Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([CH2:5][NH:6][CH2:7][C:8]([OH:10])=[O:9])([OH:4])([OH:3])=[O:2].[OH-].[Na+].[CH2:13]1O[CH:14]1[CH2:15][CH3:16]>O>[CH2:14]([CH:15]1[CH2:16][N:6]([CH2:5][P:1]([OH:4])([OH:3])=[O:2])[CH2:7][C:8](=[O:10])[O:9]1)[CH3:13]
Reactant: O=C(O)CNCP(=O)(O)O
Reactant: CCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC1CN(CP(=O)(O)O)CC(=O)O1
Reaction time: 8 h

Procedure:
To a solution of N-phosphonomethylglycine (8.5 grams, 0.05 mole) in 30 ml. of water is added 50% aqueous sodium hydroxide (8.0 grams). The solution is cooled, and 1,2-butylene oxide (3.6 grams, 0.05 mole) is added, after which the solution is rotated overnight on a polymer wheel. Additional amounts of 1,2-butylene oxide are added to complete the reaction, and any unreacted butylene oxide is then extracted with ethyl ether and benzene. A portion of the reaction product is diluted with water and passed through a column of ion exchange resin in the acid form. Cuts 3 through 20 are collected, combined and evaporated to dryness to give 6-ethyl-4-phosphonomethyl-2-morpholinone as a friable glassy solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][C:29]=1[F:30])[O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH3:24])=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[F:31][C:32]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:33]=1[CH2:34]Br>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][C:29]=1[F:30])[O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][N:14]([CH2:34][C:33]2[CH:36]=[CH:37][C:38]([F:40])=[CH:39][C:32]=2[F:31])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH3:24])=[CH:11][CH:10]=1)[CH:2]=[CH2:3]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: C=CCOc1cc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)ccc1F
Product: C=CCOc1cc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)ccc1F

Procedure:
The product from Example 305E and 2,4-difluorobenzyl bromide were processed as described in Example 6B to provide the title compound. MS (ESI+) m/z 535 (M+H)+.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:15][C:16]([F:22])([F:21])[CH:17]([OH:20])[CH2:18][CH3:19]>>[CH3:14][S:11]([C:8]1[CH:9]=[CH:10][C:2]([O:20][CH:17]([C:16]([F:22])([F:21])[F:15])[CH2:18][CH3:19])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Reactant: CCC(O)C(F)(F)F
Product: CCC(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F

Procedure:
Prepared in analogy to Example A14(c) from 2-fluoro-5-methanesulfonyl-benzoic acid (Example A14(b)) and rac-1,1,1-trifluoro-butan-2-ol. MS (m/e): 325.0 ([M−H]−, 100%)
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:32])=O)=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[C:33]([N:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1)(=[O:35])[CH3:34]>>[C:33]([N:36]1[CH2:41][CH2:40][CH:39]([NH:42][C:30]([C:27]2[CH:28]=[CH:29][C:24]([C:6]3[C:5]([C:3]([OH:2])=[O:4])=[CH:10][C:9]([C:11]4[S:12][CH:13]=[C:14]([C:16]5[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=5)[N:15]=4)=[CH:8][CH:7]=3)=[CH:25][CH:26]=2)=[O:32])[CH2:38][CH2:37]1)(=[O:35])[CH3:34]
Reactant: CC(=O)N1CCC(N)CC1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Product: CC(=O)N1CCC(NC(=O)c2ccc(-c3ccc(-c4nc(-c5ccc(Cl)c(Cl)c5)cs4)cc3C(=O)O)cc2)CC1
Yield: 4 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 1-acetylpiperidin-4-amine (available from Aldrich Chemical Company, Inc.; 88 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4′-(1-acetyl-piperidin-4-ylcarbamoyl)-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (5 mg, 4%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.19 (br s, 1H), 8.45 (s, 1H), 8.33 (s, 3H), 8.19 (d, J=7.8 Hz, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.90 (d, J=8.0 Hz, 2H), 7.76 (d, J=8.3 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 2H), 4.35 (d, J=12.3 Hz, 1H), 4.05 (br s, 1H), 3.85 (d, J=13.3 Hz, 1H), 3.16 (t, J=11.8 Hz, 1H), 2.69 (d, J=13.3 Hz, 1H), 2.02 (s, 3H), 1.78-1.93 (m, 1H), 1.18-1.58 (m, 4H).
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:10]=2[CH:11]=O)[CH2:3]1.[NH:20]1[C:27](=[O:28])[CH2:26][C:24](=[O:25])[NH:23][C:21]1=[O:22]>CO>[CH3:1][C@@H:2]1[O:7][C@@H:6]([CH3:8])[C@@H:5]2[C:26]3([CH2:11][C:10]4[C:9]([N:4]2[CH2:3]1)=[CH:16][CH:15]=[C:14]([N+:17]([O-:19])=[O:18])[CH:13]=4)[C:24](=[O:25])[NH:23][C:21](=[O:22])[NH:20][C:27]3=[O:28]
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: C[C@H]1CN(c2ccc([N+](=O)[O-])cc2C=O)C[C@H](C)O1
Solvent: CO
Product: C[C@@H]1O[C@@H](C)CN2c3ccc([N+](=O)[O-])cc3CC3(C(=O)NC(=O)NC3=O)[C@@H]12
Temperature: 60 °C

Procedure:
2-[(2S,6S)-2,6-Dimethylmorpholin-4-yl]-5-nitrobenzaldehyde (298 mg, 1.12 mmol) is combined with barbituric acid (159 mg, 1.12 mmol, Aldrich) in a vial with MeOH (2 mL). The sealed reaction is heated to 60° C. on a shaker block for 21 hours and then the solvent is evaporated. The product is purified on a Biotage Flash 40M+ using a 1:1 mixture of EtOAc and toluene as eluent Product is dried under vacuum yielding a yellow-orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.91, 1.24, 2.91, 3.56, 3.63, 3.83-3.91, 3.95, 4.07, 4.14-4.24, 6.85, 7.83, 7.98, 11.59, 11.89.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][C@@H:22]([O:24]C(=O)C3C=CC([N+]([O-])=O)=CC=3)[CH3:23])[C:13](=[O:36])[N:12]([CH3:37])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][C@@H:22]([OH:24])[CH3:23])[C:13](=[O:36])[N:12]([CH3:37])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](CCCCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O)OC(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](O)CCCCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O
Reaction time: 2 h
Yield: 79.4 %

Procedure:
(S)-7-benzyl-1(5-(4-nitrobenzoyloxy)hexyl)-3-methylxanthine (25 g, 49.5 mmol) was added to a solution for sodium hydroxide (3.36 g, 84 mmol) in methanol (200 ml). After stirring for 2 hours, the pH was adjusted to 4 by addition of 1 N hydrochloric acid solution. After concentrating under reduced pressure, the residue was partitioned between water (150 ml) and ethyl acetate (300 ml). The organic layer was washed with saturated aqueous sodium chloride solution (150 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 20% hexane-ethyl acetate to provide (S)-7-benzyl-1-(5-hydroxyhexyl)-3-methylxanthine (14 g). c) A mixture of (S)-7-benzyl-1-(5-hydroxyhexyl)-3-methylxanthine (14 g, 39 mmol), acetic acid (100 ml), methanol (50 ml), and 10% palladium on carbon (5 g) was treated with hydrogen gels (40 psi) for 14 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 10% methanol-ethyl acetate to give (S)-1-(5-hydroxyhexyl)-3-methylxanthine (6.5 g).
Reaction SMILES: [CH2:1]([PH:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.[NH2:18][C@H:19]([C:27]([NH:29][C@H:30]([C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:1]([P:7]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([NH:18][C@H:19]([C:27]([NH:29][C@H:30]([C:35]([O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:28])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC[PH](=O)OCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Product: CCCCCCP(=O)(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1)OCc1ccccc1

Procedure:
Hexylphosphinic acid, phenylmethyl ester is reacted with L-phenylalanyl-L-leucine, phenylmethyl ester, hydrochloride salt according to the procedure of Example 1(c) to yield N-[N-[hexyl(phenylmethoxy)phosphinyl]-L-phenylalanyl]-L-leucine, phenylmethyl ester.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]>[CH2:14]([C:11]1[CH:10]=[CH:9][C:8]([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([N:7]([C:8]4[CH:9]=[CH:10][C:11]([CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:12][CH:13]=4)[C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Reactant: CC(C)Cc1ccc(Nc2ccccc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)Cc1ccc(N(c2ccccc2)c2ccc(-c3ccc(N(c4ccccc4)c4ccc(CC(C)C)cc4)cc3)cc2)cc1
Yield: 45.6 %

Procedure:
17.6 g (0.078 mol) of N-phenyl-p-isobutylaniline, 12.6 g (0.031 mol) of 4,4'-diiodobiphenyl, 12.9 g (0.093 mol) of anhydrous potassium carbonate, and 0.89 g (0.014 mol) of copper powder were mixed. The mixture was then allowed to undergo reaction at a temperature of 190° to 220° C. for 12 hours. The reaction product was then extracted with 70 ml of toluene. The insoluble contents were removed by filtration. The filtrate was then concentrated to obtain an oily material. The crude product thus obtained was then purified by column chromatography (carrier: silica gel; elute: 1/6 mixture of toluene and n-hexane) to obtain 8.5 g (yield: 45.7%) of N,N'-bis(p-isobutylphenyl)-N,N'-diphenylbenzidine. The melting point of the product was from 133.8° C. to 135.3° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[O:11]=[C:12]1[N:18]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C@H:28]([CH2:43][C:44]3[CH:49]=[C:48]([CH3:50])[C:47]([OH:51])=[C:46]([CH3:52])[CH:45]=3)[C:29]([N:31]3[CH2:36][CH2:35][CH:34]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)[CH2:33][CH2:32]3)=[O:30])=[O:26])[CH2:21][CH2:20]2)[CH2:17][CH2:16][C:15]2[CH:53]=[CH:54][CH:55]=[CH:56][C:14]=2[NH:13]1>C(Cl)Cl>[O:11]=[C:12]1[N:18]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C@H:28]([CH2:43][C:44]3[CH:49]=[C:48]([CH3:50])[C:47]([O:51][CH:1]=[O:3])=[C:46]([CH3:52])[CH:45]=3)[C:29]([N:31]3[CH2:32][CH2:33][CH:34]([N:37]4[CH2:38][CH2:39][O:40][CH2:41][CH2:42]4)[CH2:35][CH2:36]3)=[O:30])=[O:26])[CH2:21][CH2:20]2)[CH2:17][CH2:16][C:15]2[CH:53]=[CH:54][CH:55]=[CH:56][C:14]=2[NH:13]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCOCC3)CC2)cc(C)c1O
Solvent: ClCCl
Solvent: O=CO
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCOCC3)CC2)cc(C)c1OC=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 100 μL acetic anhydride and 1 mL formic acid in 3 mL DCM was stirred for 2 h at RT (formation of the mixed anhydride). Then 100 mg (0.16 mmol)-(R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-(4-morpholin-4-yl-piperidin-1-yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1.20a) were added and the reaction mixture was stirred for 2 h at RT. The reaction solution was evaporated down and the residue was again added to a solution of the mixed anhydride and stirred overnight at RT. The mixture was evaporated down i.vac. and the residue was purified by HPLC. The fractions containing the product were combined and lyophilised.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][O:20][C:21]1[CH:38]=[CH:37][C:24]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35]Br)=[CH:29][CH:28]=2)=[O:26])=[C:23]([OH:39])[CH:22]=1>>[S:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:18][CH2:19][O:20][C:21]2[CH:38]=[CH:37][C:24]([C:25]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:1][C:2]4[CH:3]=[CH:4][C:5]([C:8]5[S:9][C:10]6[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=6[N:12]=5)=[CH:6][CH:7]=4)=[CH:29][CH:28]=3)=[O:26])=[C:23]([OH:39])[CH:22]=2)=[CH:7][CH:6]=1
Reactant: Oc1ccc(-c2nc3ccccc3s2)cc1
Reactant: O=C(c1ccc(OCCBr)cc1)c1ccc(OCCBr)cc1O
Product: O=C(c1ccc(OCCOc2ccc(-c3nc4ccccc4s3)cc2)cc1)c1ccc(OCCOc2ccc(-c3nc4ccccc4s3)cc2)cc1O

Procedure:
A hot solution of 16 g. of zinc o-aminophenylmercaptide and 125 g. of 4-hydroxybenzaldehyde in 1 liter of acetic acid was treated with hydrogen sulfide for 2 hours, filtered hot, diluted with an equal volume of water and cooled. 2-(4-Hydroxyphenyl)benzothiazole (47% yield, m.p. 227°-229°) was obtained. The 2-(4-hydroxyphenyl)benzothiazole was reacted with 4,4'-bis(2-bromoethoxy)-2-hydroxybenzophenone as in Example 1 to produce Compound V.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]([C:12](OCC)=[O:13])=[CH:10][C:9]2[CH:17]=[CH:18][S:19][C:8]=2[S:7]1(=[O:21])=[O:20].CC(C[AlH]CC(C)C)C.Cl>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]([CH2:12][OH:13])=[CH:10][C:9]2[CH:17]=[CH:18][S:19][C:8]=2[S:7]1(=[O:21])=[O:20]
Reactant: CCOC(=O)C1=Cc2ccsc2S(=O)(=O)N1CCCOC
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: C1CCOC1
Product: COCCCN1C(CO)=Cc2ccsc2S1(=O)=O
Reaction time: 4 h
Yield: 99.8 %

Procedure:
To a solution of the product from Step B (3.70 g, 11.18 mmol) in anhydrous THF (50 mL) at ambient temperature under nitrogen was added DIBAL (50 mL of a 1.0 M solution, 50.0 mmol). After stirring for 4 h the reaction mixture was cooled (ice bath) and 2N HCl (100 mL) was added over a 10 min period. THF was evaporated and the aqueous mixture was extracted with ethyl acetate (2×100 mL). The combined extracts were dried (MgSO4), filtered and evaporated to give a viscous oil (3.23 g), which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2[O:12][C:11](C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][S:32]([NH:35][CH3:36])(=[O:34])=[O:33]>>[CH:11]([OH:12])=[O:33].[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:31][S:32]([NH:35][CH3:36])(=[O:33])=[O:34])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: CNS(=O)(=O)Cc1ccccc1Br
Product: CNS(=O)(=O)Cc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1
Product: O=CO

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 1-(2-bromophenyl)-N-methylmethanesulfonamide. MS (ESI): mass calcd. for C18H17FN4O2S, 372.11; m/z found, 373.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.34 (s, 1H), 8.25 (s, 1H), 7.99 (m, 1H), 7.68-7.60 (m, 1H), 7.50-7.40 (m, 2H), 7.39-7.31 (m, 3H), 4.36 (s, 2H), 2.49 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:9]([C:12](=[O:16])[CH2:13][O:14]C)[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.S(=O)(=O)(O)O>C(O)(=O)C>[O:16]=[C:12]1[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:4]=2)=[C:10]([NH2:11])[O:14][CH2:13]1
Reactant: COCC(=O)C(C#N)c1cccc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: NC1=C(c2cccc(C(F)(F)F)c2)C(=O)CO1

Procedure:
In this example a solution containing 31.7 g of (3-trifluoromethylphenyl)-methoxyacetyl-acetonitrile and 24.5 g of concentrated sulfuric acid in 125 ml of acetic acid was refluxed for about 15-20 minutes. The acetic acid was then evaporated off. The residue was mixed with ethyl ether and washed with saturated aqueous sodium bicarbonate solution. The mixture was then dried over magnesium sulfate. The ethyl ether was evaporated off and the residue triturated with a mixture of petroleum ether and ethyl ether affording 20.9 g of the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].CC1(C)COB([C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=2[F:38])OC1>>[F:38][C:31]1[CH:32]=[C:33]([C:34]#[N:35])[CH:36]=[CH:37][C:30]=1[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC1(C)COB(c2ccc(C#N)cc2F)OC1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccc(C#N)cc4F)c3)cnc2c1F
Yield: 9 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 4-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-3-fluorobenzonitrile were coupled in the same way as in Example 30 to give 2,2′-difluoro-5′-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridin-3-yl]biphenyl-4-carbonitrile as an off-white solid (9 mg, 9%): δH (400 MHz, d6-DMSO) 1.56 (6H, s), 7.27 (1H, t, J 7), 7.60 (1H, t, J 9), 7.81-7.92 (5H, m), 8.05 (1H, d, J 10), 8.47 (1H, d, J 7); m/z (ES+) 408 [MH+].
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:55]([C:58]1[CH:59]=[N:60][CH:61]=[CH:62][CH:63]=1)=[C:56]=[O:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:56]([NH:55][C:58]2[CH:59]=[N:60][CH:61]=[CH:62][CH:63]=2)=[O:57])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C=Nc1cccnc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)Nc2cccnc2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 46 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 3-isocyanatopyridine as starting materials in 46% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.00 (s, 1H), 9.41 (m, 2H), 9.24 (s, 1H), 8.98 (s, 2H), 8.40 (m, 1H), 8.30 (m, 3H), 8.20 (s, 1H), 7.72 (m, 1H), 7.65 (s, 1H), 7.30 (d, 1H), 7.05 (d, 1H), 4.15 (m, 2H), 2.98 (m, 6H), 2.32 (m, 2H), 2.12 (m, 1H), 1.80 (m, 2H), 1.20 (m, 2H). LCMS for C30H31ClN9O2 (M+H)+: m/z=584.2.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH:19]([F:21])[F:20])[CH:13]=2)[C:6]([O:9][CH2:10][CH3:11])=[N:7][CH:8]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][C:33]([C:36]#[N:37])=[N:34][CH:35]=2)O1.CCO.C(=O)(O)[O-].[Na+]>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.C1C=CC=CC=1>[F:20][CH:19]([F:21])[O:18][C:14]1[CH:13]=[C:12]([C:5]2[N:4]=[C:3]([CH2:2][C:30]3[CH:31]=[N:32][C:33]([C:36]#[N:37])=[N:34][CH:35]=3)[CH:8]=[N:7][C:6]=2[O:9][CH2:10][CH3:11])[CH:17]=[CH:16][CH:15]=1
Reactant: CCOc1ncc(CBr)nc1-c1cccc(OC(F)F)c1
Reactant: CC1(C)OB(c2cnc(C#N)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: CCOc1ncc(Cc2cnc(C#N)nc2)nc1-c1cccc(OC(F)F)c1
Temperature: 125 °C
Yield: 53.2 %

Procedure:
Into a 5 mL microwave vial was combined 5-(bromomethyl)-3-(3-(difluoromethoxy)phenyl)-2-ethoxypyrazine (Intermediate 1, 176.00 mg, 0.49 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-carbonitrile (124.55 mg, 0.54 mmol), EtOH (2.45 mL), benzene (7.00 mL), tetrakis(triphenylphosphine)palladium(0) (56.63 mg, 0.05 mmol), and sodium bicarbonate (1.38 mL, 1.15 mol/L; 1.59 mmol). The vial was sealed, purged with nitrogen and heated to 125° C. under microwave conditions for 15 minutes. Water was removed from the reaction with a pipette, and the crude reaction mixture was filtered thru CELITE®, and washed with EtOAc (3×5 mL). The combined organic layers were dried (Na2SO4), and the solvent was removed under reduced pressure. Purification (FCC, SiO2, 0-30%, EtOAc/hexanes) afforded the title compound as a white solid (100 mg, 53%). 1H NMR (400 MHz, CD3OD) δ 8.94 (s, 2H), 8.17 (s, 1H), 7.95-7.90 (m, 1H), 7.85 (t, J=1.8 Hz, 1H), 7.46 (t, J=8.2 Hz, 1H), 7.19 (dd, J=2.3, 7.8 Hz, 1H), 7.04-6.61 (m, 1H), 4.49 (q, J=7.0 Hz, 2H), 4.30-4.25 (m, 2H), 1.44 (t, J=7.0 Hz, 3H). [M+H]=384.15.
Reaction SMILES: [CH2:1]=[O:2].C([Al](CCCCCCCCCC)[CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])CCCCCCCCC>CCCCCC>[CH2:1]([OH:2])/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCC=C[Al](CCCCCCCCCC)CCCCCCCCCC
Reactant: C=O
Solvent: CCCCCC
Product: CCCCCCCCCC/C=C\CO
Yield: 21.5 %

Procedure:
Similarly to the procedure described in Example 1, a 17% slurry of 159 grams (5.29 moles) of paraformaldehyde in n-hexane was treated with 1488 grams (3.12 moles) of di-n-decyl dodecenyl aluminum (obtained from tri-n-decyl aluminum and acetylene). Distillation of the hydrolysis product was performed under 0.35 mm Hg. The product fraction was removed at 89°-99° C. There was obtained 133 grams (0.67 moles) of cis-2-tridecen-1-ol (13.3% of theoretical yield), having a purity of 92%. Identity of the compound was confirmed by ir and nmr spectral analyses.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([OH:8])[CH2:3]1.C(N(CC)C(C)C)(C)C.[Cl:18][C:19]1[C:20]([C:32](Cl)=[O:33])=[N:21][O:22][C:23]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=1>ClCCl>[Cl:18][C:19]1[C:20]([C:32]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][C@H:4]([OH:8])[CH2:3]2)=[O:33])=[N:21][O:22][C:23]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=1
Reactant: N[C@@H]1CCC[C@H](O)C1
Reactant: O=C(Cl)c1noc(-c2ccc(F)c(F)c2)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N[C@@H]1CCC[C@H](O)C1)c1noc(-c2ccc(F)c(F)c2)c1Cl
Reaction time: 2 h

Procedure:
A suspension of (1S,3R)-3-aminocyclohexanol (46 mg, 0.40 mmol), N,N-diisopropylethylamine (0.21 mL, 1.20 mmol) and dichloromethane (15 mL) under argon was treated with a dichloromethane (15 mL) solution of 4-chloro-5-(3,4-difluorophenyl)-isoxazole-3-carbonyl chloride (112 mg, 0.40 mmol) at room temperature. After stirring for 2 hours the volatiles were removed in vacuo, and the residue was purified initially by silica gel chromatography, eluting with dichloromethane to 4% methanol in dichloromethane followed by RP HPLC (H2O/MeCN/MeOH 48/48/4 [vol./vol.]) to afford the title compound: (86 mg, 0.24 mmol).