Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][NH:11][CH2:12][C:13]([OH:15])=[O:14].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:11]([CH3:10])[CH2:12][C:13]([OH:15])=[O:14])=[CH:3][CH:4]=1)#[N:7]
Reactant: CNCC(=O)O
Reactant: N#Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN(CC(=O)O)c1ccc(C#N)cc1
Temperature: 100 °C

Procedure:
In a 500-ml pear-shaped flask, 4-fluorobenzonitrile (10.44 g, 86.26 mmoles), N-methylglycine (8.45 g, 94.89 mmoles) and potassium carbonate (14.28 g, 103.48 mmoles) were placed, followed by addition of 200 ml of dimethylsulfoxide as a solvent. A water cooling pipe was attached to the flask, and the reaction was carried out with heating on an oil bath heated at 100° C. for 9 hours with stirring using a magnetic stirrer. After cooling naturally, the reaction mixture was dissolved in 1 liter of water and subjected to acidolysis with 1/10N HCl, followed by filtration of a precipitate. After washing with water well, the precipitate was washed with hexane/benzene (4/1 in volume ratio). The yield of the product after dried was 14.21 g (74.79 mmoles, 86.7%). The melting point was 64.5° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10]([C@H:13]1[C:17](=[O:18])[O:16][C:15](=[O:19])[NH:14]1)([CH3:12])[CH3:11]>C(OCC)(=O)C.CN(C)C1C=CN=CC=1>[C:1]([N:14]1[C@@H:13]([CH:10]([CH3:12])[CH3:11])[C:17](=[O:18])[O:16][C:15]1=[O:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)[C@@H]1NC(=O)OC1=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)[C@H]1C(=O)OC(=O)N1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
Benzoyl chloride (295 mg, 2.1 mmol) was dissolved in ethyl acetate (21 mL), followed by the addition of (S)-4-isopropyl-2,5-oxazolidinedione (L-valine-NCA) (286 mg, 2.0 mmol) under ice cooling. Further, a solution of 4-dimethylaminopyridine (257 mg, 2.1 mmol) in ethyl acetate (11 mL) was added dropwise under ice cooling over 20 minutes. The resulting mixture was allowed to rise as was in temperature from 09. After the mixture was stirred at room temperature for 2 hours, a precipitated salt was filtered off, and the filtrate was concentrated under reduced pressure. The concentration residue was re-dissolved in a mixed solvent consisting of ethyl acetate (5 mL) and hexane (5 mL), and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure to afford the title compound as white crystals (351 mg, 80%).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].Cl[C:27]1[N:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][N:28]=1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1.CCOC(C)=O>[CH2:33]([C:30]1[CH:29]=[N:28][C:27]([N:23]2[CH2:24][CH2:25][CH:20]([CH2:19][O:18][C:15]3[CH:16]=[CH:17][C:12]([C:9]4[CH:8]=[CH:7][C:6]([S:3]([CH3:2])(=[O:5])=[O:4])=[CH:11][CH:10]=4)=[CH:13][CH:14]=3)[CH2:21][CH2:22]2)=[N:32][CH:31]=1)[CH3:34]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)cc2)cc1
Reactant: CCc1cnc(Cl)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCc1cnc(N2CCC(COc3ccc(-c4ccc(S(C)(=O)=O)cc4)cc3)CC2)nc1
Temperature: 80 °C
Yield: 34.4 %

Procedure:
A mixture of 4-({[4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)piperidine hydrochloride (70 mg, 0.18 mmol), 2-chloro-5-ethylpyrimidine (30 μL, 0.24 mmol) and diisopropylethylamine (0.10 mL, 0.55 mmol) in NMP (3 mL) was heated at 80° C. overnight. After more 2-chloro-5-ethylpyrimidine (0.1 mL) was added, the reaction mixture was heated at 80° C. for 4 h. The mixture was cooled to ambient temperature, and was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a brown oil. The crude product was purified by chromatography on a silica gel column eluted with 50% EtOAc/hexane followed by trituration with hot hexanes containing 1% MeOH to give 28 mg (34%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.18 (bs, 2H), 7.96 (d, 2H, J=8.3 Hz), 7.72 (d, 2H, J=8.5 Hz), 7.54 (d, 2H, J=8.8 Hz), 6.99 (d, 2H, J=8.8 Hz), 4.85-4.70 (m, 2H), 3.88 (d, 2H, J=6.3 Hz), 3.08 (s, 3H), 3.00-2.85 (m, 2H), 2.55-2.40 (m, 2H), 2.20-2.05 (m, 1H), 2.00-1.90 (m, 2H), 1.45-1.30 (m, 2H), 1.19 (t, 3H, J=7.5 Hz); LRMS (ESI), m/z 452 (M+H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]([CH3:22])([OH:21])[CH3:20])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[CH:23]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH2:24]>>[CH3:28][S:25]([CH2:23][CH2:24][O:21][C:19]([CH3:22])([CH3:20])[CH2:18][N:6]1[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=[C:5]1[CH2:4][O:3][CH2:1][CH3:2])(=[O:27])=[O:26]
Reactant: C=CS(C)(=O)=O
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC(C)(C)O
Product: CCOCc1nc2cnc3ccccc3c2n1CC(C)(C)OCCS(C)(=O)=O
Yield: 64.4 %

Procedure:
Using the general method of Example 8 Part D, 1-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol (2.0 g, 6.7 mmol) was reacted with methyl vinyl sulfone (1.42 g, 13.4 mmol). The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide crude product as an oil. This material was purified by column chromatography (silica gel eluting with 95/5 dichloromethane/methanol) to provide 1.75 g of 1-{2-[2-(methylsulfonyl)ethoxy]-2-methylpropyl}-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline as a colorless foam.
Reaction SMILES: [N+:1]1([O-])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C[Si]([C:16]#[N:17])(C)C.CN(C)C(Cl)=O>[N+](CC)([O-])=O>[C:16]([C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[N:1]=1)#[N:17]
Reactant: [O-][n+]1cccc2c1CCCC2
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Solvent: CC[N+](=O)[O-]
Product: N#Cc1ccc2c(n1)CCCC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 17.2 %

Procedure:
5,6,7,8-Tetrahydroquinoline N-oxide (3.0 g, 19.1 mmol) was dissolved in nitroethane (30 ml), and trimethylsilyl cyanide (2.1 g, 21.0 mmol) and N,N-dimethylcarbamoyl chloride (2.1 g, 19.1 mmol) were added thereto. The reaction mixture was stirred at room temperature for 3 days, concentrated under reduced pressure, combined with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried. The solvent was evaporated under reduced pressure. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (2:1, v/v) to give the titled compound (0.52 g, 17%).
Reaction SMILES: [OH-].[K+].[CH:3]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=O.Br[C:12]1[S:13]C=[N:15][N:16]=1>>[S:13]1[CH:12]=[N:16][N:15]=[C:3]1[N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1
Reactant: Brc1nncs1
Reactant: O=CN1CCNCC1
Agent: [K+]
Agent: [OH-]
Product: c1nnc(N2CCNCC2)s1

Procedure:
The starting 1-(1,3,4-thiadiazol-2-yl)-piperazine was prepared by hydrolyzing with alcoholic potassium hydroxide the crude formyl derivative, itself prepared by condensing 1-formyl piperazine with 2-bromo-1,3,4-thiadiazole melting at 74° C. (Goerdeler and al., Ber 89 1534 (1956)).
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[CH2:4][CH2:3]1.C(Cl)(Cl)Cl.[BrH:17]>C(OCC)(=O)C>[Br:17][CH:4]1[CH2:3][CH:2]([CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:12]
Reactant: CC1CCC(=O)c2ccccc21
Reactant: Br
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC1CC(Br)C(=O)c2ccccc21

Procedure:
Commercially available 4-methyl-1-tetralone, 32.0 grams, contained in 250 ml. of chloroform and 50 ml. of ethyl acetate is heated to boiling. A mixture of 98.3 grams of cupric bromide and 50 ml. of ethyl acetate is heated to its reflux temperature. After all of the hydrogen bromide is evolved, the mixture is maintained at its reflux temperature for an additional hour. The reaction mixture is filtered while hot, the residue washed with boiling chloroform and the combined filtrates evaporated to dryness in vacuo. The residue is dissolved in a minimum of methylene chloride, placed upon an alumina column and eluted with methylene chloride. The eluate is concentrated and the desired 2-bromo-4-methyl-1-tetralone obtained as a dark oil.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][C:8]3([CH2:14][CH2:13][N:12]([CH:15]([C:19]4[CH:24]=[CH:23][C:22]([C:25]5[CH:34]=[C:33]6[C:28]([CH:29]=[CH:30][CH:31]=[N:32]6)=[CH:27][CH:26]=5)=[CH:21][C:20]=4[F:35])[C:16]([OH:18])=O)[CH2:11][CH2:10]3)[O:7][CH2:6][C:5]2=[O:36])[CH2:3][CH2:2]1.Cl.C[N:39](C)CCCN=C=NCC.[Br-].[NH4+]>ClCCl.CN(C)C1C=CN=CC=1>[CH:1]1([N:4]2[CH2:9][C:8]3([CH2:14][CH2:13][N:12]([CH:15]([C:19]4[CH:24]=[CH:23][C:22]([C:25]5[CH:34]=[C:33]6[C:28]([CH:29]=[CH:30][CH:31]=[N:32]6)=[CH:27][CH:26]=5)=[CH:21][C:20]=4[F:35])[C:16]([NH2:39])=[O:18])[CH2:11][CH2:10]3)[O:7][CH2:6][C:5]2=[O:36])[CH2:2][CH2:3]1
Reactant: O=C(O)C(c1ccc(-c2ccc3cccnc3c2)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [Br-]
Solvent: ClCCl
Product: NC(=O)C(c1ccc(-c2ccc3cccnc3c2)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.4 %

Procedure:
A solution of 2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(quinolin-7-yl)phenyl)acetic acid (0.257 mmol) in dichloromethane (2 mL) was treated with N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.386 mmol) and 4-(dimethylamino)pyridine (1.030 mmol) at room temperature. This mixture was stirred for ten minutes at which point ammonium bromide (0.309 mmol) was added. The reaction was allowed to stir at room temperature overnight. The reaction was then concentrated to dryness under a stream of nitrogen. The resulting crude product was purified by reverse phase HPLC (10-40% acetonitrile with 0.1% TFA/water with 0.1% TFA). Fractions containing the desired product were combined and the pH of the resulting mixture was adjusted to ˜10 with 30% w/v aq ammonium hydroxide. This mixture was concentrated to a minimal volume in vacuo and was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Lyophilization from water afforded the title product as a white solid (47 mg, 35%). MS(ES)+ m/e 489.5 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([O:10]C(=O)C)[C:7]([CH3:14])=[N:6][C:5]=1[C:15](=O)[NH:16][C:17]([C:22](=[O:24])[NH2:23])([CH3:21])[CH:18]([CH3:20])[CH3:19].P(Cl)(Cl)(Cl)(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>O=P(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([OH:10])[C:7]([CH3:14])=[N:6][C:5]=1[C:15]1[NH:23][C:22](=[O:24])[C:17]([CH:18]([CH3:20])[CH3:19])([CH3:21])[N:16]=1
Reactant: COC(=O)c1cc(OC(C)=O)c(C)nc1C(=O)NC(C)(C(N)=O)C(C)C
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc(O)c(C)nc1C1=NC(C)(C(C)C)C(=O)N1

Procedure:
A solution of 47 g (0.129 mol) 5-acetoxy-2-(1-carbamoyl-1,2-dimethylpropyl-carbamoyl)-6-methyl-nicotinic acid methyl ester and 93.8 g phosphorus pentachloride in 470 ml phosphoroxychloride in stirred 12 hours at room temperature. The solution is then hydrolysed with ice and neutralized with sodium carbonate. The product is extracted with ethyl acetate, the extract is then dried across magnesium sulfate and compressed. The crude product is recrystallized from ethyl acetate/isopropyl ester.
Reaction SMILES: NC(CC1C=CC(OC(C)(C)C)=CC=1)C(N(CC(OCC)OCC)CC1C=CC=C2C=1NN=C2)=O.[CH2:36]([NH:43][C:44](=[O:54])[NH:45][C@H:46]([CH2:51][CH:52]=[CH2:53])[CH2:47][C:48]([OH:50])=[O:49])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[CH2:36]([NH:43][C:44](=[O:54])[NH:45][CH:46]([CH2:51][CH:52]=[CH2:53])[CH2:47][C:48]([OH:50])=[O:49])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: C=CC[C@H](CC(=O)O)NC(=O)NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CCOC(CN(Cc1cccc2cn[nH]c12)C(=O)C(N)Cc1ccc(OC(C)(C)C)cc1)OCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCC(CC(=O)O)NC(=O)NCc1ccccc1
Reaction time: 0.67 h

Procedure:
To a solution of 2-Amino-3-(4-tert-butoxy-phenyl)-N-(2,2-diethoxy-ethyl)-N-(1H-indazol-7-ylmethyl)-propionamide in CH2Cl2 (50 mL) was added a solution of (3R)-3-(3-Benzyl-ureido)-hex-5-enoic acid (1.6 g, 6.1 mmol), EDCl (1.17 g, 1.2 eq), HOBt (0.93 g, 1.2 eq), DIEA (2.13 mL, 12.2 mmol) in CH2Cl2(100 mL) stirred for 40 min. The reaction mixture was stirred at room temperature for 14 h, and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The crude compound was used next step without further purification. MS ESI 727 (M+H), 749 (M+Na)
Reaction SMILES: [N:1]([C:4]1[N:9]=[N:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1)=[C:2]=[O:3].[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][NH:15]1>C1COCC1>[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][N:15]1[C:2]([NH:1][C:4]1[N:9]=[N:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1)=[O:3]
Reactant: c1ccc2c(c1)CNC2
Reactant: COC(=O)c1ccc(N=C=O)nn1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)N2Cc3ccccc3C2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 6-isocyanatopyridazine-3-carboxylate (5.26 g, 29.4 mmol) in THF (100 mL), a solution of isoindoline (5.24 g, 4.41 mmol) in THF (50 mL) was added at 0° C. The reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered and the precipitate was washed with cold EtOAc and dried in high vacuum to give the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:20][O:21][CH2:22][CH2:23][CH2:24][NH2:25]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:25][CH2:24][CH2:23][CH2:22][O:21][CH3:20])[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Fc1ccc(-c2ccc3nc(Cl)nc(Cl)c3n2)cc1
Reactant: COCCCN
Solvent: C1COCCO1
Product: COCCCNc1nc(Cl)nc2ccc(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
A mixture of 2,4-dichloro-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine (60 mg, 0.2 mmol) and 3-methoxypropylamine (89 mg, 1.0 mmol) in dioxane (5 ml) was stirred at room temperature for 1 hour. After concentration under reduced pressure, the residue was purified by silica gel flash chromatography, the mobile phase being a mixture of methanol/dichloromethane in a volume ratio of 1:80, affording the pure title compound (69 mg, yield 99%) as a white solid which was characterised as follows: MS (m/z): 347 ([M+H]+, 100).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:33]=[CH:32][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:31])[C@:15]([CH2:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:24])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:34](Cl)([CH3:37])(=[O:36])=[O:35].N1C=CC=CC=1>CC(C)=O>[CH3:30][C:27]([CH3:28])([CH3:29])[CH2:26][CH2:25][C@@:15]1([CH3:24])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]([OH:23])=[C:13]([C:8]2[NH:7][C:6]3[CH:32]=[CH:33][C:3]([NH:2][S:34]([CH3:37])(=[O:36])=[O:35])=[CH:4][C:5]=3[S:10](=[O:12])(=[O:11])[N:9]=2)[C:14]1=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)CC[C@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)CC[C@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21

Procedure:
A solution of Example 48G (0.250 g, 0.510 mmol), mesyl chloride (0.158 mL, 2.04 mmol), and pyridine (0.330 mL, 4.08 mmol) in acetone (3 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.[C:20]([N:28]1[CH:34]=[CH:33][N:32]=[CH:31][CH2:30][N:29]1[C:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>CCOCC>[C:20]([N:28]1[CH2:34][CH2:33][N:32]([CH2:11][CH2:10][CH2:9][CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:31][CH2:30][N:29]1[C:35](=[O:42])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Fc1ccc(C(CCCBr)c2ccc(F)cc2)cc1
Reactant: O=C(c1ccccc1)N1C=CN=CCN1C(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)N1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CCN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 4,4-bis(4-fluorophenyl)butyl bromide (2.08 g), 1,2-dibenzoyl-1H-1,2,5-triazepine (2.0 g), powdered anhydrous sodium carbonate (2.71 g) and N,N-dimethylformamide (20 ml, dried over 4A molecular sieves) was stirred at room temperature under a nitrogen atmosphere for three days. The mixture was filtered and the filtrate was evaporated under oil pump vacuum to an oil. The oil was chromatographed on a column of silica gel; elution with ethyl acetate-dichloromethane (2:3) giving a major product. The hydrochloride salt of the titled compound was formed in ether from this material; wt. 2.0 g (52%), mp=216°-218°.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([C:14]#[CH:15])=[CH:13][C:8]=2[C:7](=[O:16])[N:6]([CH3:17])[C:5]2[CH:18]=[CH:19][CH:20]=[N:21][C:4]1=2)[CH3:2].Br[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1>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.C(N(CC)CC)C>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([C:14]#[C:15][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:13][C:8]=2[C:7](=[O:16])[N:6]([CH3:17])[C:5]2[CH:18]=[CH:19][CH:20]=[N:21][C:4]1=2)[CH3:2]
Reactant: Brc1cccnc1
Reactant: C#Cc1cnc2c(c1)C(=O)N(C)c1cccnc1N2CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCN1c2ncc(C#Cc3cccnc3)cc2C(=O)N(C)c2cccnc21
Temperature: 85 °C
Yield: 66.2 %

Procedure:
A mixture containing 5,11-dihydro-11-ethyl-8-ethynyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.19 g, 0.68 mmol), 3-bromopyridine (0.07 mL, 0.73 mmol), tetrakis(triphenylphosphine)palladium(0), triethylamine (2 mL), and 1 crystal of BHT was heated at 85° C. in a sealed tube for 7 hours. Solvent was removed, and the residue was purified by flash chromatography, eluting with ethyl acetate/hexanes, and recrystallization from ethanol/hexanes to give 0.16 g of the title compound as yellow crystals, m.p. 178°-180° C.
Reaction SMILES: Cl.[OH:2][C@H:3]1[C@@H:7]([OH:8])[CH2:6][NH:5][CH2:4]1.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([C:19]([NH:21][CH2:22][C:23](O)=[O:24])=[O:20])=[CH:13]2>C(Cl)Cl.CN(C=O)C>[OH:2][C@H:3]1[C@@H:7]([OH:8])[CH2:6][N:5]([C:23](=[O:24])[CH2:22][NH:21][C:19]([C:14]2[NH:15][C:16]3[C:12]([CH:13]=2)=[CH:11][C:10]([Cl:9])=[CH:18][CH:17]=3)=[O:20])[CH2:4]1
Reactant: O=C(O)CNC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: O[C@@H]1CNC[C@@H]1O
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1C[C@@H](O)[C@@H](O)C1)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 1 h

Procedure:
(3R,4S)-3,4-Dihydroxypyrrolidine hydrochloride (the cis, or meso isomer, 1.79 mmol) and [(5-chloro-1H-indole-2-carbonyl)-amino]-acetic acid (0.85 mmol) were coupled according to procedure A (1:1 CH2Cl2/DMF reaction solvent) with the following workup: the reaction mixture was concentrated, the residue suspended in 10 ml EtOAc and 10 ml 2 N NaOH, the solids filtered and washed successively with aqueous 1 N NaOH, EtOAc, aqueous 1 N HCl, H2O, and ether. This washing sequence was repeated and the resulting solids were suspended in EtOAc, stirred for 1 hour, filtered and dried: Yield 252 mg, 88%; HPLC (60/40) 2.33 minutes (93%); TSPMS 338/340 (MH+, 100%);
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH3:15])[NH:12]C(=O)N[C:9]1=[O:14].[OH-].[Na+].NC(C1C=CC=CC=1F)(C)[C:20](O)=[O:21].S(Cl)(Cl)=O>CO>[CH3:20][O:21][C:9](=[O:14])[C:8]([NH2:12])([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH3:15]
Reactant: CC1(c2ccccc2F)NC(=O)NC1=O
Reactant: CC(N)(C(=O)O)c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C(C)(N)c1ccccc1F

Procedure:
The hydrolysis of the (RS)-5-(2-fluoro-phenyl)-5-methyl-imidazolidine-2,4-dione with 3 N sodium hydroxide solution and esterification of the resulting (RS)-2-amino-2-(2-fluoro-phenyl)-propionic acid with methanol and thionylchloride yielded the (RS)-2-amino-2-(2-fluoro-phenyl)-propionic acid methylester as a light yellow liquid. The purity of the product allowed using it in the next step without further purification. MS (ISP): m/z=198.2 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([CH3:15])[CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[Cl-].[C:85]([O:89][C:90](=[O:93])[CH2:91][Zn+])([CH3:88])([CH3:87])[CH3:86].[NH4+].[Cl-].[Cl-].[Na+].O>O1CCCC1.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]>[CH3:15][C:4]1[C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][N:7]=[C:2]([CH2:91][C:90]([O:89][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:93])[CH:3]=1
Reactant: Cc1cc(Br)ncc1NC(=O)C(C)(C)C
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(CC(=O)OC(C)(C)C)ncc1NC(=O)C(C)(C)C

Procedure:
N-(6-bromo-4-methylpyridin-3-yl) pivalamide (0.644 g, 2.375 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl X-Phos (0.068 g, 0.143 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.065 g, 0.071 mmol) were dissolved in tetrahydrofuran (30 ml) then added 2-(tert-butoxy)-2-oxoethylzinc chloride (14.25 ml, 7.13 mmol). The mixture was placed into three tubes and microwaved at 100° C. for 1.5 hr. The reactions were poured into NH4Cl/brine solution and extracted with ETOAc (2×), dried over Na2SO4, filtered and concentrated. The residue was chromatographed through an 80 g ISCO Redi-sep column and eluted with ethyl acetate/hexane 1:2 to yield tert-butyl 2-(4-methyl-5-pivalamidopyridin-2-yl)acetate: LC-MS: M+1=307, 251 (M-56)