Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH:12]=O)[C:6]=2[CH:5]=[CH:4]1)[CH3:2].[CH3:14][NH2:15].[BH4-].[Na+].O>CO>[CH2:1]([N:3]1[C:11]2[C:6](=[C:7]([CH2:12][NH:15][CH3:14])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)[CH3:2]
Reactant: CN
Reactant: CCn1ccc2c(C=O)cccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCn1ccc2c(CNC)cccc21
Reaction time: 3 h
Yield: 90.8 %

Procedure:
1-Ethyl-1H-indole-4-carbaldehyde (2.40 mg, 13.8 mmol) was dissolved in anhydrous methanol (62 mL). Methylamine (6.00 mL of 33% solution in ethanol, 48.2 mmol) was added and the reaction was stirred for 3 h. The solution was concentrated to a greenish brown oil and then dissolved in anhydrous methanol (62 mL). Sodium borohydride (539 mg, 14.3 mmol) was added and the mixture was stirred overnight at room temperature. Water (90 mL) was added and the solution was concentrated. Sodium hydroxide (15 mL, 1N) was added and the aqueous layer was extracted with ethyl acetate (3×50 mL). Combined organic layers were dried over Na2SO4, filtered and concentrated to afford the title compound ((1-ethyl-1H-indol-4-yl)-N-methylmethanamine) (2.36 g, 91%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 7.33-7.30 (m, 2H), 7.10-6.97 (m, 2H), 6.52 (d, J=3.0 Hz, 1H), 4.17 (q, J=7.2 Hz, 2H), 3.88 (s, 2H), 2.30 (s, 3H), 1.33 (t, J=7.2 Hz, 3H).
Reaction SMILES: [N-]=[C:2]=[O:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1.O=C(Cl)OC(Cl)(Cl)Cl.[C:23]([OH:27])([CH3:26])([CH3:25])[CH3:24]>CCOC(C)=O.C(Cl)Cl>[C:23]([O:27][C:2](=[O:3])[NH:11][C:8]1[CH:9]=[CH:10][C:5]([Cl:4])=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13])([CH3:26])([CH3:25])[CH3:24]
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CC(C)(C)O
Reactant: [N-]=C=O
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1[N+](=O)[O-]

Procedure:
Compound A6 was prepared via the isocyanate from commercially available 4-chloro-2-nitro-phenylamine [CAS-No. 89-63-4] (5.0 g, 29 mmol) with diphosgene (1.75 mL, 14.5 mmol) in EtOAc (60 mL), followed by treatment with tert-BuOH (30 mL) in CH2Cl2 (60 mL) according to the general procedure A (method a).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][CH:4]=1)=O.[CH3:13][C:14]1([CH3:29])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]2[CH:19]=[C:18]([C:26](=[O:28])[CH3:27])[CH:17]=[CH:16][C:15]1=2.Cl>[OH-].[Na+].CO>[O:28]=[C:26]([C:18]1[CH:17]=[CH:16][C:15]2[C:14]([CH3:29])([CH3:13])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]=2[CH:19]=1)[CH:27]=[CH:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(C(=O)C=Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.9 %

Procedure:
Methyl 4-formylbenzoate (1.28 g, 7.83 mmol) was added to a solution of 1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanone (Compound 1, 1.80 g, 7.83 mmol) in 10 mL of 1 N NaOH and 20 mL of methanol. After stirring at room temperature for 18 h, the reaction mixture was acidified with 1N HCl and extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with brine (1×10 mL), dried (MgSO4) and concentrated at reduced pressure. Recrystallization (acetonitrile) gave the title compound (1.70 g, 60% yield) as a white solid:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:9]([F:19])[C:8](Cl)=[C:7]([C:21](=O)[CH3:22])[N:6]=1)=[O:4].[K].CC(=[N:28][NH2:29])C.CC(=NO)C>>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:9]([F:19])[C:8]2[C:7](=[C:21]([CH3:22])[NH:28][N:29]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(C(C)=O)c(Cl)c(F)c1Nc1ccccc1F
Reactant: CC(C)=NN
Agent: CC(C)=NO
Agent: [K]
Product: COC(=O)c1nc2c(C)[nH]nc2c(F)c1Nc1ccccc1F

Procedure:
The title compound is prepared from 6-acetyl-5-chloro-4-fluoro-3-(2-fluorophenylamino)-pyridine-2-carboxylic acid methyl ester (prepared in Example 8) and the potassium salt of acetone hydrazone in place of the potassium salt of acetone oxime by the method previously described in step H of Example 8.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[CH3:18][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>O1CCCC1.C(OCC)(=O)C>[CH3:17][C:11]([C:4]1[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=[C:2]([F:1])[CH:3]=1)([CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)C(C)c1cc(F)cc2ccoc12
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)c1cc(F)cc2ccoc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of 0.17 gm (0.71 mMol) ethyl 2-(5-fluorobenzofur-7-yl)propionate (EXAMPLE 39) in 2.5 mL tetrahydrofuran was cooled to −78° C. To this solution were added 0.89 mL (0.89 mmol) lithium bis(trimethylsilyl)amide (1.0 M in hexane). After stirring at −78° C. for 1 hour, the reaction mixture was quenched by the addition of 0.13 mL (2.13 mMol) iodomethane. The reaction mixture was allowed to warm to room temperature and was diluted with ethyl acetate. This mixture was then washed sequentially with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The remaining organics were concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with hexane containing 20% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.16 gm (90%) of the desired compound.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([F:12])[CH:5]=1)=[O:3].[CH:13]1([Mg]Br)[CH2:15][CH2:14]1.C1(C(C2C=CC(Cl)=CC=2)(O)C)CC1>O1CCCC1>[CH:13]1([C:2]([C:4]2[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([F:12])[CH:5]=2)([OH:3])[CH3:1])[CH2:15][CH2:14]1
Reactant: Br[Mg]C1CC1
Reactant: COc1ccc(C(C)=O)cc1F
Agent: CC(O)(c1ccc(Cl)cc1)C1CC1
Solvent: C1CCOC1
Product: COc1ccc(C(C)(O)C2CC2)cc1F

Procedure:
The title compound was prepared starting from 1.50 g (8.92 mmol) of 3-fluoro-4-methoxyacetophenone and 35.7 ml (17.8 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran in analogy to the synthesis of the compound from Example 138A. 1.38 g (74% of theory) of the title compound were obtained.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[O:9]>O>[CH:1]1[CH:2]=[C:3]([CH2:4][C:6]2[C:1]([OH:7])=[CH:2][CH:3]=[CH:4][CH:5]=2)[C:8]([OH:9])=[CH:5][CH:6]=1
Reactant: Oc1ccccc1
Reactant: C=O
Solvent: O
Product: Oc1ccccc1Cc1ccccc1O

Procedure:
Stoichiometrically excess phenol and formaldehyde are introduced into a preparation step 1 (from a reaction step to a phenol-removal step). More specifically, to a reactor equipped with, for instance, a stirring machine, a temperature control device, a reflux condenser, a complete condenser and a vacuum device, there are charged phenol, formaldehyde and an acid catalyst and these ingredients are reacted at a determined temperature for a desired period with stirring. Then the acid catalyst, the water formed during the reaction and the unreacted phenol are removed from the reaction product to give crude bisphenol F 2.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9](=[CH:14][CH3:15])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.C([N-]C(C)C)(C)C.[Li+].CN(C)P(N(C)C)(N(C)C)=O.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:51])(=O)=O)=CC=1>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:51])([CH:14]=[CH2:15])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC=C1CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC1(F)CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
2-Chloro-9-cyclopentyl-7-ethylidene-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (1.01 g, 3.30 mmol) in dry tetrahydrofuran (10 mL) was added to 1:1 molar 2 M lithium diisopropyl amide in tetrahydrofuran and hexamethyl phosphoramide (HMPA) (3.96 mmol each) in tetrahydrofuran (5 mL) at −78° C. After 20 minutes, N-fluorobenzene sulfonimide (2.46 mmol) was added dropwise to it. Continued the reaction at −78° C. for 30 minutes, and then elevated the temperature to 0° C. for 30 minutes. After disappearing the starting material, cooled the reaction flask to −78° C., then quenched with sat. ammonium chloride solution (6 mL). At room temperature, the resultant reaction mixture was taken into ethyl acetate (70 mL), washed with ammonium chloride solution and finally with water, dried over sodium sulphate and evaporated. Purified the product using column chromatography with hexane:ethyl acetate mixtures to give the product. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.53-2.10 (m, 8H) 3.38 (s, 3H) 3.63-3.88 (m, 1H) 4.12 (m, 1H) 4.96 (quin, J=8.59 Hz, 1H) 5.41 (d, J=11.12 Hz, 1H) 5.49 (dd, J=17.18, 2.02 Hz, 1H) 6.02 (ddd, J=17.37, 14.72, 10.86 Hz, 1H) 7.97 (s, 1H). [M+H] calculated for C15H18ClFN4O, 325. found 325.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:25])[NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].Br[CH2:27][C:28]1[S:32][C:31]2[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:30]=2[CH:29]=1.CC#N.O>C(O)=O>[Cl:37][C:35]1[CH:34]=[CH:33][C:31]2[S:32][C:28]([CH2:27][N:10]3[C:9]4[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([OH:2])=[O:4])[C:13]=4[N:12]=[C:11]3[C:14](=[O:25])[NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH:22]([CH3:23])[CH3:24])[CH2:18][CH2:17]3)=[CH:29][C:30]=2[CH:36]=1.[Cl:37][C:35]1[CH:34]=[CH:33][C:31]2[S:32][C:28]([CH2:27][N:12]3[C:13]4[C:5]([C:3]([OH:2])=[O:4])=[CH:6][CH:7]=[CH:8][C:9]=4[N:10]=[C:11]3[C:14](=[O:25])[NH:15][CH:16]3[CH2:17][CH2:18][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:20][CH2:21]3)=[CH:29][C:30]=2[CH:36]=1
Reactant: COC(=O)c1cccc2[nH]c(C(=O)NC3CCN(C(C)C)CC3)nc12
Reactant: Clc1ccc2sc(CBr)cc2c1
Solvent: O=CO
Solvent: O
Solvent: CC#N
Product: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)cccc3n2Cc2cc3cc(Cl)ccc3s2)CC1
Product: CC(C)N1CCC(NC(=O)c2nc3cccc(C(=O)O)c3n2Cc2cc3cc(Cl)ccc3s2)CC1

Procedure:
1-(5-Chloro-benzo[b]thiophen-2-ylmethyl)-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid and 3-(5-Chloro-benzo[b]thiophen-2-ylmethyl)-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-3H-benzoimidazole-4-carboxylic acid were prepared by a procedure according to example 81 starting from 200 mg (0.58 mmol) 2-(1-Isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid methyl ester and 151.9 mg (0.58 mmol) 2-bromomethyl-5-chloro-benzo[b]thiophene. Hydrolysis of the resulting esters and purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave the title compounds as their formiates in form of white amorphous solids.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]=O.[C:16]([O-:19])([O-])=O.[K+].[K+]>CO>[CH2:1]([N:8]([CH2:14][O:19][CH3:16])[CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: C=O
Reactant: C[Si](C)(C)CNCc1ccccc1
Agent: [K+]
Solvent: CO
Product: COCN(Cc1ccccc1)C[Si](C)(C)C
Temperature: 12.5 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
To a stirred solution of benzyl-trimethylsilanylmethyl-amine (Preparation 28, 25 g, 128.86 mmol) in methanol (300 mL), formaldehyde solution (37-41% w/v, 4.253 g, 141.75 mmol) was added at 0° C. Resulting reaction mixture was stirred at 0° C. for 1 hour and 10-15° C. for 3 hours. K2CO3 (21.34 g, 154.69 mmol) was added to reaction mixture and reaction was stirred at 10-15° C. for 2 hours. After complete consumption of starting material, the resulting reaction mixture was filtered through Buchner funnel; solid was washed by ethyl acetate (3×20 mL). Combined filtrate was concentrated in vacuo to afford product as faint yellow oil (23 g, Crude). Crude compound was used as such for next reaction. (m/z): 195.1 (M+H).
Reaction SMILES: C(O)(C)(C)C.[K].[CH3:7][C:8]1[C:12]([CH:13]=[O:14])=[CH:11][NH:10][N:9]=1.F[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=1>CN(C)C=O.C(OCC)(=O)C>[F:22][C:21]1[C:16]([N:10]2[CH:11]=[C:12]([CH:13]=[O:14])[C:8]([CH3:7])=[N:9]2)=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1n[nH]cc1C=O
Reactant: Fc1cccnc1F
Agent: [K]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nn(-c2ncccc2F)cc1C=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.6 %

Procedure:
Potassium t-Butyl alcohol (29.25 g, 260.68 mmol) is added to a solution of 3-methyl-1H-pyrazole-4-carbaldehyde (26.00 g, 236.12 mmol) in dimethylformamide (250 mL) cooled with an aqueous bath. The mixture is stirred at room temperature for 10 min. Then, 2,3-difluoropyridine (25 g, 217.24 mmol) is added and the mixture is stirred at room temperature for 20 hr. The mixture is poured over an ice/water mixture and extracted in ethyl acetate (3×20 mL). Organics are dried over magnesium sulfate and solvent evaporated in vacuo. The residue is purified by silica gel chromatography using as eluent hexane/isopropyl alcohol to afford a crude material with residual dimethylformamide. The material is then dissolved in ethyl acetate (100 mL) and washed with water (3×20 mL). Aqueous phase is extracted with ethyl acetate (2×20 mL). Combined organics are dried over sodium sulfate and concentrated to give 19 g of the title compound. MS (m/z): 206 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O>C(#N)C>[Br:13][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[OH:1])[O:9][C:8](=[O:12])[CH2:7][CH2:6]2
Reactant: O=C1CCc2ccc(O)cc2O1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: O=C1CCc2cc(Br)c(O)cc2O1
Reaction time: 0.17 h
Yield: 54.9 %

Procedure:
A solution of Intermediate 1 (20 g) in acetonitrile (50 ml) was added with N-bromosuccinimide (20 g, WAKO) under ice cooling, and stirred for 10 minutes under ice cooling, and then stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and then recrystallized from acetonitrile to obtain the title compound (15 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[N:17][C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([Sn](CCCC)(CCCC)[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)CCC>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[N:17][C:12]3=[N:11][CH:10]=2)=[CH:3][C:2]=1[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)cc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)cc1-c1cccnc1

Procedure:
3-(3-Bromo-4-fluorophenyl)-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 3-tri-n-butylstannylpyridine as described in Example 32 to give 3-[4-fluoro-3-(pyridin-3-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine: δH (400 MHz, DMSO) 7.51 (1H, d, J 7), 7.53-7.64 (2H, m), 7.85-7.89 (1H, m), 8.03 (1H, dd, J 7 and 2), 8.12 (1H, dd, J 8 and 2), 8.34 (1H, s), 8.66 (1H, dd, J 5 and 2), 8.90 (1H, t, J 2), 9.38 (1H, d, J 7); m/z (ES+) 359 (M++H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[CH:19]=[C:18]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH:25]=2)=[O:21])[CH:17]=[C:16]([CH3:38])[C:12]=1[C:13]([OH:15])=O.Cl.[CH3:40][C:41]([CH3:54])([O:43][C:44]([NH:46][CH2:47][C@@H:48]([C:50]([O:52][CH3:53])=[O:51])[NH2:49])=[O:45])[CH3:42].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl.C(OCC)(=O)C>[Cl:10][C:11]1[CH:19]=[C:18]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][Si:31]([C:34]([CH3:36])([CH3:35])[CH3:37])([CH3:32])[CH3:33])[CH:25]=2)=[O:21])[CH:17]=[C:16]([CH3:38])[C:12]=1[C:13]([NH:49][C@H:48]([C:50]([O:52][CH3:53])=[O:51])[CH2:47][NH:46][C:44]([O:43][C:41]([CH3:54])([CH3:42])[CH3:40])=[O:45])=[O:15]
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Reactant: Cc1cc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc(Cl)c1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
Diisopropylethylamine (2.11 mL, 12.1 mmol) was added to a solution of 2-chloro-4-[[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]methyl]amino]carbonyl]-6-methylbenzoic acid (Example 33; 1.32 g, 3.04 mmol) and 3-[[(1,1-dimethylethoxy)carbonyl]amino]-L-alanine, methyl ester, hydrochloride (1.54 g, 6.05 mmol) in dichloromethane (15 mL). Benzotriazol-1-yloxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent; 1.48 g, 3.35 mmol) was added and the mixture was stirred at room temperature for 4 h. The solution was diluted with ethyl acetate, washed with 1 M HCl, water, saturated aqueous sodium hydrogen carbonate, and water. The solution was then dried (MgSO4), filtered, evaporated, and chromatographed (40% ethyl acetate/petroleum ether) to give N-[2-chloro-4-[[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]methyl]amino]carbonyl]-6-methylbenzoyl]-3-[[(1,1-dimethylethoxy)carbonyl]amino]-L-alanine, methyl ester (1.57 g, 81%) as a white foam
Reaction SMILES: [Li].N.[CH:3]#[CH:4].[O:5]=[C:6]1[C:12]([CH3:14])([CH3:13])[CH2:11][C:9](=[O:10])[CH:8]=[C:7]1[CH3:15]>>[CH3:15][C:7]1[C:6]([OH:5])([C:3]#[CH:4])[C:12]([CH3:14])([CH3:13])[CH2:11][C:9](=[O:10])[CH:8]=1
Reactant: C#C
Reactant: CC1=CC(=O)CC(C)(C)C1=O
Agent: N
Agent: [Li]
Product: C#CC1(O)C(C)=CC(=O)CC1(C)C

Procedure:
Lithium (15 g, 2.2 mol) in small pieces is added within one hour to 900 ml of ammonia at -35° C. Acetylene is conducted through the mixture until the blue color has disappeared and a grey suspension results. Ketoisophorone (150 g, 1 mol) is then added dropwise. The ammonia is evaporated within 12 hours. An orange colored residue remains. Subsequently, 1 liter of ice/water is added, the mixture is treated while stirring with ether and then with 2N HCl and thereafter made acid with conc. HCl. The phases are separated and the aqueous phase is extracted four times with ether. The ether extracts are washed twice with water and with saturated sodium chloride solution, dried, filtered and concentrated. In this manner there are obtained 166 g of crude 3,5,5-trimethyl-4-hydroxy-4-ethynylcyclohex-2-en-1-one. This crude product is dissolved almost completely in 500 ml of ether and then cooled to -25°. In this manner there are obtained 86.2 g (48%) of crystalline 3,5,5-trimethyl-4-hydroxy-4-ethynylcyclohex-2-en-1-one. The mother liquor is dissolved in 140 ml of isopropyl ether and cooled to 0°. In this manner there are obtained a further 25 g (14%) of crystals of the desired compound.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=2)O1.[Br:23][C:24]1[S:25][C:26](Br)=[N:27][N:28]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Br:23][C:24]1[S:25][C:26]([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH:10]=2)=[N:27][N:28]=1
Reactant: Brc1nnc(Br)s1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2nnc(Br)s2)CC1
Temperature: 100 °C
Yield: 46.2 %

Procedure:
To a 5 mL microwave vial was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (247 mg, 0.8 mmol), 2,5-dibromo-1,3,4-thiadiazole (98 mg, 0.4 mmol), K3PO4 (212 mg, 1.0 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), 1,4-dioxane (2 mL), and water (0.4 mL). The mixture was purged with N2 for 10 min, then heated to 100° C. in the microwave for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/Heptane) to afford 64 mg (46%) of tert-butyl 4-(5-bromo-1,3,4-thiadiazol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate: MS (M+2)=348.1; 1H NMR (400 MHz, CHLOROFORM-d) δ 6.46 (td, J=3.0, 1.9 Hz, 1H), 4.15 (d, J=3.0 Hz, 2H), 3.64 (t, J=5.6 Hz, 2H), 2.73 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [CH2:1](P(CCCC)CCCC)CCC.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:28]1([S:34]([CH2:37][C:38]2[C:43]([C:44]([OH:46])=[O:45])=[C:42]([OH:47])[C:41]([C:48]3[CH:52]=[CH:51][O:50][CH:49]=3)=[CH:40][CH:39]=2)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O[CH2:54][CH2:55][N:56]([CH3:64])[C:57](=[O:63])[O:58][C:59]([CH3:62])([CH3:61])[CH3:60]>C1COCC1.O.C(OCC)(=O)C>[C:28]1([S:34]([CH2:37][C:38]2[C:43]([C:44]([O:46][CH3:1])=[O:45])=[C:42]([O:47][CH2:54][CH2:55][N:56]([C:57]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:63])[CH3:64])[C:41]([C:48]3[CH:52]=[CH:51][O:50][CH:49]=3)=[CH:40][CH:39]=2)(=[O:36])=[O:35])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: CCCCP(CCCC)CCCC
Reactant: O=C(O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCCN(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
Tri-n-butylphosphine (0.054 g) was added dropwise to a cooled solution of di-isopropyl azodicarboxylate (0.065 g) in dry THF (1 ml) at 0° C. The resultant solution was warmed to room temperature for 10 minutes then re-cooled to 0° C. A mixture of methyl 6-(benzenesulphonylmethyl)-3-(furan-3-yl)-2-hydroxybenzoate (Intermediate 114, 0.05 g) and t-butyl N-(2-hydroxyethyl)-N-methylcarbamate (0.025 g) in THF (1 ml) was added dropwise and the reaction mixture was warmed to room temperature and stirred for 3 hours. Ethyl acetate and water were added and the organic layer was dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane (1:3) to give methyl 6-(benzenesulphonylmethyl)-2-[2-(N-t-butoxycarbonyl-N-methylamino)ethoxy]-3-(furan-3-yl)benzoate (0.054 g) as a gum.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([S:18][C:19]3[CH:20]=[C:21]([C:25]([OH:30])([CH2:28][CH3:29])[CH2:26][CH3:27])[CH:22]=[CH:23][CH:24]=3)=[CH:7][CH:8]=2)[N:3]=1.[NH2:31][NH2:32].[CH3:33]CO>>[C:12]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([S:18][C:19]4[CH:20]=[C:21]([C:25]([OH:30])([CH2:28][CH3:29])[CH2:26][CH3:27])[CH:22]=[CH:23][CH:24]=4)=[CH:7][CH:8]=3)[N:3]3[CH:33]=[N:31][N:32]=[C:2]3[CH:11]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCO
Reactant: NN
Reactant: CCC(O)(CC)c1cccc(Sc2ccc3c(-c4ccccc4)cc(Cl)nc3c2)c1
Product: CCC(O)(CC)c1cccc(Sc2ccc3c(-c4ccccc4)cc4nncn4c3c2)c1

Procedure:
10n (200 mg, 0.46 mmol) was treated with anhydrous hydrazine (2 mL) in EtOH (2 mL) at 60° C. for 1 hour. The reaction was concentrated and diluted with CH2Cl2 and water. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was then treated with ethyl orthoformate (2.5 mL) in EtOH (5 mL) at 65° C. overnight. The mixture was concentrated and diluted with EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography to give the desired product, 10o. The hydrochloride salt was prepared by dissolving the product in CH2Cl2, adding 1N HCl in ether, and concentrating the mixture.