Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C>[C:11]1([C:2]2[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=2)[C:8]([OH:10])=[O:9])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(O)c1ccnc(Br)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccnc(-c2ccccc2)c1
Temperature: 150 °C
Yield: 53 %

Procedure:
Preparation H1, Step 1: A mixture of 2-bromo-4-pyridinecarboxylic acid (1.1 g, 5.45 mmol), phenylboronic acid (1.3 g, 10.9 mmol), 2.0 M potassium phosphate (aq) (8.2 mL, 16.34 mmol), and DMF (10 mL) in a 20 mL microwave tube was degassed under vacuum/Ar. A catalytic amount of tetrakis(triphenylphosphine)palladium(0) was added to the tube, the mixture was degassed again, the tube was sealed, and the reaction was heated at 150° C. in the microwave for 30 min. The reaction mixture was filtered, the filtrate was concentrated in-vacuo, and the residue was dissolved in water (10 mL). The mixture was acidified to pH=6 with the addition of 1.0 N HCl, and the resulting precipitate was collected by filtration, rinsed with two portions of ice-cold water, and air dried to yield 575 mg of 2-phenylisonicotinic acid as an off-white solid. MS (ES+)=200 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([C:16]([CH3:20])([CH3:19])[CH2:17][OH:18])([OH:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[C:3]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[C:4]([C:9]([N:11]2[CH2:12][C:13]([C:16]([CH3:20])([CH3:19])[CH:17]=[O:18])([OH:15])[CH2:14]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(CO)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CC(C)(C=O)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
A mixture of 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(2-hydroxy-1,1-dimethylethyl)azetidin-3-ol (200 mg, 0.38 mmol) and Dess-Martin periodinane (240 mg, 0.57 mmol) in dichloromethane (2 mL) was stirred at room temperature for 2 hours. 10% aqueous sodium thiosulfate (2 mL), and saturated aqueous sodium bicarbonate (2 mL) was added and the mixture was stirred at room temperature for 15 minute. The mixture was partitioned and the aqueous layer was extracted twice using dichloromethane. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo, to afford a white solid which was purified by column chromatography. Eluting with 30% ethyl acetate in hexanes, the isolated product was concentrated in vacuo to afford 100 mg, 0.20 mmol (53%) of 2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]-2-methylpropanal as a white solid, which was immediately dissolved in tetrahydrofuran (2 mL). To the solution was added isopropylamine (34 μL, 0.40 mmol), followed by triacetoxyborohydride (212 mg, 1.0 mmol). The solution was stirred at room temperature for 15 hours. The reaction mixture was concentrated in vacuo and partitioned between 20% aqueous citric acid and ethyl acetate. The aqueous portion was extracted twice using ethyl acetate, and the combined organic portion was washed with saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow oil which was purified by preparative reverse phase HPLC. The isolated product was concentrated in vacuo to afford 50 mg, 0.07 mmol (36%) of 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{1,1-dimethyl-2-[(1-methylethyl)amino]ethyl}azetidin-3-ol acetate salt as a white solid. 1H NMR (400 MHz, DMSO): 8.47 (br s, 1H), 7.55 (d, 1H), 7.36-7.29 (m, 2H), 7.22-7.15 (m, 1H), 6.68-6.63 (m, 1H), 4.17-4.08 (m, 2H), 3.76-3.73 (m, 1H), 3.56-3.52 (m, 1H), 2.58-2.51 (m, 1H), 2.45-2.37 (m, 2H), 0.92 (t, 6H), 0.78 (d, 6H); MS (EI) for C23H27F3IN3O2: 562 (MH+).
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[S:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][O:18][C:19]([C:21]#[C:22][C:23](OC)=[O:24])=[O:20]>CO>[CH3:17][O:18][C:19](=[O:20])[CH:21]=[C:22]1[S:9][C:8](=[N:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[N:10]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:23]1=[O:24]
Reactant: S=C(NC1CCCCC1)NC1CCCCC1
Reactant: COC(=O)C#CC(=O)OC
Solvent: CO
Product: COC(=O)C=C1SC(=NC2CCCCC2)N(C2CCCCC2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
A mixture of N,N'-dicyclohexylthiourea (10.0 g, 42 mmoles) and dimethylacetylenedicarboxylate (7.8 g, 55 mmoles) in methanol (100 mls) is stirred at room temperature for 16 hours, then warmed on a steambath for 45 minutes and cooled. The precipitate is filtered off, rinsed with cold methanol and dried. This gave the product as white crystals, (11.3 g), mp 97°-98° C.
Reaction SMILES: OC(O)=O.[Cl:5][C:6]1[CH:11]=[C:10]([O:12]C)[C:9]([O:14]C)=[CH:8][C:7]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17].ClC1C=CC(OC)=C(OC)C=1.C(Cl)(=O)C1C=CC=CC=1.II.N1C=CC=CC=1OC(=O)C1C=CC=CC=1>FC(F)(F)C(O)=O>[OH:12][C:10]1[C:9]([OH:14])=[CH:8][C:7]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[C:6]([Cl:5])[CH:11]=1
Reactant: COc1cc(Cl)c(C(=O)c2ccccc2)cc1OC
Agent: COc1ccc(Cl)cc1OC
Agent: II
Agent: O=C(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(Cl)c1ccccc1
Product: O=C(c1ccccc1)c1cc(O)c(O)cc1Cl

Procedure:
The afore-mentioned dihydroxyketone can also be obtained in two stages analogously to Example 9a) and b). The (2-chloro-4,5-dimethoxyphenyl)-phenylmethanone required for this purpose can be obtained by acylating 4-chloro-1,2-dimethoxybenzene with benzoyl chloride in the presence of iodine. It is easier to obtain, however, if one equivalent of 4-chloro-1,2-dimethoxybenzene is heated in a bomb tube at 150° for 2 hours with 1.1 equivalents of (2-pyridinyl)-benzoate in trifluoroacetic acid. After working up and demethylation in a manner analogous to Example 9b), the desired (4,5-dihydroxy-2-chlorophenyl)-phenylmethanone is obtained.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:26][CH2:27][CH2:28][OH:29]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][S:26][CH2:27][CH2:28][OH:29])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: OCCS
Product: O=C(CCCSCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 66 %

Procedure:
Following a procedure similar to that described in Example 1, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 2-mercaptoethanol as starting materials, in relative proportions similar to those used in that Example, and carrying out the reaction at 80° C. for 5 hours, the title compound was obtained in a 66% yield.
Reaction SMILES: [Cl:1][C:2]1[C:26]([O:27][CH2:28][CH3:29])=[CH:25][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:24])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([OH:23])[CH:16]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:30][CH2:31][CH3:32].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([O:30][CH2:31][CH3:32])=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:15]3[CH:16]=[C:17]([O:23][S:34]([CH3:33])(=[O:36])=[O:35])[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=3)=[O:24])[CH2:9][CH2:8]2)=[CH:25][C:26]=1[O:27][CH2:28][CH3:29]
Reactant: CS(=O)(=O)Cl
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cc(O)cc(OC)c3)CC2)cc(OCC)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OS(C)(=O)=O)c3)CC2)cc(OCC)c1Cl

Procedure:
In analogy to the procedure described in example 72a), N-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-3-hydroxy-5-methoxy-benzamide (example 258) was reacted with methanesulfonyl chloride, N-ethyl-diisopropylamine in CH2Cl2 at rt to yield the title compound as colorless solid. MS: 541.2 (MH+).
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[C:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CCCCCC.O1CCCC1>[CH2:17]([C:16]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:23][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: COC(=O)CC(C)=O
Reactant: CCCCCCC(=O)c1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCC1(c2ccccc2)CC(O)=CC(=O)O1

Procedure:
The title compound was prepared as described in General Method 1 using 25 mmol of methyl acetoacetate, 27.5 mmol of NaH 60% dispersion in oil, 26.25 mmol of 1.6 M n-butyl lithium in hexane, 25 mmol of heptanophenone and 70 mL of tetrahydrofuran. Upon concentrating the reaction, a solid precipitated out which was triturated with ether and filtered (m.p. 119-120.5° C.). 1H NMR (CDCl3) δ 0.84 (t, 3 H), 1.1-1.4 (m, 8 H), 1.9-2.0 (m, 2 H), 2.89 (d, 1 H), 2.93 (d, 1 H), 3.24 (d, 1 H), 3.35 (d, 1 H), 7.2-7.5 (m, 5 H).
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[CH3:37])=[C:27]([CH2:38][O:39][CH3:40])[CH:26]=3)[O:22][N:21]=2)=[CH:16][C:3]=1[CH2:4][N:5]([CH3:15])[CH2:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9]>Cl.O1CCOCC1>[CH3:40][O:39][CH2:38][C:27]1[CH:26]=[C:25]([C:23]2[O:22][N:21]=[C:20]([C:17]3[CH:16]=[C:3]([CH:2]=[CH:19][CH:18]=3)[CH2:4][N:5]([CH3:15])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])[N:24]=2)[CH:30]=[CH:29][C:28]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:37]
Reactant: COCc1cc(-c2nc(-c3ccc(F)c(CN(C)CCC(=O)OC(C)(C)C)c3)no2)ccc1-c1ccccc1C
Agent: Cl
Solvent: C1COCCO1
Product: COCc1cc(-c2nc(-c3cccc(CN(C)CCC(=O)O)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 30 h

Procedure:
tert-butyl N-(2-fluoro-5-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzyl)-N-methyl-beta-alaninate obtained in step 1 was dissolved in HCl in dioxane (4M, 10 mL), stirred at RT for 30 h. After this time, solvents were removed under vacuum, residue was triturated with Et2O and filtered to give the title compound as an off-white powder. 1H NMR (DMSO-d6, 300 MHz) δ 12.74 (bs, 1H), 10.38 (bs, 1H), 8.36-8.33 (m, 1H), 8.23-8.20 (m, 1H), 8.18-8.15 (m, 1H), 7.87-7.84 (m, 1H), 7.72 (t, J=7.8 Hz, 1H), 7.44 (d, J=7.9 Hz, 1H), 7.37-7.28 (m, 3H), 7.15-7.13 (m, 1H), 4.48 (bs, 2H), 4.23 (d, J=12.7 Hz, 1H), 4.16 (d, J=12.7 Hz, 1H), 3.25 (s, 3H), 2.89-2.84 (m, 2H), 2.70 (s, 3H), 2.03 (s, 3H). LC/MS (Method B): 472.4 (M+H)+. HPLC (Method A) Rt 4.53 min (purity: 97.4%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:30]([N-:33]C(C)C)(C)[CH3:31].[Li+].CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.BrCC#N.Cl>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1([CH2:31][C:30]#[N:33])[CH2:11][CH2:10][CH:9]([O:12][Si:13]([C:26]([CH3:28])([CH3:27])[CH3:29])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Reactant: CC(C)[N-]C(C)C
Agent: Cl
Agent: N#CCBr
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(CC#N)CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 47 %

Procedure:
Treat a −78° C. solution of 4-(tert-butyl-diphenyl-silanyloxy)-cyclohexanecarboxylic acid ethyl ester (21.22 g, 51.7 mmol) in THF (200 mL) with a 2M solution of lithium diisopropylamide in heptane/THF/ethylbenzene (31 mL, 62.0 mmol) and stir at −78° C. for 15 minutes under N2. Warm the reaction to −20° C. and then re-cool to −78° C. Treat the reaction with bromoacetonitrile (9.30 g, 77.5 mmol) and stir at −78° C. for 1 hour. Warm the reaction to room temperature and stir 1 hour. Acidify the reaction with 1 N HCl, dilute with ethyl acetate, and wash with water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford crude product that is purified with a 0 to 20% ethyl acetate in hexanes gradient on silica gel to afford 10.96 g (47%) of the titled product. Rf=0.25 and 0.21 (5/1 hexanes/ethyl acetate). MS (m/z): 450 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:28][C:29](=[O:42])[CH:30]([N:35]([CH3:41])[CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:31][CH:32]([CH3:34])[CH3:33])[C:17](=[O:27])[NH:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25]O[CH2:23][CH2:22]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1(CCN)CCCC[CH2:44]1.[N-]=C=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([NH:28][C:29](=[O:42])[CH:30]([N:35]([CH3:41])[CH2:36][CH2:37][CH:38]([CH3:39])[CH3:40])[CH2:31][CH:32]([CH3:33])[CH3:34])[C:17](=[O:27])[NH:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:44][CH2:23][CH2:22]2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCN1CCCCC1
Reactant: CC(C)CCN(C)C(CC(C)C)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NCCN1CCOCC1
Agent: [N-]=C=O
Solvent: ClCCl
Product: CC(C)CCN(C)C(CC(C)C)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NCCN1CCCCC1
Reaction time: 48 h

Procedure:
A suspension of N-(2-methylbutyl)-N-methyl-leucine-tyrosine(OBn) -Kaiser oxime resin (Example 57, IIc) in CH2Cl2 was treated with 1.5 equivalents of 2-piperdin-1-ylethylamine. The suspension was shaken for 48 hours. After the reaction was completed, additional CH2Cl2 and 1 equivalent of polymer supported isocyanate was added. After the suspension was shaken for 48 hours, the resin was filtered off, and the solvent was evaporated to yield the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:28]=[N:27][NH:26][C:5]2=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[N:13]([C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=[C:15]([Cl:17])[CH:16]=1)[O:8][C:7]2=[O:25].Cl.[C:30]1([NH2:36])([CH:33]2[CH2:35][CH2:34]2)[CH2:32][CH2:31]1.C(N(CC)CC)C>CN(C)C=O>[C:30]1([NH:36][C:7]([C:6]2[C:11]([NH:10][C:9]([C:12]3[N:13]([C:18]4[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][N:19]=4)[N:14]=[C:15]([Cl:17])[CH:16]=3)=[O:8])=[C:2]([Cl:1])[CH:3]=[C:4]3[C:5]=2[NH:26][N:27]=[CH:28]3)=[O:25])([CH:33]2[CH2:35][CH2:34]2)[CH2:32][CH2:31]1
Reactant: NC1(C2CC2)CC1
Reactant: O=c1oc(-c2cc(Cl)nn2-c2ncccc2Cl)nc2c(Cl)cc3cn[nH]c3c12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC1(C2CC2)CC1)c1c(NC(=O)c2cc(Cl)nn2-c2ncccc2Cl)c(Cl)cc2cn[nH]c12
Temperature: 50 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
To a solution of 400 mg (0.78 mmol) of the above 5-chloro-7-[5-chloro-2-(3-chloro-pyridin-2-yl)-2H-pyrazol-3-yl]-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 8 mL of N,N-dimethylformamide is added 262 mg (1.96 mmol) of bicyclopropyl-1-ylamine hydrochloride and 273 μL (1.96 mmol) of triethylamine. The reaction is stirred at 50° C. for 16 hours and then concentrated in vacuo. The residue is taken-up with water and tert-butylmethylether. The phases are separated and the aqueous layer is washed twice with tert-butylmethylether. The combined organic layers are washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (SiO2, hexanes/ethyl acetate 1:1 to 1:2, gradient) affords 380 mg (91%) of the product as a white solid; LC/MS:530/532 (M+H)+, m.p.: 173-175° C.
Reaction SMILES: [C:1]([C:5]1[CH:32]=[CH:31][C:8]2[N:9]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:10]([CH2:12][CH:13]3[CH2:16][CH:15]([C:17](N(OC)C)=[O:18])[CH2:14]3)=[N:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:32]=[CH:31][C:8]2[N:9]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[C:10]([CH2:12][CH:13]3[CH2:16][CH:15]([CH:17]=[O:18])[CH2:14]3)=[N:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)C1CC(Cc2nc3cc(C(C)(C)C)ccc3n2COCC[Si](C)(C)C)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc2c(c1)nc(CC1CC(C=O)C1)n2COCC[Si](C)(C)C
Reaction time: 2.5 h
Yield: 130.5 %

Procedure:
To a solution of 3-[(5-tert-butyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl)methyl]-N-methoxy-N-methylcyclobutane-1-carboxamide (0.61 g, 1.32 mmol) in tetrahydrofuran (15 ml) was added dropwise 1M diisobutylaluminum hydride solution in toluene (3.29 ml) under N2 at −10° C. The reaction was stirred at this temperature for 2.5 h before being quenched by the addition of methanol (2 ml) and stirred for 5 mins. The solution was poured onto saturated aq. Rochelle's salt (20 ml), diluted with Et2O (30 ml) and stirred for 30 min. This was then separated and the organic layer was washed with Rochelle's salt (30 ml), sat. NaHCO3 (30 ml), and brine (30 nil). This was dried (MgSO4) and concentrated to afford the title compound (0.69 g, 130%) as a colourless gum which was used crude in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:3]=1.[C:18]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])[C@@H:19]([CH3:21])O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@@H:19]([CH3:21])[C:18]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:4]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:3]=1
Reactant: C[C@@H](O)C(=O)OC(C)(C)C
Reactant: CC1(C)OB(c2cc(Cl)ccc2O)OC1(C)C
Product: C[C@H](Oc1ccc(Cl)cc1B1OC(C)(C)C(C)(C)O1)C(=O)OC(C)(C)C

Procedure:
The subtitle compound was prepared by the method of Example 2 step a) using the product from step e) and tert-butyl (R)-(+) lactate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH3:9].C1C(=O)N(Br)C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[Br-].[C:31]1([P:37]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl.C1C=CC=CC=1>[Br-:1].[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH2:9][P+:37]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1c(Br)cccc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Agent: [Br-]
Solvent: c1ccccc1
Solvent: ClCCl
Product: Brc1cccc(Br)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 95 %

Procedure:
Bromination of 2,6-dibromotoluene with NBS/AIBN, followed by reaction of the crude bromide with triphenylphosphine, using the procedure described in example 102, except that the reaction time for the bromination was 3 h, gave the phosphonium salt (516) (95%) as a cream powder, mp (CH2Cl2/benzene) 241–243° C. 1H NMR (CDCl3) δ 7.78 (m, 9H), 7.64 (m, 6H), 7.40 (br d, J=7.9 Hz, 2H), 6.99 (td, J=8.0, 2.5 Hz, 1H), 5.58 (d, J=14.1 Hz, 2H). Found: C, 47.06; H, 3.37. C25H20Br3P.3/4 CH2Cl2 requires C, 47.23; H, 3.31.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1F)[C:5]([C:7]1[C:12]([O:13][CH2:14][O:15][CH3:16])=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6].[C-:21]#[N:22].[K+].O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[C:21]#[N:22])[C:5]([C:7]1[C:12]([O:13][CH2:14][O:15][CH3:16])=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6]
Reactant: [C-]#N
Reactant: COCOc1cccnc1C(=O)c1ccc(F)c(Br)c1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COCOc1cccnc1C(=O)c1ccc(C#N)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
To a solution of 2-(3-bromo-4-fluorobenzoyl)-3-methoxymethoxypyridine (4.68 g) in dimethyl sulfoxide (50 mL) was added potassium cyanide (2.7 g) at 0° C. The mixture was stirred for 3 hours while raising the temperature to room temperature. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The extract solution was washed with water and a saturated aqueous saline solution, successively, and dried (sodium sulfate) and then concentrated. The concentrate was purified by means of a silica gel column (ethyl acetate--hexane) to afford 2-(3-bromo-4-cyanobenzoyl)-3-methoxymethoxypyridine (4.59 g) (compound B-6). Physical properties and spectrum date of the product are shown in Table 3 and Table 4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH3:11][NH:12][CH3:13].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:12]([CH3:13])[CH3:11])=[O:10])=[N:6][CH:7]=1
Reactant: CNC
Reactant: O=C(O)c1ccc(Br)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(Br)cn1

Procedure:
To a solution of 5-bromopyridine-2-carboxylic acid (1.5 g, 7.4 mmol), dimethyl amine (1.3 gm, 16 mmol), diisopropylethyl amine (excess) in DMF (10 mL) was added a solution of HATU in DMF (5 mL). After stirring the reaction for 14 hours at room temperature, the solvent was removed under reduced vacuum. The residue was taken up in ethyl acetate, washed with 1 N HCl (2x), brine (2×), 1 N NaOH (2×), brine (3×), dried over MgSO4, and concentrated. The crude was product was used in subsequent steps without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:21])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1.[CH2:22]=[O:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:21])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:22][OH:23]
Reactant: C=O
Reactant: O=C(c1ccccc1Cl)c1cc(Cl)ccc1-n1ccnc1
Product: O=C(c1ccccc1Cl)c1cc(Cl)ccc1-n1ccnc1CO

Procedure:
In the manner given in Example 1, 3.16 g. of 2',5-dichloro-2-(imidazol-1-yl)benzophenone is heated in a bomb with 37% aqueous formaldehyde solution to give 2',5-dichloro-2-[2-(hydroxymethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].O=[C:16]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][C:18]([O:20]C)=[O:19].C[O-].[Na+].[OH-].[Na+]>CO.O>[CH2:22]([C:16]1[N:1]([C:4]2[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=2)[N:2]=[N:3][C:17]=1[C:18]([OH:20])=[O:19])[CH2:23][CH2:24][CH3:25]
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Reactant: CCCCC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCc1c(C(=O)O)nnn1-c1ccc(C(=O)NCC)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a solution of 4-azido-N-ethylbenzamide (1.00 g) obtained in Example 43a) and methyl 3-oxoheptanoate (1.10 g) in methanol (50 ml) was added a solution of sodium methoxide in methanol (1.35 g, 28%). The reaction mixture was stirred at room temperature for 8 hr and at 70° C. for 3 hr, and 1M aqueous sodium hydroxide solution (11 ml) was added. The reaction mixture was stirred at 70° C. for 1 hr, cooled to room temperature, diluted with water, and methanol was evaporated under reduced pressure. The residual aqueous solution was acidified (pH=1) with 1M hydrochloric acid under ice-cooling, the insoluble material was collected by filtration and washed with water to give the title compound as a brown powder (1.66 g, 99%).