Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:36]=[CH:35][C:6]([C:7]([NH:9][C@H:10]([C:18]2[NH:19][CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[N:33]=C(C)O[N:30]=4)=[CH:25][CH:24]=3)[N:22]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])=[C:5]([F:37])[CH:4]=1)#[N:2].C(C1C=CC(C(O)=[O:45])=C(F)C=1)#N>>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([C:21]2[N:22]=[C:18]([C@@H:10]([NH:9][C:7](=[O:8])[C:6]3[CH:35]=[CH:36][C:3]([C:1]([NH2:2])=[O:45])=[CH:4][C:5]=3[F:37])[CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:19][CH:20]=2)=[CH:28][CH:27]=1)(=[NH:30])[NH2:33]
Reactant: Cc1nc(-c2ccc(-c3c[nH]c([C@H](Cc4ccccc4)NC(=O)c4ccc(C#N)cc4F)n3)cc2)no1
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Product: N=C(N)c1ccc(-c2c[nH]c([C@H](Cc3ccccc3)NC(=O)c3ccc(C(N)=O)cc3F)n2)cc1
Yield: 90 %

Procedure:
Part C: 4-Cyano-2-fluoro-N-((S)-1-{4-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-1H-imidazol-2-yl}-2-phenyl-ethyl)-benzamide: The compound of Example 183 Part B was coupled to 4-cyano-2-fluorobenzoic acid using the procedure of Example 176 Part B to provide the amide in 90% yield. 1H NMR (500 MHz, CDCl3) δ ppm 2.64 (s, 3H) 3.43 (dd, J=13.75, 7.15 Hz, 1H) 3.58 (dd, J=13.75, 7.70 Hz, 1H) 5.38 (q, J=7.15 Hz, 1H) 7.20-7.33 (m, 7H) 7.42 (d, J=9.90 Hz, 1H) 7.54 (d, J=8.25 Hz, 2H) 7.86 (s, 1H) 8.05 (d, J=8.25 Hz, 2H) 8.14 (t, J=7.70 Hz, 1H) 9.43 (s, 1H). m/z 493.1 (M+H)+.
Reaction SMILES: COC1C=CC([C@@H]([NH:11][C@H:12]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:13][C:14]([O:16][CH3:17])=[O:15])C)=CC=1.C([SiH](CC)CC)C.[ClH:31]>C(O)=O.C(OCC)(=O)C.CO>[ClH:31].[ClH:31].[NH2:11][C@H:12]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)C[C@H](N[C@@H](C)c1ccc(OC)cc1)c1cccnc1
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: O=CO
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C[C@H](N)c1cccnc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 13 %

Procedure:
A mixture of methyl N-[(S)-1-(4-methoxyphenyl)ethyl)-(S)-3-amino-3-(3-pyridyl)propanoate (57.35 g, 0.148 mol) and triethylsilane (25.81 g, 0.222 mol) in formic acid (120 mL) was heated to 90° C. (oil-bath) while stirring. The initial suspension became a clear solution after 5 minutes at 90° C. Heating and stirring was continued for 2 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure at 50° C. to give a residual oil. The residual oil was dissolved in ethyl acetate (300 mL) and methanol (100 mL). The solution was filtered. The filtrate was treated slowly with 9.8 M HCl in methanol (30.2 mL, 0.296 mol) with stirring. The resulting solution was diluted with ethyl acetate (200 mL) and heated on a steam-bath to remove excess methanol until the solution became cloudy. The mixture was then stirred at room temperature overnight and the solid product crystallized from the solution. Ethyl acetate (150 mL) was added to the suspension and the mixture was stirred for another 2 h. The solid was collected by filtration and washed with 200 mL of ethyl acetate, then dried in vacu for 1 h. The desired product was obtained as a white powder (27.05 g, 72% yield).
Reaction SMILES: Cl[CH2:2][CH:3]=O.C([O:9][C:10](=[O:28])[C:11]1[C:16]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=2[Cl:25])=[C:15]([F:26])[C:14]([NH2:27])=[N:13][CH:12]=1)(C)(C)C>CCO>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:16]2[C:11]([C:10]([OH:9])=[O:28])=[CH:12][N:13]3[CH:2]=[CH:3][N:27]=[C:14]3[C:15]=2[F:26])=[C:19]([Cl:25])[CH:20]=1
Reactant: CC(C)(C)OC(=O)c1cnc(N)c(F)c1Nc1ccc(Br)cc1Cl
Reactant: O=CCCl
Solvent: CCO
Product: O=C(O)c1cn2ccnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 70 °C
Reaction time: 10 h
Yield: 73.7 %

Procedure:
Chloroacetaldehyde (23 μL, 0.360 mmol) was added to a mixture of 6-amino-4-(4-bromo-2-chlorophenylamino)-5-fluoronicotinic acid tert-butyl ester (45) (75 mg, 0.180 mmol) in EtOH (1 mL). After stirring the reaction mixture at 70° C. for 10 hours, an additional 10 μL chloro-acetaldehyde was added and heating was continued for 33 hours. The reaction mixture was cooled to room temperature and desired product (46) was collected by filtration. The filtrate was diluted with EtOAc and washed with water, saturated NaHCO3 and brine. The organic layer was dried (Na2SO4) and concentrated to give additional product (46) (51 mg, 74% combined recovery).
Reaction SMILES: C(S([N:7]1[C:11]2[CH:12]=[C:13]([C:16](=[CH:23][Cl:24])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:25])(=O)=O)(C)C.[OH-].[Na+]>CC(C)=O.O>[NH2:25][C:8]1[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[CH:23][Cl:24])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][C:11]=2[N:7]=1
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(C(=CCl)c3ccccc3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Nc1nc2cc(C(=CCl)c3ccccc3)ccc2[nH]1

Procedure:
1-Isopropylsulfonyl-2-amino-6-(α-chloromethylenebenzyl)benzimidazole is reacted with sodium hydroxide in acetone and water by the method of Example 43 to give 2-amino-6-(α-chloromethylenebenzyl)benzimidazole. The latter compound is reacted with phenylsulfonyl chloride and sodium hydroxide in dichloromethane to give 1-phenylsulfonyl-2-amino-6-(α-chloromethylenebenzyl)benzimidazole.
Reaction SMILES: C[O-].[Na+].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:19][C:18]3[C:13](=[C:14]([Cl:23])[C:15]([Cl:22])=[C:16]([O:20][CH3:21])[CH:17]=3)[C:12]2=[O:24])=[CH:7][CH:6]=1.IC.[CH:27]1C=CC=CC=1>O.CN(C)C=O>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2([CH3:27])[CH2:19][C:18]3[C:13](=[C:14]([Cl:23])[C:15]([Cl:22])=[C:16]([O:20][CH3:21])[CH:17]=3)[C:12]2=[O:24])=[CH:7][CH:6]=1
Reactant: c1ccccc1
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccc(Br)cc1)C2
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccc(Br)cc1)C2
Reaction time: 2 h

Procedure:
Sodium methoxide (28.4 g., 0.522 mole) is added to a stirred mixture of 2-(4-bromophenyl)-5-methoxy-6,7-dichloro-1-indanone (134.6 g., 0.348 mole), iodomethane (217 ml., 3.48 mole), dry benzene (1700 ml.) and dry dimethylformamide (1700 ml.) under nitrogen in an ice-water bath. The reaction mixture is left to come to ambient temperature over 2 hours, then poured into water (8 l.) to precipitate 92.2 g. of 2-(4-bromophenyl)-2-methyl-5-methoxy-6,7-dichloro-1-indanone, m.p. 200°-203° C., which is not soluble in the benzene present.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([C:11](=O)[CH2:12][O:13][CH3:14])=[C:5](OC)[CH2:6][O:7][CH3:8].[Br:17][C:18]1[CH:19]=[C:20]([NH:24][NH2:25])[CH:21]=[CH:22][CH:23]=1>>[CH3:1][O:2][C:3]([C:4]1[C:5]([CH2:6][O:7][CH3:8])=[N:25][N:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([Br:17])[CH:19]=2)[C:11]=1[CH2:12][O:13][CH3:14])=[O:16]
Reactant: NNc1cccc(Br)c1
Reactant: COCC(=O)C(C(=O)OC)=C(COC)OC
Product: COCc1nn(-c2cccc(Br)c2)c(COC)c1C(=O)OC

Procedure:
In analogy to the procedures described for intermediates 1A-E, the title compound has been obtained by i) condensation of methyl 4-methoxyacetoacetate with methoxyacetyl chloride to give 4-methoxy-2-(2-methoxy-acetyl)-3-oxo-butyric acid methyl ester; ii) methylation of 4-methoxy-2-(2-methoxy-acetyl)-3-oxo-butyric acid methyl ester with methyl trifluoromethanesulfonate to give (E and/or Z)-3,4-dimethoxy-2-(2-methoxy-acetyl)-but-2-enoic acid methyl ester; iii) condensation of (E and/or Z)-3,4-dimethoxy-2-(2-methoxy-acetyl)-but-2-enoic acid methyl ester with (3-bromo-phenyl)-hydrazine to give 1-(3-bromo-phenyl)-3,5-bis-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester; iv) reaction of 1-(3-bromo-phenyl)-3,5-bis-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester with (E)-2-(4-chlorophenyl)vinyl boronic acid to give 1-{3-[(E)-2-(4-chloro-phenyl)-vinyl]-phenyl}-3,5-bis-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester; v) saponification of 1-{3-[(E)-2-(4-chloro-phenyl)-vinyl]-phenyl}-3,5-bis-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester to give the title compound as light brown solid. MS: 411.2 ([M−H]−, 1 Cl).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]([Cl:20])([Cl:19])[C:8]([N:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)=[O:9]>>[Cl:20][C:7]([Cl:6])([Cl:19])[C:8]([N:10]1[CH2:11][C:12]2[C:17](=[CH:16][CH:15]=[C:14]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:13]=2)[CH2:18]1)=[O:9]
Reactant: O=C(N1Cc2ccccc2C1)C(Cl)(Cl)Cl
Reactant: O=S(=O)(O)Cl
Product: O=C(N1Cc2ccc(S(=O)(=O)Cl)cc2C1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
Chlorosulfonic acid (5.22 mL, 78.5 mmol) was cooled to −78° C. and 2,2,2-trichloro-1-(1,3-dihydro-2 H-isoindol-2-yl)ethanone (1.32 g, 5.00 mmol) was added thereto. The reaction mixture was warmed to room temperature and stirred for 30 min. The reaction mixture was poured into ice water and the mixture was extracted three times with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was powdered with hexane and collected by filtration to afford 2-(trichloroacetyl)-2,3-dihydro-1 H-isoindole-5-sulfonyl chloride as a pale green powder (1.38 g).
Reaction SMILES: C1([CH:7]([O:14][C:15]([C@@H:17]2[N:21]3[C:22](=[O:35])[C@@H:23]([NH:24][C:25](=[O:34])[CH2:26][O:27]C4C=CC=CC=4)[C@H:20]3[S@@:19](=O)[C:18]2([CH3:38])[CH3:37])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)C=CC=CC=1.[C:39](Br)(=O)[CH3:40]>N1C=CC=CC=1>[C:8]1([CH:7]([O:14][C:15]([C:17]2[N:21]3[C:22](=[O:35])[C@@H:23]([NH:24][C:25](=[O:34])[CH2:26][O:27][C:40]4[CH:39]=[CH:37][CH:18]=[CH:17][CH:15]=4)[C@H:20]3[S:19][CH2:37][C:18]=2[CH3:38])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)Br
Reactant: CC1(C)[C@H](C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2[S@]1=O
Solvent: c1ccncc1
Product: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Temperature: 25 °C

Procedure:
(1S,3S,5R,6R) 2,2-Dimethyl-6-phenoxyacetamidopenam-3-carboxylic acid-1-oxide diphenylmethyl ester (55.06 gms, 100.00 mmoles) was dissolved in sieve-dried, peroxide-free dioxane (550 mls) at 25° C. with good agitation. To this solution, in order, were added pyridine (24.21 mls, 23.73 gms, 300.00 mmmoles), acetyl bromide (1.48 mls, 2.46 gms, 20.00 mmoles) and methylsilyl triisocyanate (89% pure, 21.30 mls, 25.34 gms, 133.33 mmoles). The slurry was heated to reflux (ca 100° C.) for 4 hours. The reaction mixture was then cooled to 25° C. and filtered, with the clear yellow filtrate being concentrated in vacuo at 50° C. to a highly viscous oil. The oil was dissolved in hot 2-propanol (~80° C., 3000 mls), filtered, and allowed to cool to 25° C. The slurry was cooled to 0°-5° C. for 2 hours, filtered, and washed with 2-propanol (0°-5° C., 400 mls), and oven-dried at 45° C. to constant weight. Yield: 38.6 gms, 75% of white crystalline title compound. The 80 MHz H' NMR spectrum was clean and consistent for the desired structure.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13](Cl)[CH:12]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O-])(=[O:20])C.[NH4+]>C(O)=O.O>[Cl:1][C:2]1[C:3]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:20])[CH:12]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(=O)[O-]
Reactant: Clc1cnc(COc2ccnc(Cl)c2)c(Cl)c1
Agent: [NH4+]
Solvent: O
Solvent: O=CO
Product: O=c1cc(OCc2ncc(Cl)cc2Cl)cc[nH]1
Yield: 83.3 %

Procedure:
3,5-Dichloro-2-((2-chloropyridin-4-yloxy)methyl)pyridine (1.15 g, 4.03 mmol) and ammonium acetate (1.55 g, 20.0 mmol) were heated to 110° C. in a mixture of formic acid (20 mL) and water (20 mL) for 5 days. The mixture was concentrated to remove most of the liquid and then adjusted to pH 8 with NaHCO3 solution. The solid was filtered off to provide the title compound (910 mg, 82%) as a tan solid: 1H NMR (300 MHz, DMSO-d6) δ 11.1 (br s, 1H), 8.66 (d, J=2.1 Hz, 1H), 8.34 (d, J=2.1 Hz, 1H), 7.25 (d, J=7.3 Hz, 1H), 5.90-5.87 (dd, J=7.3, 2.8 Hz, 1H), 5.82 (d, J=2.6 Hz, 1H), 5.20 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[C:19]1([C:25]#[CH:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:19]1([C:25]#[C:26][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccccc1Br
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1ccccc1C#Cc1ccccc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To a solution of methyl 2-bromobenzoate 34 (166 μL, 1.163 mmol) in acetonitrile (2906 μL) was added triethylamine (972 μL, 6.98 mmol) and phenylacetylene 35 (140 μl, 1.279 mmol). Then copper (I) iodide (11.07 mg, 0.058 mmol), and bis(triphenylphosphine)-palladium(II) chloride (20.40 mg, 0.029 mmol), were successively added, degassing between and after each addition of catalysts. The mixture was stirred at 75° C. overnight. The reaction mixture was partitioned between EtOAc and 1M HCl. The aqueous layer was extracted with fresh EtOAc and the combined organic layers were washed with water, brine, dried over MgSO4. The residue was purified via Biotage using EtOAc/Hex ((0:100 to 10:90); 25+S column), to afford compound 36 (157 mg, 57%). LRMS (ESI): (calc.) 236.08 (found) 237.2 (MH)+
Reaction SMILES: C([O:4][CH2:5][C:6](=[O:28])[C@:7]1([OH:27])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C:21](=[CH:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)(=O)C.CO>C(Cl)Cl>[OH:27][C@:7]1([C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C:21](=[CH:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)[C:6](=[O:28])[CH2:5][OH:4]
Reactant: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Solvent: CO
Solvent: ClCCl
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Temperature: 0 °C
Yield: 89.8 %

Procedure:
At room temperature, 1.5 g of 21-acetoxy-17-hydroxy-4,9(11)-pregnadiene-3,20-dione in 40 ml is agitated for 2 hours at room temperature with 15 ml of methanol 0.2N methanolic potassium hydroxide solution. The reaction mixture is introduced into ice water. The precipitated product is suctioned off, dissolved in methylene chloride, washed with water, and dried over sodium sulfate, thus obtaining 1.2 g of 17,21-dihydroxy-4,9(11) pregnadiene3,20-dione; mp 248.2° C.
Reaction SMILES: N[C@@H]([CH2:7][C:8]1[CH:13]=CC(OCCCC)=C[CH:9]=1)C(NC)=O.N[C@@H](CC1C=CC(OCCCC)=CC=1)C(OC)=O.[CH2:37]([O:41][C:42]1[CH:47]=[CH:46][C:45]([CH2:48][C@H:49]([NH:54][C:55]([C@@H:57](/[CH:67]=[CH:68]/[CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][C:75]([F:84])([F:83])[CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH3:82])[C@@:58]([OH:66])([CH2:62][CH2:63][O:64][CH3:65])[C:59]([OH:61])=[O:60])=[O:56])[C:50](=[O:53])[NH:51][CH3:52])=[CH:44][CH:43]=1)[CH2:38][CH2:39][CH3:40]>>[CH2:37]([O:41][C:42]1[CH:43]=[CH:44][C:45]([CH2:48][C@H:49]([NH:54][C:55]([C@@H:57](/[CH:67]=[CH:68]/[CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][C:75]([F:83])([F:84])[CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH3:82])[C@@:58]([OH:66])([CH2:62][CH2:63][O:64][CH3:65])[C:59]([O:61][C:8]([CH3:13])([CH3:9])[CH3:7])=[O:60])=[O:56])[C:50](=[O:53])[NH:51][CH3:52])=[CH:46][CH:47]=1)[CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCC(F)(F)CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(OCCCC)cc1)C(=O)NC)[C@@](O)(CCOC)C(=O)O
Reactant: CCCCOc1ccc(C[C@H](N)C(=O)NC)cc1
Agent: CCCCOc1ccc(C[C@H](N)C(=O)OC)cc1
Product: CCCCCCCC(F)(F)CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc1ccc(OCCCC)cc1)C(=O)NC)[C@@](O)(CCOC)C(=O)OC(C)(C)C

Procedure:
tert-Butyl (E)-(2S,3S)-3-[(S)-2-(4-butoxy-phenyl)-1-methylcarbamoyl-ethylcarbamoyl]-12,12-difluoro-2-hydroxy-2-(2-methoxy-ethyl)-nonadec-4-enoate (PSI (LC/MS positive mode) ink 739 (M+H); Rt 2.72 min.) was synthesized using (S)-2-amino-3-(4-butoxy-phenyl)-N-methyl-propionamide and the conditions at 50° C. for 2.5 days instead of methyl (S)-2-amino-3-(4-butoxy-phenyl)-propionate and the conditions in Step B-7′. (E)-(2S,3S)-3-[(S)-2-(4-Butoxy-phenyl)-1-methylcarbamoyl-ethylcarbamoyl]-12,12-difluoro-2-hydroxy-2-(2-methoxy-ethyl)-nonadec-4-enoic acid (No. 5514404) was synthesized under conditions similar to those in the following Step B-8′.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Cl)=[CH:33][CH:32]=1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][C:13]1[CH:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=1)[CH2:37][C:34]1[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCNCc1ccc(Cl)nc1
Reactant: COc1ccc(CCl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CN(CCNC(=O)OC(C)(C)C)Cc2ccc(Cl)nc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.8 %

Procedure:
A stirred solution of 1.5 grams (0.0052 mole) of (tert-butoxy)-N-(2-{[(6-chloro(3-pyridyl))methyl]amino}ethyl)carboxamide and 2.3 mL (0.013 mole) of diisopropylethyl amine in about 15 mL of methylene chloride was cooled to 0° C., and 0.7 mL (0.0052 mole) of (4-methoxyphenyl)methyl chloride in about 3 mL of methylene chloride was added dropwise. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature, where it stirred during an 18 hour period. After this time, analysis of the reaction mixture by thin layer chromatography (TLC) indicated that no reaction had taken place. The reaction mixture was then heated at reflux for two hours, after which TLC analysis indicated that no reaction had taken place. The methylene chloride solvent was removed under reduced pressure from the reaction mixture, which was replaced with chloroform. The reaction mixture was heated at reflux during one hour, and then it was allowed to cool to ambient temperature, where it stirred during an 18 hour period. After this time TLC analysis indicated the presence of some reaction product. The reaction mixture was then heated at reflux for about a nine hour period and then it was allowed to cool to ambient temperature as it stirred during an additional 18 hour period. After this time the chloroform solvent was removed under reduced pressure from the reaction mixture, which was replaced with acetonitrile. The reaction mixture was then stirred at ambient temperature during a four hour period, warmed to 60° C. where it stirred for a ten hour period, and finally stirred at ambient temperature during a 60 hour period. The reaction mixture was concentrated under reduced pressure to a residue, and the residue was purified with column chromatography on silica gel. Elution was accomplished using 30% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under reduced pressure, yielding 1.6 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[N:6]=[CH:7][C:2]([N:26]5[CH2:30][CH2:29][CH2:28][C:27]5=[O:31])=[N:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2cnc(Br)cn2)CC1
Reactant: O=C1CCCN1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2cnc(N3CCCC3=O)cn2)CC1
Yield: 2 %

Procedure:
Using (5-bromopyrazin-2-yl) [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (100 mg) described in Preparation Example 243 and pyrrolidin-2-one (25 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (2 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.[CH3:12][C@H:13]1[CH2:18][NH:17][CH2:16][C@@H:15]([CH3:19])[NH:14]1.C(N(CC)CC)C>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:17]1[CH2:16][C@H:15]([CH3:19])[NH:14][C@H:13]([CH3:12])[CH2:18]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2Cl)C[C@H](C)N1

Procedure:
1.0 g (5.21 mmol) of 3,4-dichloronitrobenzene (Fluke, Buchs, Switzerland), 624 mg (5.47 mmol) cis-2,6-dimethylpiperazine (Aldrich, Buchs, Switzerland) and 580 mg (5.73 mmol) triethylamine in 20 ml of EtOH are heated in a microwave oven at 170° C. for 6 h and 180° C. for 2 h. The reaction mixture is evaporated to dryness and then taken in EtOAc. The organic layers is extracted with 1 M aqueous HCl (5×) and the combined aqueous layers are basified with NaHCO3 and extracted with CH2Cl2 (3×), washed with brine, dried over MgSO4, filtered and evaporated to dryness to give the title compound as a yellow solid. ES-MS: 270 (M+H)+; analytical HPLC: tret=2.72 minutes (Grad 1).
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([NH:15][C:16]3[C:21]([Cl:22])=[CH:20][C:19]([I:23])=[CH:18][C:17]=3[Cl:24])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12](Cl)[N:11]=[CH:10][CH:9]=3.[CH3:27][O-:28].[Na+]>CO.O>[Br:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([NH:15][C:16]3[C:21]([Cl:22])=[CH:20][C:19]([I:23])=[CH:18][C:17]=3[Cl:24])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([O:28][CH3:27])[N:11]=[CH:10][CH:9]=3
Reactant: C[O-]
Reactant: Clc1cc(I)cc(Cl)c1Nc1nc2ccc(Br)cc2c2c(Cl)nccc12
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nccc2c(Nc3c(Cl)cc(I)cc3Cl)nc3ccc(Br)cc3c12
Temperature: 25 °C

Procedure:
To a solution of 9-bromo-1-chloro-N-(2,6-dichloro-4-iodophenyl)benzo[c]-2,6-naphthyridin-5-amine (1.56 g, 2.69 mmol) in methanol (30 mL) was added sodium methoxide (10 mL, 25% in methanol) and heated the reaction to 100° C. for 45min. The reaction was cooled to room temperature and a few drops of water were added to quench the reaction. The organic layer was evaporated under vacuum and the residue was diluted with ethyl acetate and extracted with water. The organic layer was separated, dried with sodium sulfate, filtered and evaporated. The residue was taken to the next step without purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:23])[CH2:21][Br:22])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1.[O:41]1[CH:46]=[CH:45][CH2:44][CH2:43][CH2:42]1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:23][CH:42]2[CH2:43][CH2:44][CH2:45][CH2:46][O:41]2)[CH2:21][Br:22])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=COCCC1
Reactant: O=c1ccc2c([C@@H](O)CBr)ccc(OCc3ccccc3)c2[nH]1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=c1ccc2c([C@H](CBr)OC3CCCCO3)ccc(OCc3ccccc3)c2[nH]1
Temperature: 22 °C
Reaction time: 18 h

Procedure:
A suspension of 8-(benzyloxy)-5-[(1R)-2-bromo-1-hydroxyethyl]quinolin-2(1H)-one (100 mg) and pyridinium tosylate (14 mg) in dry DCM (2 ml) was treated with 2,3-dihydropyran (61.2 μl) and stirred at 22° C. for 18 h. The reaction mixture was concentrated in vacuo and purified by chromatography (Hexane-EtOAc 2:1, biotage) to give the title compound (77 mg). Rf [EtOAc-Hexane (1:1)] 0.54