Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[S:10][C:11]([C:14]([OH:16])=O)=[CH:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[F:18][C:19]1([F:25])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[F:18][C:19]1([F:25])[CH2:24][CH2:23][N:22]([C:14]([C:11]2[S:10][C:9]([C:8]#[C:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:13][CH:12]=2)=[O:16])[CH2:21][CH2:20]1
Reactant: FC1(F)CCNCC1
Reactant: O=C(O)c1cnc(C#Cc2ccccc2)s1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cnc(C#Cc2ccccc2)s1)N1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 92.8 %

Procedure:
In a small culture tube, 2-phenylethynyl-thiazole-5-carboxylic acid (28 mg, 0.12 mmol) [Intermediate 1], 4,4-difluoropiperidine hydrochloride (23 mg, 0.14 mmol) (Oakwood Products, Inc. (West Columbia, S.C., USA) and dichloromethane (1.5 mL) were added. To the mixture, PyBOP® (76 mg, 0.14 mmol) was added, followed by N,N-diisopropylethylamine (63 μL, 0.36 mmol), and the reaction was stirred at room temperature for about 17 hours. Afterwards, the crude reaction mixture was directly purified by Preparative TLC, eluting with 40% EtOAc in hexanes to give 37 mg (92%) of the titled compound, (4,4-difluoro-piperidin-1-yl)-(2-phenylethynyl-thiazol-5-yl)-methanone, as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.99 (s, 1H), 7.66-7.59 (m, 2H), 7.49-7.37 (m, 3H), 3.92-3.82 (m, 4H), 2.18-2.01 (m, 4H). LC/MS (Method 3), RT=1.43 min. Calculated [M+H]+=333; Observed [M+H]+=333.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[N:20])[CH:14]=2)[C@@H:10]([NH2:12])[CH3:11])=[CH:4][CH:3]=1.[OH:21][C:22]([CH3:32])([CH3:31])[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([C:13]2[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=2)[C:19]#[N:20])[C@@H:10]([NH:12][CH:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([OH:21])([CH3:32])[CH3:31])[CH3:11])=[CH:4][CH:3]=1
Reactant: C[C@H](N)[C@@H](Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Reactant: CC(C)(O)C(=O)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: C[C@H](NC(c1ccccc1)C(C)(C)O)[C@@H](Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Reaction time: 3 h

Procedure:
To a solution of 250 mg (0.877 mmol) of 3-(4-chlorophenyl)-2(S)(3-cyanophenyl)-1(S)-methyl-propylamine in 3 mL of dichloroethane, 134 μL (0.88 mmol) of 2-hydroxy-2-methylpropiophenone and 280 mg (1.32 mmol) of sodium triacetoxyborohydride were added. After stirring for 3 hr, the reaction was quenched with water and the organic layer was removed with a pipet. This layer was purified by prep TLC using 50% EtOAc/hexane as an eluant to isolate 3-(1(S)-(4-chlorobenzyl)-2(S)-((2-hydroxy-2-methyl-1-phenylpropyl)amino)propyl)benzonitrile (diastereomer A) as a higher Rf isomer (LC-MS: m/e=433 (M+1), 3.09 min) and 3-(1(S)-(4-Chlorobenzyl)-2(S)-((2-hydroxy-2-methyl-1-phenylpropyl)amino)propyl)benzonitrile (diastereomer B) as a lower Rf isomer. LC-MS: m/e=433 (M+1), 3.09 min.
Reaction SMILES: [C:1]([C:6]1[C:7]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:8]([CH:18]=[O:19])[C:9]([CH:15]([CH3:17])[CH3:16])=[N:10][C:11]=1[CH:12]([CH3:14])[CH3:13])([O:3]CC)=O.[CH2:27]([Mg]Br)[CH3:28]>C(OCC)(=O)C.CCCCCC>[CH:15]([C:9]1[C:8]([CH2:18][OH:19])=[C:7]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[C:6]([CH:1]([OH:3])[CH2:27][CH3:28])=[C:11]([CH:12]([CH3:13])[CH3:14])[N:10]=1)([CH3:16])[CH3:17]
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(C=O)c1-c1ccc(F)cc1
Reactant: CC[Mg]Br
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCC(O)c1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 5-carboethoxy-2,6-diisopropyl-4-(4-fluorophenyl)-3-pyridinecarboxaldehyde (Example 1, Step E) and ethyl magnesium bromide, according to the procedures described in Example 93. 1H NMR (300 MHz, CDCl3): δ 7.15 (m, 4 H), 4.40 (dq, J=3.7, J=5.2 Hz, 1 H), 4.30 (d, 5.5 Hz, 2 H), 3.72 (septet, J=6.6 Hz, 1 H), 3.42 (septet, 6.6 Hz, 1 H), 1.88 (m, 1 H), 1.63 (t, J=5.5 Hz, 1 H), 1.27 (m, 14 H), 0.804 (t, J=7.36 Hz, 3 H). FAB-MS: calcd for (C21H28NFO2) 345, found 346 (M+H). Anal. Calcd for C21H28NO2F: C, 76.84; H, 8.69; N, 3.90. Found: C, 76.67; H, 8.76; N, 3.77. mp 173-175° C. Rf=0.2 (20% ethyl acetate/hexane);
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][C:6]([C:12]2[NH:13][C:14](=[O:21])[C:15]([CH:18]([CH3:20])[CH3:19])([CH3:17])[N:16]=2)=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9])=[O:2].[CH2:22]([OH:26])[CH:23](O)[CH3:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:24][CH:23]1[CH2:22][O:26][CH:1]([C:3]2[CH:4]=[N:5][C:6]([C:12]3[NH:13][C:14](=[O:21])[C:15]([CH:18]([CH3:19])[CH3:20])([CH3:17])[N:16]=3)=[C:7]([CH:11]=2)[C:8]([OH:10])=[O:9])[O:2]1
Reactant: CC(O)CO
Reactant: CC(C)C1(C)N=C(c2ncc(C=O)cc2C(=O)O)NC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1COC(c2cnc(C3=NC(C)(C(C)C)C(=O)N3)c(C(=O)O)c2)O1
Temperature: 25 °C
Yield: 74 %

Procedure:
A solution of 5-formyl-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinic acid, 5-(dimethyl acetal) (0.65 g, 0.00194 mol), 1,2-propanediol (0.65 g, 0.0085 mol) and a catalytic amount of p-toluenesulfonic acid in toluene is heated at reflux temperature for 2 hours. The reaction mixture is cooled to room temperature, concentrated in vacuo and the residue is dissolved in methylene chloride. The methylene chloride solution is washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a solid. The solid is chromatographed using silica gel and a gradient elution of 100% methylene chloride to 5% methanol in methylene chloride to yield the title compound as a yellow solid (0.5 g, 74%), mp 50°-52° C., identified by IR and NMR spectral analyses.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:20]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@@H:21]1[O:28][C@H:27]([CH2:29]O)[C@@H:25]([OH:26])[C@H:23]([OH:24])[CH2:22]1.C(Br)(Br)(Br)[Br:39].CO>N1C=CC=CC=1>[Br:39][CH2:29][C@H:27]1[O:28][C@@H:21]([O:20][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:22][C@@H:23]([OH:24])[C@@H:25]1[OH:26]
Reactant: OC[C@H]1O[C@@H](OCc2ccccc2)C[C@@H](O)[C@@H]1O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: c1ccncc1
Product: O[C@H]1[C@H](O)C[C@H](OCc2ccccc2)O[C@@H]1CBr
Temperature: 50 °C
Yield: 72.6 %

Procedure:
A solution of triphenylphosphine (4.5 g, 17.3 mmol, 2.2 eq) in pyridine (30 mL) was added dropwise to a cooled solution of Compound 1 (2.0 g, 7.9 mmol) and CBr4 (3.1 g, 9.4 mmol) in pyridine (30 mL) at zero degrees C. The mixture was then heated at 50° C. for 10 hours. After cooling, methanol (5 mL) was added dropwise, and the mixture was concentrated. The product was purified by flash column chromatography with CHCl3—MeOH (32:1) to give 1.82 g (yield 73 percent) of Compound 2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]([O:16]CC)=[O:15])[N:13]=1.[Li+].[OH-].Cl>C1COCC1.CO>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]([OH:16])=[O:15])[N:13]=1
Reactant: CCOC(=O)c1csc(-c2c(F)cccc2F)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1csc(-c2c(F)cccc2F)n1
Reaction time: 16 h
Yield: 88 %

Procedure:
To a solution of ethyl 2-(2,6-difluorophenyl)thiazole-4-carboxylate (1.0 eq.) in 2:1 THF/MeOH (0.17 M) was added 1.0 M LiOH (2.0 eq.). After standing for 16 hours, 1.0 M HCl (2.0 eq.) was added and the THF/MeOH was removed in vacuo. The resulting solid was filtered, rinsed with H2O and dried, yielding 2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (88%) as a crusty solid. LCMS (m/z): 251.1 (MH+); LC Rt=2.68 min.
Reaction SMILES: C(O)=O.[C:4]([NH:8][S:9]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][CH2:25][C:26]3[CH:31]=[N:30][C:29]([CH3:32])=[C:28]4[O:33]C(C)(C)[O:35][CH2:36][C:27]=34)=[CH:20][CH:19]=2)=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:11])=[O:10])([CH3:7])([CH3:6])[CH3:5]>O>[C:4]([NH:8][S:9]([C:12]1[C:13]([C:18]2[CH:19]=[CH:20][C:21]([NH:24][CH2:25][C:26]3[CH:31]=[N:30][C:29]([CH3:32])=[C:28]([OH:33])[C:27]=3[CH2:36][OH:35])=[CH:22][CH:23]=2)=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:11])=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: Cc1ncc(CNc2ccc(-c3ccccc3S(=O)(=O)NC(C)(C)C)cc2)c2c1OC(C)(C)OC2
Solvent: O=CO
Solvent: O
Product: Cc1ncc(CNc2ccc(-c3ccccc3S(=O)(=O)NC(C)(C)C)cc2)c(CO)c1O
Temperature: 100 °C
Yield: 67.4 %

Procedure:
To a solution of 10% formic acid in water (50 mL) was added 3-[(2,2,8-trimethyl-4H-[1,3] dioxino [4,5-c]pyridin-5-ylmethyl)-amino]-benzonitrile (1) (336 mg, 0.7 mmol) and the reaction mixture was heated at 100° C. under nitrogen atmosphere. The reaction mixture was then concentrated to dryness. The resulting pale yellow solid was dissolved in small amount of dichloromethane and diethyl ether was added to induce precipitation of a yellow solid. The 4′-[(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-amino]-biphenyl-2-sulfonic acid tert-butylamide (2) (215 mg, 70% yield) was collected by filtration as a pale yellow solid.
Reaction SMILES: [C:1](OC)(OC)(OC)[CH2:2][CH2:3][CH3:4].Cl.N1C=CC=CC=1.[NH2:18][C:19]1[CH:20]=[N:21][C:22]2[C:27]([C:28]=1[NH:29][CH2:30][C:31]([CH3:34])([OH:33])[CH3:32])=[CH:26][CH:25]=[C:24]([Br:35])[CH:23]=2>C1(C)C=CC=CC=1>[Br:35][C:24]1[CH:25]=[CH:26][C:27]2[C:28]3[N:29]([CH2:30][C:31]([CH3:34])([OH:33])[CH3:32])[C:1]([CH2:2][CH2:3][CH3:4])=[N:18][C:19]=3[CH:20]=[N:21][C:22]=2[CH:23]=1
Reactant: CCCC(OC)(OC)OC
Reactant: CC(C)(O)CNc1c(N)cnc2cc(Br)ccc12
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCc1nc2cnc3cc(Br)ccc3c2n1CC(C)(C)O
Yield: 76.7 %

Procedure:
Trimethyl orthobutyrate (11.61 mL, 72.6 mmol) and catalytic pyridine hydrochloride were added to a solution of 1-(3-amino-7-bromoquinolin-4-ylamino)-2-methylpropan-2-ol (22.51 g, 72.6 mmol) in anhydrous toluene (120 mL), and the reaction was heated at reflux for two hours. The solvent was removed under reduced pressure, and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was removed under reduced pressure until a precipitate began to form. Hexanes were added, and the precipitate was isolated by filtration to provide 20.17 g of 1-(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.Cl[C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1>>[CH2:2]1[C:41]2[C:35](=[CH:36][CH:37]=[C:38]([NH:39][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:40]=2)[CH2:5][CH2:4][NH:3]1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: Nc1ccc(Cl)cc1
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 4-chloroaniline by a procedure similar to Example 27, Step D. 1H NMR (400 MHz, DMSO-d6) δ 6.67 (d, 1H, J=5.2 Hz), 7.18 (t, 1H, J=7.0 Hz), 7.26-7.32 (m, 4H), 7.38 (d, 1H, J=7.7 Hz), 7.49-7.66 (m, 4H), 7.73 (d, 1H, J=8.9 Hz), 7.84 (d, 1H, J=8.7 Hz), 8.06 (s, 1H), 8.35 (d, 1H, J=5.4 Hz), 8.45 (d, 1H, J=8.9 Hz), 8.90 (d, 1H, J=6.8 Hz), 9.79 (s, 1H), 10.98 (s, 1H); ESIMS (M+H)+=553.
Reaction SMILES: [C:1]1([C:7]2[CH:57]=[CH:56][C:10]([CH2:11][N:12]3[C:16]4=[N:17][CH:18]=[CH:19][CH:20]=[C:15]4[N:14]=[C:13]3[CH2:21][O:22][C:23]3[CH:55]=[CH:54][C:26]([CH2:27][CH:28]4[S:32][C:31](=[O:33])[N:30](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[C:29]4=[O:53])=[CH:25][CH:24]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C>O>[C:1]1([C:7]2[CH:57]=[CH:56][C:10]([CH2:11][N:12]3[C:16]4=[N:17][CH:18]=[CH:19][CH:20]=[C:15]4[N:14]=[C:13]3[CH2:21][O:22][C:23]3[CH:55]=[CH:54][C:26]([CH2:27][CH:28]4[S:32][C:31](=[O:33])[NH:30][C:29]4=[O:53])=[CH:25][CH:24]=3)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1SC(Cc2ccc(OCc3nc4cccnc4n3Cc3ccc(-c4ccccc4)cc3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=O)C(Cc2ccc(OCc3nc4cccnc4n3Cc3ccc(-c4ccccc4)cc3)cc2)S1

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 0.9 g of 5-(4-{3-(4-phenylbenzyl)imidazo[5,4-b]pyridin-2-ylmethoxy}benzyl)-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 55) and 36 ml of a 3:1 by volume mixture of acetic acid and water were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 1:3 by volume mixture of hexane and ethyl acetate as the eluent, to give 450 mg of the title compound, melting at 189°-191° C.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1Cl.[NH:10]([CH2:14][CH2:15][OH:16])[CH2:11][CH2:12][OH:13]>>[OH:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][OH:16])[C:2]1[N:4]=[C:5]([N:10]([CH2:14][CH2:15][OH:16])[CH2:11][CH2:12][OH:13])[N:7]=[C:8]([N:10]([CH2:14][CH2:15][OH:16])[CH2:11][CH2:12][OH:13])[N:1]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: OCCNCCO
Product: OCCN(CCO)c1nc(N(CCO)CCO)nc(N(CCO)CCO)n1

Procedure:
It is known that cyanuric chloride will react with diethanolamine to yield hexakis(2-hydroxyethyl)melamine (Jour. Am. Chem. Soc. 73,2984 (1951). ##STR1## wherein R1 is N(CH2CH2OH)2
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]([C:11]1[CH:23]=[CH:22][C:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:13][CH:12]=1)[C:7]([O:9]C)=[O:8])(=[O:3])[CH3:2].[OH-].[K+]>C1COCC1.CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:1]([NH:4][CH2:5][CH:6]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:22][CH:23]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)C(CNC(C)=O)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)NCC(C(=O)O)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-{1-[(acetylamino)methyl]-2-methoxy-2-oxoethyl}benzoate (530 mg, 1.65 mmol) in THF (9 mL) and MeOH (3 mL) was added KOH (1N, 1.98 mL, 1.98 mmol). After stirring at room temperature for 1 h, the mixture was diluted with 0.5 M citric acid and extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), and concentrated to yield 3-(acetylamino)-2-[4-(tert-butoxycarbonyl)phenyl]propanoic acid as a white powder. MS (ESI) calcd [M+Na]+ 330.1, found 330.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1I.C([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)(OC(C)(C)C)=O.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>O1CCOCC1.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: FC(F)(F)c1ccc(I)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(C)(C)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(N2CCNCC2)c(Cl)c1
Temperature: 100 °C
Yield: 10 %

Procedure:
A mixture of 0.5 g (1.6 mmol) of 3-chloro-4-iodobenzotrifluoride 0.7 g (3.8 mmol), N-Boc-piperazine, 41 mg (0.04 mmol) Tris(dibenzylideneacetone)dipalladium chloroform complex, 0.44 g (4.43 mmol) sodium-t-butoxide and 48 mg (0.16 mmol) tri-o-tolylphosphine in 6 ml dioxane was heated overnight at 100° C. The solution was allowed to cool to room temperature, taken up in ether (30 ml) and washed with brine (25 ml). The organic layer was dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude oil was chromatographed over on silica gel: Eluent: Heptane-AcOEt 0-10% over 15 min to provide the title compound (0.06 g, 10%) as a brown oil, MS (m/e): 365.1 (MH+, 100%).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=O)[C:6]([Cl:8])=[O:7].[CH3:11][O:12][C:13](=[O:23])[C:14]([CH3:22])([C:16]1[CH:21]=[CH:20]C=[CH:18][CH:17]=1)[CH3:15]>C(Cl)Cl>[CH3:11][O:12][C:13](=[O:23])[C:14]([C:16]1[CH:17]=[CH:18][C:5]([C:6]([Cl:8])=[O:7])=[CH:20][CH:21]=1)([CH3:22])[CH3:15]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)C(C)(C)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C(C)(C)c1ccc(C(=O)Cl)cc1
Reaction time: 0.5 h

Procedure:
To a suspension of AlCl3 (500.0 mg, 3.75 mmol) in CH2Cl2 at −10° C. was added dropwise oxalyl chloride (476.0 mg, 3.75 mmol) in CH2Cl2. The mixture was stirred at this temperature for 30 min. Then a solution of 2-methyl-2-phenyl-propionic acid methyl ester (178.0 mg, 1.0 mmol) in CH2Cl2 was added. The resulted mixture was stirred at −10° C. for 1 hr and rt overnight. The mixture was filtered through a pad of celite, the solvent and excess oxalyl chloride was removed under reduced pressure. The residue was dissolved in chlorobenzene and refluxed for 4 hr. Solvent was removed and the residue was dried to give 2-(4-chlorocarbonyl-phenyl)-2-methyl-propionic acid methyl ester.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=1.[H][H]>[Pd].C(O)C>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=1
Reactant: [H][H]
Reactant: COC(=O)Cc1ccc(C#CCCO)cc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)Cc1ccc(CCCCO)cc1
Yield: 99.3 %

Procedure:
A solution of methyl 4-(4-hydroxybutyn-1-yl)phenylacetate (178 mg, 0.82 mmole) and 10% palladium on carbon (30 mg) in ethanol (2 mL) were stirred under a balloon of hydrogen for 3 days at room temperature. The mixture was filtered and the filtrate concentrated in vacuo to give the title compound (181 mg) as an oil. NMR (CDCl3): δ 1.52 (s, 1H); 1.64 (m, 2H); 1.71 (m, 2H); 2.65 (t, 2H); 3.61 (s, 2H); 3.68 (t, 2H); 3.71 (s, 3H); 7.15 (d, 2H); 7.21 (d, 2H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[N:4]1.[CH3:10][Si:11]([CH2:14][CH2:15][O:16][CH2:17]Cl)([CH3:13])[CH3:12]>CN(C=O)C>[CH3:10][Si:11]([CH3:13])([CH3:12])[CH2:14][CH2:15][O:16][CH2:17][N:3]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[N:4]1
Reactant: O=Cc1cc[nH]n1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc(C=O)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred suspension of NaH (274 mg, 11.4 mmol) in DMF (20 mL) was added solution of 1H-pyrazole-3-carbaldehyde (1.0 g, 10.4 mmol) in DMF (10 mL) dropwise at 0° C. and the mixture was stirred at room temperature for 10 min. The reaction mixture was cooled to 0° C. and SEM-Cl (1.90 g, 11.4 mmol) was added dropwise. The mixture was warmed to room temperature and stirred at the same temperature for 16 h. The reaction mixture was quenched with water and extracted with EtOAc (3×20 mL). The combined organic layers were washed water (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10% EtOAc/hexane as eluent) to provide compound A75-1 (350 mg, 29%) as colorless gum.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[Cl:13].[C:14]([S:18][C:19](=[O:24])[CH2:20][C:21](=[O:23])[CH3:22])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([S:18][C:19](=[O:24])[CH:20]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[Cl:13])[C:21](=[O:23])[CH3:22])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(=O)CC(=O)SC(C)(C)C
Reactant: CS(=O)(=O)c1ccc(CBr)c(Cl)c1
Product: CC(=O)C(Cc1ccc(S(C)(=O)=O)cc1Cl)C(=O)SC(C)(C)C

Procedure:
The title compound was prepared by the method of Preparation 34a using 1-bromomethyl-2-chloro-4-methanesulfonylbenzene and 3-oxothiobutyric acid S-tert-butyl ester.
Reaction SMILES: [CH2:1]([CH:3]1[O:8][C:7]2[CH:9]=[C:10](I)[CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1)[CH3:2].[CH3:14][N:15](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[CH2:1]([CH:3]1[CH2:4][O:5][C:6]2[CH:12]=[CH:11][C:10]([C:14]#[N:15])=[CH:9][C:7]=2[O:8]1)[CH3:2]
Reactant: CCC1COc2ccc(I)cc2O1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCC1COc2ccc(C#N)cc2O1
Temperature: 80 °C
Yield: 92 %

Procedure:
A solution of 2-ethyl-7-iodo-2,3-dihydro-1,4-benzodioxine (486 mg, 1.68 mmol) in DMF (3 mL) is degassed by repeatedly evacuating the flask and filling with N2. Zn(CN)2 (117 mg, 1.0 mmol), and Pd(PPh3)4 (97 mg, 0.084 mmol) are added, and the resulting solution is degassed, and is then heated to 80° C. for 1.5 h. The reaction is allowed to cool, poured into water and extracted two times with ether. The combined organic extracts are dried (Na2SO4), filtered and concentrated in vacuo. The resulting material is purified by column chromatography (step gradient, 25-50% CH2Cl2 in hexanes) to give 3-ethyl-2,3-dihydro-1,4-benzodioxine-6-carbonitrile as a clear oil (296 mg, 92%). 1H NMR (400 MHz, CDCl3) δ 7.16, 7.13, 6.91, 4.31, 4.05, 3.93, 1.7, 1.6, 1.08.
Reaction SMILES: [F:1][C:2]1[C:3]([C:17]([O:19]C)=[O:18])=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.O.[OH-].[Li+]>O1CCCC1.O>[F:1][C:2]1[C:3]([C:17]([OH:19])=[O:18])=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: COC(=O)c1cc2nc(-c3ccccc3)nn2cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2nc(-c3ccccc3)nn2cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
A mixture of methyl 6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (600 mg, 2.21 mmol) and lithium hydroxide monohydrate (186 mg, 4.42 mmol) in tetrahydrofurane (10 ml) and water (2.0 ml) is stirred for 3 hours at 25° C. The solvent is evaporated, the residue diluted with water (ca 10 ml) and acidified with 2N aqueous hydrochloric acid (2.2 ml), the precipitated red solid is collected by filtration, washed with water and dried affording 6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid (497 mg. 87.4%) as a pink solid. Mp.: >250° C. MS: m/z=329.2 (M−H+).