Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[N:9][S:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=1.[CH2:16]([Mg]Cl)[CH2:17][CH3:18]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:9][S:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[CH2:16][CH2:17][CH3:18])[CH:5]=[N:6][CH:7]=1
Reactant: CCC[Mg]Cl
Reactant: CC(C)(C)S(=O)N=Cc1cncc(Br)c1
Solvent: C1CCOC1
Product: CCCC(NS(=O)C(C)(C)C)c1cncc(Br)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid 1-(5-bromo-pyridin-3-yl)-methylideneamide (22 g, 74 mmol) in anhydrous THF (750 mL) at −78° C. is added n-propylmagnesium chloride (2.0 N in ether, 89 mL, 180 mmol) dropwise over 15 min. After stirring at −78° C. for 3 hours, the reaction mixture is then allowed to warm gradually to room temperature overnight. The reaction mixture is quenched by slow addition of saturated aqueous ammonium chloride solution (100 mL) and extracted with EtOAc (2×300 mL). The combined organic phases are washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material is purified by flash chromatography on silica gel (eluted with 20 to 50% EtOAc/hexanes) to afford 2-methyl-propane-2-sulfinic acid 1-(5-bromo-pyridin-3-yl)-butylamide (16 g, 65%) as a yellow solid.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[CH2:11][C:12](Cl)=[O:13]>ClCCl>[CH3:1][NH:2][C:12](=[O:13])[CH2:11][C:5]1[C:4]([F:3])=[CH:9][CH:8]=[CH:7][C:6]=1[F:10]
Reactant: O=C(Cl)Cc1c(F)cccc1F
Reactant: CN
Solvent: ClCCl
Product: CNC(=O)Cc1c(F)cccc1F

Procedure:
25 ml of methylamine solution (33% in ethanol) are diluted with 90 ml of dichloromethane. While cooling, 9.52 g (50 mmol) of 2,6-difluorophenylacetyl chloride dissolved in 10 ml of dichloromethane are added dropwise in such a manner that the temperature of the reaction mixture does not exceed 10°. The reaction mixture is stirred for a further hour at 10° and then extracted three times with water. The organic phase is dried over magnesium sulphate and concentrated. The crude product is recrystallised from dichloromethane/petroleum ether and yields 8.57 g (92.6% of the theoretical yield) of 2,6-difluorophenylacetic acid methylamide of m.p. 163°-164°.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Br)ccc1N
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cc(Br)ccc1NCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-amino-5-bromobenzoate (10.0 g, 43.5 mmol) in dichloromethane (0.5 M, 90 mL) at 0° C. were added p-anisaldehyde (7.9 mL, 65 mmol) and acetic acid (1.2 mL, 22 mmol). Sodium triacetoxyborohydride (18.4 g, 87.0 mmol) was added portion-wise to the solution mixture. The reaction was allowed to warm to room temp and stirred overnight. Upon completion, the reaction was poured into saturated sodium bicarbonate (200 mL). The product was extracted with dichloromethane (3×75 mL). The combined organic extractions were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified via flash chromatography (silica, 1:1 hexanes/dichloromethane) to yield methyl 5-bromo-2-[(4-methoxybenzyl)amino]benzoate. HRMS (M+H)=350.0381. 1H NMR (400 MHz, CDCl3) 8.08 (b, 1H), 8.10 (d, 1H), 7.36 (dd, 1H), 7.24 (d, 2H), 6.88 (d, 2H), 6.54 (d, 1H), 4.35 (s, 2H), 3.86 (s, 3H), 3.80 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1.C(N(CC)CC)C.C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(c2ccnc(Cl)n2)CC1

Procedure:
2.0 g (13.4 mmol) of 2,4-dichloropyrimidine, 2.32 g (14.7 mmol) of ethyl piperidine-4-carboxylate and 4.6 ml (33 mmol) of triethylamine were stirred in 20 ml of DMF at 50° C. for 4 hours. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[CH3:19][N:20]1[CH2:25][CH2:24][CH:23]([Mg]Cl)[CH2:22][CH2:21]1>O1CCCC1.C(#N)C>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]2[CH:6]=[CH:5][C:18]3[CH:17]=[CH:16][CH:15]=[CH:4][C:3]=3[CH:2]([CH:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[C:8]=2[CH:9]=1
Reactant: COc1ccc2c(c1)C(Cl)c1ccccc1C=C2
Reactant: CN1CCC([Mg]Cl)CC1
Solvent: CC#N
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(C1CCN(C)CC1)c1ccccc1C=C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A cooled solution of 5.4 grams (0.021 mole) of 5-chloro-3-methoxy-5H-dibenzo[a,d]cycloheptene in 60 milliliters of tetrahydrofuran was added dropwise under an atmosphere of nitrogen to 50 milliliters of a cooled solution of 0.49M 1-methyl-4-piperidylmagnesium chloride in tetrahydrofuran (Grignard solution) over a period of about 40 minutes. After completion of the addition, the mixture was stirred at room temperature for 2 hours and then at reflux temperature for fifteen minutes. The reaction mixture was then cooled and the product recovered from the reaction mixture by concentrating the mixture in vacuo to dryness, adding toluene to dissolve the organic product, filtering off the magnesium, and then separating, washing and drying the toluene solution in a manner similar to that described in Example I. The toluene was vaporized from the dried solution to obtain a residue which was dissolved in acetonitrile, recrystallized therefrom and the crystals dried at 78° C./0.2 mm. Hg over phosphorus pentoxide for four hours to obtain the desired 4-(3-methoxy-5H-dibenzo[a,d]cyclohepten-5 -yl)-1-methylpiperidine product, m.p. 122°-23° C. Elemental analyses were as follows:
Reaction SMILES: Br[C:2]1[C:3]2[NH:7][C:6]([C:8](C3C(C)=CC=CC=3C)=[C:9]3[N:34]=[C:12]([C:13](Br)=[C:14]4[NH:32][C:17](=[C:18](C5C(C)=CC=CC=5C)[C:19]5[CH:20]=[CH:21][C:22]=1[N:23]=5)[CH:16]=[CH:15]4)[CH:11]=[CH:10]3)=[CH:5][CH:4]=2.C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:3]12[CH:2]=[C:22]3[N:23]=[C:19]([CH:20]=[CH:21]3)[CH:18]=[C:17]3[NH:32][C:14]([CH:15]=[CH:16]3)=[CH:13][C:12]3=[N:34][C:9]([CH:10]=[CH:11]3)=[CH:8][C:6]([NH:7]1)=[CH:5][CH:4]=2
Reactant: Cc1cccc(C)c1-c1c2nc(c(Br)c3ccc([nH]3)c(-c3c(C)cccc3C)c3nc(c(Br)c4ccc1[nH]4)C=C3)C=C2
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3

Procedure:
The general procedure was used to couple 5,15-dibromo-10,20-di(2′,6′-dimethylphenyl)porphyrin (0.034 g, 0.05 mmol) with (+)-dihydrocholesterol (0.1556 g, 0.4 mmol), using Pd2(dba)3 (0.0046 g, 0.005 mmol) and DPEphos (0.0107 g, 0.02 mmol) in the presence of Cs2CO3 (0.0652 g, 0.2 mmol). The reaction was conducted in toluene (5 mL) at 100° C. for 20 h. The title compound was isolated by flash column chromatography (silica gel, ethyl acetate:hexanes (v/v)=1:10) as purple solids (0.053 g, 82%). 1H NMR (300 MHz, CDCl3): δ 9.43 (d, J=4.8 Hz, 4H), 8.65 (d, J=4.8 Hz, 4H), 7.63 (t, J=7.5 Hz, 2H), 7.49 (d, J=7.5 Hz, 4H), 5.02 (m, 2H), 2.32-0.55 (m, 92H), 1.93 (s, 12H), −2.42 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 141.0, 139.6, 135.6, 128.2, 127.0, 117.5, 91.8, 56.4, 56.2, 54.3, 45.0, 42.5, 39.9, 39.5, 37.1, 36.1, 35.8, 35.7, 35.4, 32.0, 29.4, 28.7, 28.2, 28.0, 24.2, 23.8, 22.8, 22.6, 21.8, 21.2, 18.6, 12.6, 12.1. UV-vis (CHCl3, λmax, nm): 418, 518, 555, 600, 659. HRMS-MALDI ([M+H]+): calcd for C90H123N4O2, 1291.9641; found: 1291.9650 with an isotope distribution pattern that is the same as calculated one.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Br.[NH2:21][C@H:22]1[CH2:27][CH2:26][O:25][C:23]1=[O:24].C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C.O>[CH2:4]([O:3][C:1]([NH:11][C@H:12]([C:17]([NH:21][C@H:22]1[CH2:27][CH2:26][O:25][C:23]1=[O:24])=[O:19])[CH2:13][CH:14]([CH3:15])[CH3:16])=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: N[C@H]1CCOC1=O
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H]1CCOC1=O
Temperature: 20 °C
Reaction time: 15 h
Yield: 68 %

Procedure:
3.51 g (13.25 mmol) of Cbz-L-Leucine, 2.41 g (1 eq.) of (S)-2-amino-4-butyrolactone hydrobromide, 1.97 g of HOBT (1.1 eq.) and 5.59 g (2.2 eq.) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) is dissolved in 60 ml of anhydrous DMF then 7.64 ml (3.3 eq.) of N,N-diisopropylethylamine is added. The reaction mixture is stirred for 15 hours at 20° C. before being poured into 200 ml of a 1/1 mixture of ethyl acetate/water. After stirring and decantation, the organic solution is washed successively with 100 ml of a saturated solution of NaHCO3, 50 ml of water, 100 ml of a 1M solution of citric acid and finally 100 ml of a solution of salt water. The organic phase is dried over sodium sulphate, filtered and concentrated to dryness under vacuum. The oil obtained is washed using isopentane and then crystallized from a dichloromethane/isopentane mixture. A white solid is obtained with a yield of 68%. Melting point: 130-131° C.
Reaction SMILES: [N+:1]1([O-:8])[C:2]([CH3:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.C([O-])(C)(C)C.[K+].[F:15][C:16]([F:26])([F:25])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O>>[F:15][C:16]([F:25])([F:26])[C:17]1[CH:18]=[C:19]([CH:20]=[CH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N+:1]=2[O-:8])[CH:22]=[CH:23][CH:24]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: Cc1cccc[n+]1[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: [O-][n+]1ccccc1C=Cc1cccc(C(F)(F)F)c1

Procedure:
Following the general method described in example 2a, 2-picoline-1-oxide was reacted with potassium tert.-butanolate and 3-trifluoromethyl-benzaldehyde. After extraction and chromatography the title compound was obtained as a yellow solid material. MS: m/e=265 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:10]1[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=[C:2]([Cl:1])[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cnc(Cl)cc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cnc(Cl)cc1CBr
Temperature: 25 °C

Procedure:
A mixture of methyl 6-chloro-4-methylnicotinate (2.50 g, 13.5 mmol), N-bromosuccinimide (2.88 g, 16.2 mmol) and benzoyl peroxide (0.14 g, 0.56 mmol) in carbon tetrachloride (100 mL) was refluxed under an atmosphere of nitrogen overnight. The mixture was cooled to room temperature, and filtered through a pad of celite. The mixture was concentrated. The residue was purified by combi-flash chromatography (ethyl acetate in hexanes: 30%) to afford the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH2:11])[C:3]=1[C:12]#[C:13][Si](C)(C)C.[F-].[K+].C>CN(C=O)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH2:11])[C:3]=1[C:12]#[CH:13]
Reactant: C[Si](C)(C)C#Cc1c(N)ncc([N+](=O)[O-])c1Cl
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#Cc1c(N)ncc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of 4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine (1.98 g, 7.34 mmol) in DMF (25 mL) was added potassium fluoride on alumina (40 wt %, 2.67 g, 18.35 mmol). The suspension was stirred at ambient temperature for about 1 h. Activated charcoal (0.3 g) was added and the suspension was filtered through Celite®, washing with DMF (150 mL). The solvent was removed under reduced pressure and the crude material was purified by silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM to afford 4-chloro-3-ethynyl-5-nitropyridin-2-amine (1.03 g, 71%) as a yellow solid: LC/MS (Table 1, Method n) Rt=0.59 min; MS m/z: 196 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9](S(O)(=O)=O)[CH:8]=[CH:7]2.[NH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH:25]=[C:24]([OH:27])[CH:23]=[CH:22]2.[H-].[Na+].CI>CN(C)C=O.O>[NH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH:25]=[C:24]([OH:27])[CH:23]=[CH:22]2.[CH3:24][O:27][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][CH:3]=[C:2]2[NH2:1])=[CH:7][CH:8]=1
Reactant: Nc1cccc2ccc(S(=O)(=O)O)cc12
Agent: Nc1cccc2ccc(O)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2cccc(N)c2c1
Reaction time: 4 h

Procedure:
8-Amino-naphthalen-2-ol was prepared from 8-amino-2-naphthalenesulphonic acid (commercially available) according to the literature (J. Org. Chem. 1949, p351). To a solution of 8-amino-naphthalen-2-ol (8.00 g) in dry N,N-dimethylformamide (80 mL) was added sodium hydride (60% dispersion in mineral oil, 3.2 g) carefully. After stirring for 4 hours the reaction mixture was cooled in an ice bath and methyl iodide (3.13 mL) was added dropwise. The reaction mixture was then stirred at room temperature for 3 days. Water (10 mL) was then added and the volatiles were removed in vacuo. The residue was dissolved in chloroform, washed with water, dried (MgSO4) and the solvent removed in vacuo to yield a dark oil. This was purified using flash chromatography (chloroform) to yield 7-methoxy-naphthalen-1-ylamine as a dark brown liquid (2.92 g).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]([C:18]1[CH:19]=[N:20][CH:21]=[N:22][CH:23]=1)[CH2:10][C:11]([O:13][C:14](C)(C)[CH3:15])=[O:12].[ClH:24]>C(O)C.O1CCOCC1>[ClH:24].[NH2:8][CH:9]([C:18]1[CH:23]=[N:22][CH:21]=[N:20][CH:19]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)CC(N)c1cncnc1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC(N)c1cncnc1

Procedure:
The t-butyl 3-amino-3-(5-pyrimidinyl)propanoate trifluoroacetate salt (1 g), prepared as in example 22, Step 2 was dissolved in 100 mL dry ethanol and 10 mL 4N HCl in dioxane and stirred at room temperature until transesterification was complete. The solvents were removed in vacuo and the residue taken up in ethyl acetate and diethyl ether. The resulting precipitate was filtered, washed with ether and dried (0.8 g) 1H NMR (300 MHz) (d6-DMSO) d 1.05 (t, J=7 Hz, 3H), 3.25 (m, 2H), 4.05 (q, J=7 Hz, 2H), 4.7 (m, 1H), 9.05 (s, 1H), 9.25 (s, 1H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].Cl[CH2:11][C:12](=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.[I-].[K+]>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:11][C:12](=[O:14])[CH3:13]
Reactant: Oc1ccc(F)cc1Br
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)COc1ccc(F)cc1Br
Yield: 109.3 %

Procedure:
A mixture of 1.9 gm (10 mMol) 2-bromo-4-fluorophenol, 0.92 gm (10 mMol) chloroacetone, 0.1 gm potassium iodide, and 1.4 gm (10 mMol) potassium carbonate in 100 mL tetrahydrofuran was heated at reflux for 4 hours. The mixture was concentrated under reduced pressure and the residue partitioned between dichloromethane and 1 N sodium hydroxide. The phases were separated and the aqueous phase extracted well with dichloromethane. The organic phases were combined, washed with 1 N sodium hydroxide, dried over sodium sulfate and concentrated under reduced pressure. The residual 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 2.7 gm (100%) of the desired compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:20])[CH3:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[N:3]=1.[C:22]([NH:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:24])[CH3:23]>>[NH2:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:20])[CH3:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:29]3[CH:30]=[CH:31][C:26]([NH:25][C:22](=[O:24])[CH3:23])=[CH:27][CH:28]=3)[CH:8]=2)[N:3]=1
Reactant: CC(=O)N1CCN(c2nc(N)nc3ccc(Br)cc23)CC1
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Product: CC(=O)Nc1ccc(-c2ccc3nc(N)nc(N4CCN(C(C)=O)CC4)c3c2)cc1
Yield: 91 %

Procedure:
This compound was synthesized from the product of example 18 and 4-acetamidophenyl-boronic acid in 91% yield, using the procedure described for example 7, and was characterized by its mass spectrum as follows: MS (m/z): 405 ([M+H]+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Si:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH3:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([Si:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([CH3:15])[CH2:9][N:10]2[C:14]([Br:23])=[N:13][CH:12]=[N:11]2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C[Si](Cn1cncn1)(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: C[Si](Cn1ncnc1Br)(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 86.2 %

Procedure:
A mixture of 1.5 g (0.0050 mol) of bis(4-fluorophenyl)(methyl)(1H-1,2,4-triazol-1-ylmethyl)silane, 0.98 g (0.0055 mol) of N-bromosuccinimide and ~1 mg of azobisisobutyltronitrile in 10 mL of CCl4 was warmed to 60°, then illuminated with a high intensity lamp (Roxter Model 5900) for 20 minutes. The mixture was cooled, filtered, and evaporated, and the residue was flash chromatographed (10% ether/methylene chloride) to give 1.7 g of the title compound as an oil: ir (neat) 3030, 2960, 1590, 1498, 1479, 1339, 1265, 1231, 1162, 1108, 1033, 825, 789, 733 cm-1. nmr (CDCl3) δ0.7 (s, 9H), 4.2 (s, 2H, 7.1 (t, 4H), 7.5 (m, 4H), 7.8 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:16]#[C:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: C#Cc1ccccc1
Reactant: Nc1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Nc1cccc(C#Cc2ccccc2)n1

Procedure:
A solution of 2-amino-6-bromopyridine (200 mg, 1.16 mmol), 1-phenylacetylene (142 mg, 1.39 mmol), bis(triphenylphosphine) palladium (II) chloride (14 mg, 0.02 mmol), and CuI (2 mg, 0.01 mmol) in 2 mL triethylamine was stirred at 60° C. in a sealed tube for 18 hours. The reaction was cooled and concentrated in vacuo to a dark oil. The oil was purified by gravity column chromatography over silica gel with 2% methanol/chloroform to give the desired product as a brown oil. 400 Mhz H1NMR (CDCl3): 4.57(br s, 2H), 6.49(d, 1H), 6.93(d, 1H), 7.38(m, 3H), 7.41(t, 1H), 7.58(d, 1H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([F:31])=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:32])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:76][CH:77]1[CH2:82][CH2:81][N:80]([CH3:83])[CH2:79][CH2:78]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([F:31])=[CH:29][C:25]([C:26]([NH:76][CH:77]5[CH2:82][CH2:81][N:80]([CH3:83])[CH2:79][CH2:78]5)=[O:28])=[C:24]([F:32])[CH:23]=4)=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCC(N)CC1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)O)cc3F)ncc21
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2cc(F)c(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)cc2F)CC1
Reaction time: 0.17 h
Yield: 85.3 %

Procedure:
To a mixture of 0.0606 g (0.134 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2,5-difluoro-benzoic acid (I-232) and 4 mL of dimethylformamide was added 0.0292 g (0.216 mmole) of 1-hydroxybenzotriazole, 0.0784 g (0.207 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1083 g (0.804 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0228 g (0.20 mmole) of 4-amino-1-methylpiperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0628 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2,5-difluoro-N-(1-methyl-piperidin-4-yl)-benzamide (I-233) as a white solid.
Reaction SMILES: [Na].[N+:2]([CH2:5][C:6]([NH2:8])=[O:7])([O-:4])=[O:3].[F:9][C:10]([C:13]([CH:15]=[CH:16]OCC)=O)([F:12])[F:11].Cl>C(O)C>[N+:2]([C:5]1[C:6](=[O:7])[NH:8][C:13]([C:10]([F:12])([F:11])[F:9])=[CH:15][CH:16]=1)([O-:4])=[O:3]
Reactant: CCOC=CC(=O)C(F)(F)F
Reactant: NC(=O)C[N+](=O)[O-]
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: O=c1[nH]c(C(F)(F)F)ccc1[N+](=O)[O-]
Yield: 57.1 %

Procedure:
To ethanol (1 L) was slowly added sodium metal (4.83 g, 0.21 mol). Once the metal had dissolved, nitroacetamide (21.8 g, 0.21 mol) and (2-ethyloxyvinyl) trifluoromethyl ketone (35 g, 0.21 mol) were added, and the suspension formed was heated at reflux for 16 hrs. The resulting mixture was acidified with aqueous hydrochloric acid (1 M) and concentrated in vacuo. The residue was taken up in ethyl acetate (1 L) and the solid formed removed by filtration. The filtrate was then concentrated and the residue purified by silica chromatography to give the product as an orange solid (25.9 g, 0.12 mol, 59% yield).
Reaction SMILES: I[C@@H:2]([C@@H:10]1[O:28][C@H:13]2[CH2:14][C@@H:15]([CH3:27])[C@@H:16](/[CH:17]=[CH:18]/[C@@H:19]([OH:26])[C@H:20]([F:25])[CH2:21][CH2:22][CH2:23][CH3:24])[C@H:12]2[CH2:11]1)[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N>CCCCCC>[O:28]1[C@H:13]2[CH2:14][C@@H:15]([CH3:27])[C@@H:16](/[CH:17]=[CH:18]/[C@@H:19]([OH:26])[C@H:20]([F:25])[CH2:21][CH2:22][CH2:23][CH3:24])[C@H:12]2[CH2:11][C@@H:10]1[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: CCCC[C@@H](F)[C@H](O)/C=C/[C@H]1[C@H]2C[C@H]([C@H](I)CCCC(=O)OC)O[C@H]2C[C@H]1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CCCCCC
Product: CCCC[C@@H](F)[C@H](O)/C=C/[C@H]1[C@H]2C[C@H](CCCCC(=O)OC)O[C@H]2C[C@H]1C
Temperature: 50 °C
Yield: 95.6 %

Procedure:
To a solution of 1.0 g of [5R,6R,8R,9S,11R,12S,15R,16R]-methyl 5-iodo-6,9-epoxy-11-methyl-16-fluoro-15-hydroxyprost-(13E)-enoate in 50 ml of hexane was added 0.75 g of tri-n-butyltin hydride and a catalytic amount of 2,2'-azobis (2-methylpropionitrile). This solution was warmed to 50° C. for three hours after which the solvent was removed and the residual materials separated by silica gel chromatography to give 0.72 g of [6S,8R,9S,11R,12S,15R,16R]methyl 6,9-epoxy-11-methyl-16-fluoro-15-hydroxyprost-(13E)-enoate.