPLE 14, Part E, in 4 mL of CH2Cl2 :DMF (10:1) is added N-methyl piperidine (0.12 g, 1.2 mmol) followed by trichloroethyl chloroformate (0.93 g, 0.44 mmol). The solution is stirred for 16 hours. After this time, the solution is diluted with EtOAc. The organic layer is washed with 1N HCl, H2O, saturated NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The residue is purified by column chromatography eluting with a gradient of 1% MeOH/CH2Cl2 to 3% MeOH/CH2Cl2 to afford the title compound (0.20 g, 0.30 mmol) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C1C(=O)N([I:18])C(=O)C1>C(#N)C>[I:18][C:8]1[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:10][CH:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cccc2nccn12
Solvent: CC#N
Product: Cc1cccc2ncc(I)n12
Reaction time: 18 h

Procedure:
To 5-methyl-imidazo[1,2-a]pyridine (0.51 g, 3.0 mmol) in ACN (1 ml) at RT is added NIS (0.73 g, 3.3 mmol) and stirring continued for 18 h. The mixture is poured onto water. The precipitate is collected, washed with water and dried. Yield: 0.78 g (92%). HPLC-MS: M+H=259; tR=1.04 min (METHOD—1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1CCN(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.7 %

Procedure:
To a solution of 1-(3-nitrophenyl)piperazine (12.0 g; 58 mmol) in DMF (60 ml) was added sodium hydride (2.55 g; 64 mmol, 60% dispersion in mineral oil) in portions over 30 min. The mixture was kept under nitrogen. Ethyl 2-bromoacetate (7.1 ml; 64 mmol) was added, the mixture was stirred at ambient temperature for one hour and then poured into water (250 ml). The oily precipitate was filtered off, re-dissolved in ethyl acetate and washed with water. The organic phase was dried over magnesium sulphate and evaporated to dryness to leave 6b (11.0 g; 65%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5](B(O)O)=[CH:4][CH:3]=1.[Cl:10][C:11]1[N:16]=[C:15](Cl)[CH:14]=[CH:13][N:12]=1.C([O-])([O-])=O.[Na+].[Na+].CC#N>C(Cl)Cl.CO.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>[Cl:10][C:11]1[N:16]=[C:15]([C:5]2[S:6][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:14]=[CH:13][N:12]=1
Reactant: Cc1ccc(B(O)O)s1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(-c2ccnc(Cl)n2)s1
Temperature: 25 °C

Procedure:
A solution of 0.20 g (1.4 mmol) of 5-methyl-2-thiopheneboronic acid, 0.21 g (1.4 mmol) of 2,4-dichloropyrimidine and 49 mg (0.070 mmol) of bis(triphenylphosphine)palladium(II) chloride in 2 mL of a 2 M Na2CO3 aqueous solution and 5 mL of MeCN was heated in a microwave for 10 min at 160° C., then cooled to rt, diluted with CH2Cl2 and MeOH, and dried over MgSO4. The organic solvent was removed in vacuo, and the resulting solid was purified by flash chromatography eluting with a linear gradient of 50% EtOAc in hexane to neat EtOAc to deliver the title compound. MS (M+H)+ 211.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([C@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]3C(OC(C)(C)C)=O)([OH:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].CO.Cl>O1CCOCC1>[F:1][C:2]1[C:3]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([C@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][NH:17]3)([OH:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(O)([C@H]2CCCCN2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
1,1-dimethylethyl (2R)-2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate (74.9 mg, 0.12 mmol) was taken into methanol (1 mL) followed by addition of 4 N HCl in dioxane (1 mL) and the solution was stirred at room temperature for one hour. The solution was then concentrated and the residue partitioned with chloroform and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over anhydrous sodium sulfate then filtered and concentrated. Purification of the residue by silica gel flash chromatography using ethyl acetate then concentrated aqueous ammonia in chloroform and methanol (0.1:10:1) as eluents afforded 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2R)-piperidin-2-yl]azetidin-3-ol (57.3 mg) as a colorless amorphous solid. The free base was taken into methanol (1 mL) then brought to about pH 1 by addition of 4 N HCl in dioxane and the solution concentrated. The residue was triturated with ethyl ether to afford a suspension. The solid was collected by filtration to afford 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2R)-piperidin-2-yl]azetidin-3-ol hydrochloride salt (49 mg, 72% yield) as a colorless solid. 1H NMR (400 MHz, CDCl3): 8.43-8.39 (d, 1H), 7.41-7.38 (dd, 1H), 7.33-7.31 (dt, 1H), 7.14-7.10 (m, 1H), 6.84-6.80 (m, 1H), 6.63-6.57 (m, 1H), 4.12-3.99 (m, 4H), 3.10-3.08 (d, 1H), 2.72-2.69 (d, 1H), 2.64-2.62 (m, 1H), 1.61-1.58 (m, 2H), 1.36-1.16 (m, 4H); MS (EI) for C21H21F3IN3O2: 532 (MH+).
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13][O:14]S(C3C=CC(C)=CC=3)(=O)=O)[N:11]=2)[CH:2]=1.[CH2:32]([O:34][C:35](=[O:47])[C:36]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42](O)[CH:41]=1)([CH3:38])[CH3:37])[CH3:33].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:32]([O:34][C:35](=[O:47])[C:36]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:14][CH2:13][CH2:12][C:10]2[N:11]=[C:7]([C:3]3[CH:2]=[C:1]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:6]=[CH:5][CH:4]=3)[O:8][C:9]=2[CH3:25])[CH:41]=1)([CH3:38])[CH3:37])[CH3:33]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1cccc(OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)c1

Procedure:
A mixture of the toluene-4-sulfonic acid 2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethyl ester (66.9 mmol) and 2-(3-hydroxyphenoxy)-2-methylpropanoic acid ethyl ester (Columbia University WO 9731530) (12.5 g, 55.71 mmol) and Cs2CO3 (22.7 g, 69.6 mmol) was heated at 55° C. in DMF (45 mL) for 18 h. The reaction was partitioned between ethyl acetate (160 mL) and H2O (180 mL), and the aqueous phase extracted with ethyl acetate (150 mL). The combined organic phases were dried (MgSO4) and concentrated under reduced pressure to an oil which was purified by column chromatography (1500 mL SiO2, 10% ethyl acetate/hexanes to 20% ethyl acetate/hexanes) to provide 2-{3-[2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionic acid ethyl ester. Rf=0.50 in 20% ethyl acetate/hexanes; 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.95 (d, 1H), 7.65-7.59 (m, 3H), 7.44-7.39 (m, 3H), 7.36 (t, 1H), 7.08 (t, 1H), 6.55 (d, 1H), 6.41 (s, 1H), 6.37 (d, 1H), 4.20-4.14 (m, 4H), 2.97 (t, 2H), 2.38 (s, 3H), 1.57 (s, 6H), 1.20 (t, 3H); MS (EI) 508.2 (M+Na)+, 486.2 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C:5]1[C:9]2[C:10]([Cl:27])=[CH:11][C:12]([O:15][CH2:16][C:17]3[N:21]([CH3:22])[N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)=[C:13]([Cl:14])[C:8]=2[S:7][CH:6]=1.C1COCC1.[OH-].[Na+].Cl>CO>[Cl:27][C:10]1[C:9]2[C:5]([CH2:4][C:3]([OH:28])=[O:2])=[CH:6][S:7][C:8]=2[C:13]([Cl:14])=[C:12]([O:15][CH2:16][C:17]2[N:21]([CH3:22])[N:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=2)[CH:11]=1
Reactant: COC(=O)Cc1csc2c(Cl)c(OCc3cc(C(F)(F)F)nn3C)cc(Cl)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nc(C(F)(F)F)cc1COc1cc(Cl)c2c(CC(=O)O)csc2c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
To a mixture of methyl(4,7-dichloro-6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methoxy)-1-benzothiophen-3-yl)acetate (167.4 mg), THF (dry) (2.0 mL) and MeOH (2.0 mL) was added 1N NaOH (1.11 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was neutralized with 1N HCl and concentrated in vacuo. The precipitate was collected by filtration, and crystallized from EtOAc-hexane to give the title compound (131 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[CH3:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.CC(=O)OCC>>[CH3:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][N:23]([CH2:2][C:3]2[S:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:22][CH2:21]1
Reactant: ClCc1nc2cccnc2s1
Reactant: CSc1ccccc1N1CCNCC1
Solvent: CCOC(C)=O
Product: CSc1ccccc1N1CCN(Cc2nc3cccnc3s2)CC1

Procedure:
The product from Example 38A (150 mg, 0.81 mmol), 1-[2-(methylthio)phenyl]piperazine (160 mg, 0.98 mmol), and D1 EA (280 μL, 1.6 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.37 (s, 3H) 2.75 (m, 4H) 2.97 (m, 4H) 4.06 (s, 2H) 7.13 (m, 3H) 7.56 (dd, J=8.31, 4.58 Hz, 2H) 8.33 (dd, J=8.14, 1.36 Hz, 1H) 8.59 (dd, J=4.58, 1.53 Hz, 1H); (ESI) m/z 357 (M+H)+.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[CH:16](=[O:19])[CH2:17][CH3:18].[Cl-].[NH4+]>C1COCC1>[F:9][C:10]1[C:15]([CH:16]([OH:19])[CH2:17][CH3:18])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Fc1ccccn1
Reactant: CCC=O
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(O)c1cccnc1F
Reaction time: 2 h

Procedure:
A freshly prepared LDA solution (68.0 mmol) in 500 ml of THF is cooled to −75° C., and 6.00 g (61.8 mmol) of 2-fluoropyridine are added. The mixture is left to stir at this temperature for 2 h, in the course of which a suspension forms. Thereafter, 4.31 g (74.2 mmol) of propanal are added, in the course of which the internal temperature rises to −45° C. After 2 h, the mixture is allowed to come to RT, poured onto saturated ammonium chloride solution and extracted three times with tert-butyl methyl ether. The combined organic phases are washed with sodium chloride solution, dried over sodium sulfate and concentrated. They are purified by chromatography on silica gel (eluent: dichloromethane, then dichloromethane/methanol=25:1). This affords 8.00 g (76% of theory) of the title compound.