Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:14][NH2:15]>C(O)C>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:6]=2)[NH:15][N:14]=1
Reactant: N#Cc1cc(C(F)(F)F)ccc1Br
Reactant: NN
Solvent: CCO
Product: Nc1n[nH]c2ccc(C(F)(F)F)cc12
Temperature: 95 °C

Procedure:
A solution of 8.0 g. of 2-bromo-5-trifluoromethylbenzonitrile, 3 ml. of 95% hydrazine and 40 ml. of ethanol is kept at 45°-50° C. for 30 hours. The solution is evaporated to dryness. The residue is treated with 100 ml. of 2 N hydrochloric acid, then stirred and heated to 95° C. On cooling the aqueous layer is decanted off and treated with sodium acetate to near neutrality. The precipitate is isolated by filtration and recrystallized from benzene to yield 3-amino-5-trifluoromethylindazole, M.P. 122°-123° C.
Reaction SMILES: O(Cl)Cl.[P+5].[Br:5][C:6]1[N:7]=[C:8]([NH:15][CH:16]2[CH2:18][CH2:17]2)[C:9]2[N:10]([CH:12]=[CH:13][N:14]=2)[CH:11]=1.Cl.[OH-].[Na+].CN([CH:25]=[O:26])C>>[Br:5][C:6]1[N:7]=[C:8]([NH:15][CH:16]2[CH2:18][CH2:17]2)[C:9]2[N:10]([C:12]([CH:25]=[O:26])=[CH:13][N:14]=2)[CH:11]=1
Reactant: CN(C)C=O
Reactant: Brc1cn2ccnc2c(NC2CC2)n1
Agent: Cl
Agent: ClOCl
Agent: [Na+]
Product: O=Cc1cnc2c(NC3CC3)nc(Br)cn12
Temperature: 0 °C
Yield: 49 %

Procedure:
Phosphorus(V) oxychloride (3.9 mL, 42.68 mmol) was added dropwise to anhydrous DMF (16 mL) at 0° C. 6-bromo-N-cyclopropylimidazo[1,2-a]pyrazin-8-amine (900 mg, 3.56 mmol) was dissolved in anhydrous DMF (24 mL) and added over two minutes. The solution was place in an 85° C. oil bath for 5 h. The solution was cooled to 0° C. and conc. HCl (30 mL) was added. The mixture was basified to pH=10 w/3N NaOH (˜175 mL). The mixture was extracted with dichloromethane (3×250 mL), and the organics were washed with brine (500 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified via flash column chromatography (30% EtOAc/hexanes) to furnish 6-bromo-8-(cyclopropylamino)imidazo[1,2-a]pyrazine-3-carbaldehyde (490 mg, 49%). LCMS (ES): >95% pure, m/z 282 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH:11]([CH3:16])[C:12]([O:14]C)=[O:13].[OH-].[Na+].[CH3:19]O>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:11]([CH3:16])([CH3:19])[C:12]([OH:14])=[O:13]
Reactant: COC(=O)C(C)n1ccc2c(F)cccc21
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C(=O)O)n1ccc2c(F)cccc21
Temperature: 75 °C
Yield: 84 %

Procedure:
A mixture of 1-Methyl 2-(4-fluoro-1H-indol-1-yl)propanoate (21.3 g, 91 mmol), 1 N aq. NaOH (150 mL), and methanol (150 mL) was heated to 75° C. overnight. The volatiles were removed by evaporation under reduced pressure at 50° C. and ethyl acetate (250 mL) and water (200 mL) were added to the residue. The layers were separated and the aqueous layer was acidified with concentrated HCl to pH<1. The acidified layer was extracted with ethyl acetate (1×200 mL, 1×50 mL) and the combined extracts were washed with brine (100 mL), dried over sodium sulfate, filtered, and evaporated to dryness under reduced pressure at 50° C. to obtain the desired acid as a yellow oil (16.8 g, 76 mmol, 84% yield). 1H-NMR (300 MHz, CDCl3): δ 7.12-6.99 (m, 2H), 6.83-6.77 (m, 2H), 6.63-6.62 (m 1H), 1.92 (s, 6H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:20]([OH:21])[CH2:19][N:18]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:17]2=[O:29])=[N:13][C:12]=1[CH3:30])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>C(Cl)(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[C:20](=[O:21])[CH2:19][N:18]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[C:17]2=[O:29])=[N:13][C:12]=1[CH3:30])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N2C(=O)N(c3ccc(F)cc3)CC2O)sc1C(=O)NCc1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClC(Cl)Cl
Product: Cc1nc(N2C(=O)CN(c3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
To a solution of 2-[3-(4-fluorophenyl)-5-hydroxy-2-oxo-imidazolidin-1-yl]-4-methylthiazole-5-carboxylic acid benzylamide (0.07 g, 0.17 mmol) and tetrapropylammonium perruthenate (0.003 g, 0.008 mmol) in chloroform (15 mL) was added 4-methylmorpholine N-oxide (0.03 g, 0.22 mmol) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 1 hour, and filtered through a bed of celite. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography to afford the title compound in 18% yield (0.14 g): mp 217-219° C.; 1H NMR (300 MHz, CDCl3) δ 7.54-7.07 (m, 9H), 6.12 (t, J=5.1 Hz, 1H), 4.55 (d, J=5.1 Hz, 2H), 4.47 (s, 2H), 2.70 (s, 3H); MS (ES+) m/z 425.3 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1)[C:12](=[O:25])[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=1.[OH-].[Na+]>CO>[CH3:24][O:23][C:15]1[CH:14]=[C:13]([CH:18]=[C:17]([O:19][CH3:20])[C:16]=1[O:21][CH3:22])[C:12]([N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:36])=[O:2])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=1)=[O:25]
Reactant: COC(=O)CCCCCCCN(C(=O)c1cc(OC)c(OC)c(OC)c1)c1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)N(CCCCCCCC(=O)O)c2cccc(C(F)(F)F)c2)cc(OC)c1OC

Procedure:
As described in example 1(b), the reaction is carried out with 8.6 g (16.8 mmol) of 8-{3.4.5-trimethoxy-N-[3-(trifluoromethyl)-phenyl]-benzamido}-caprylic acid methyl ester, 0.96 g (24 mmol) of sodium hydroxide and 100 cc. of methanol. Reaction time: 24 hours, reaction temperature: 25° C. The crude product is further purified chromatographically on silicic acid gel using chloroform as eluant.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]([OH:29])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]=2O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:16]=3[O:29]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(O)Cc2cccc(Cc3ccccc3)c2O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Cc4ccccc4)c3O2)cc1
Yield: 92.5 %

Procedure:
Treatment of (±)-3-(3-benzyl-2-hydroxyphenyl)-2-hydroxypropyl 4-methylbenzenesulfonate (7.29 g, 0.018 mol) with triphenylphosphine (5.10 g, 0.019 mol) and diethylazodicarboxylate (3.39 g, 0.019 mol) generally according to the procedure described for Intermediate 5 afforded 6.57 g (94%) of (±)-(7-benzyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Anal. calcd. for C23H22O4S: C, 70.03; H, 5.62. Found: C, 68.97; H, 5.42.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C@@H:10]([NH:30][C:31](OC(C)(C)C)=[O:32])[C:11]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[N:39]1([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:41][C@H:40]1C(O)=O.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CCOC(C)=O.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C@@H:10]([NH:30][C:31]([C@@H:40]2[CH2:41][C:42]3[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:48][N:39]2[C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])=[O:32])[C:11]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][S:26]([CH3:29])(=[O:27])=[O:28])[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)c(Cl)c1)C(=O)N1CCC(c2ccccc2NS(C)(=O)=O)CC1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)c(Cl)c1)C(=O)N1CCC(c2ccccc2NS(C)(=O)=O)CC1
Temperature: 25 °C

Procedure:
To a round-bottomed flask equipped with stirring was added N-[(1R)-1-[(3,4-dichlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl}-piperidyl)-2-oxoethyl]-(tert-butoxy)carboxamide (Step a) (0.455 g, 0.8 mmol) and a saturated soln of anhydrous HCl in EtOAc (20 mL). The reaction mixture was stirred at RT for 1 h then concentrated in vacuo to provide a solid. The solid was dissolved in DMF (10 mL), stirred at 0° C. and treated with Boc-L-TicOH (Advanced ChemTech) (0.25 g, 0.9 mmol), HOAT (Aldrich) (0.122 g, 0.9 mmol), TEA (Aldrich) (0.188 mL, 1.35 mmol) then EDC (Advanced ChemTech) (0.26 g, 1.35 mmol). The reaction mixture was warmed to RT over 2 h, then stirred at RT for 12 h. The reaction mixture was diluted with EtOAc (70 mL), washed with satd NaHCO3, (50 mL), satd NaCl (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (1:1 EtOAc:hexane then 100% EtOAc) provided the title compound as a white foam (0.54 g). MS (ESI, pos. ion) m/z: 729 (M+1); MS (ESI, neg. ion) m/z: 727 (M−1). Calc'd for C36H42Cl2N4O6S: 728.22.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[C:20]([F:21])=[C:19]([F:22])[CH:18]=[CH:17][C:9]=1[NH:10][C@H:11]([CH3:16])[C:12]([O:14]C)=[O:13].[OH-].[Na+].Cl>CC(N(C)C)=O>[F:7][C:8]1[C:20]([F:21])=[C:19]([F:22])[CH:18]=[CH:17][C:9]=1[NH:10][CH:11]([CH3:16])[C:12]([OH:14])=[O:13]
Reactant: COC(=O)[C@@H](C)Nc1ccc(F)c(F)c1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(Nc1ccc(F)c(F)c1F)C(=O)O
Reaction time: 1 h
Yield: 98.3 %

Procedure:
Potassium tertiary-butoxide (123.4 mg) was suspended in DMAc (2 ml). Under ice-cooling, a solution of methyl (2R)-2-(2,3,4-trifluoroanilino)propionate (223 mg, 91% ee) in DMAc (2 ml) was added thereto. The liquid reaction mixture was stirred at the same temperature for 1 hour. Then an aqueous solution of sodium hydroxide (3 mol/l; 2 ml) was added and the mixture was stirred for 1 hour. The liquid reaction mixture was adjusted to pH 2 with an aqueous solution of hydrochloric acid (3 mol/l) and then extracted with IPE. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The crude product thus obtained was recrystallized from a solvent mixture of methylene chloride with normal hexane to thereby give the title compound (206 mg) as colorless crystals. The optical purity of this product was 0% ee. Various spectral data of this product was identical with those obtained in Example 23.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH3:21])=[N:19][N:18]=[C:17]1[CH2:22]O.P(Br)(Br)[Br:26]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH3:21])=[N:19][N:18]=[C:17]1[CH2:22][Br:26]
Reactant: Cc1nnc(CO)n1-c1ccc(Cl)cc1C(=O)c1ccccc1F
Reactant: BrP(Br)Br
Solvent: ClC(Cl)Cl
Product: Cc1nnc(CBr)n1-c1ccc(Cl)cc1C(=O)c1ccccc1F

Procedure:
In the manner given in Example 5, 2'-fluoro-5-chloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-benzophenone is treated with phosphorus tribromide in chloroform to give 2'-fluoro-5-chloro-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: P([O-])([O-])([O-])=O.[CH3:6][N:7]1[C:12]2[S:13][CH:14]=[C:15]([CH2:16][C:17]([NH:19][C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[C:27]([F:35])[CH:26]=4)[N:24]=3)=[O:18])[C:11]=2[C:10](=[O:36])[N:9]([CH3:37])[C:8]1=[O:38].[P:39]([O:51][CH2:52]I)([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].[H-].[Na+]>CN(C=O)C>[P:39]([O:51][CH2:52][N:24]1[C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:34])[F:33])=[C:27]([F:35])[CH:26]=2)=[CH:22][S:21][C:20]1=[N:19][C:17](=[O:18])[CH2:16][C:15]1[C:11]2[C:10](=[O:36])[N:9]([CH3:37])[C:8](=[O:38])[N:7]([CH3:6])[C:12]=2[S:13][CH:14]=1)([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:40]
Reactant: CC(C)(C)OP(=O)(OCI)OC(C)(C)C
Reactant: Cn1c(=O)c2c(CC(=O)Nc3nc(-c4ccc(C(F)(F)F)c(F)c4)cs3)csc2n(C)c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(CC(=O)N=c3scc(-c4ccc(C(F)(F)F)c(F)c4)n3COP(=O)(OC(C)(C)C)OC(C)(C)C)csc2n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure as described in method A for the preparation of phosphate derivatives by coupling reaction of 2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)-N-{4-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}acetamide (500 mg, 1.004 mmol) with freshly prepared di-tert-butyl iodomethyl phosphate (Intermediate 2) (1.22 g, 3.514 mmol) in the presence of sodium hydride (60% dispersion in mineral oil, 60.24 mg, 1.506 mmol) in dry DMF (5 ml) to yield 150 mg of pure product as an off-white solid. 1H NMR (300 MHz, CDCl3): δ 1.49 (s, 18H), 3.34 (s, 3H), 3.57 (s, 3H), 4.43 (s, 2H), 6.36-6.44 (m, 2H), 6.79 (s, 1H), 7.33 (s, 1H), 7.61 (t, J=7.5 Hz, 1H), 7.71-7.81 (m, 2H); ESI (m/z): 721 (M+H)+.
Reaction SMILES: NC(CCCCCCCCC(N)CCC)CCC.C(C1CC=CCCC=CCC(CCC)N=N1)CC.[CH3:37][CH2:38][CH:39]([CH:44]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH:47]([CH:56]([CH2:59][CH2:60][CH2:61][CH3:62])[CH2:57][CH3:58])[NH:46][NH:45]1)[CH2:40][CH2:41][CH2:42][CH3:43]>>[NH2:45][CH:44]([CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH:47]([NH2:46])[CH:56]([CH2:57][CH3:58])[CH2:59][CH2:60][CH2:61][CH3:62])[CH:39]([CH2:38][CH3:37])[CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCC(CC)C1CCCCCCCCC(C(CC)CCCC)NN1
Agent: CCCC(N)CCCCCCCCC(N)CCC
Agent: CCCC1CC=CCCC=CCC(CCC)N=N1
Product: CCCCC(CC)C(N)CCCCCCCCC(N)C(CC)CCCC

Procedure:
If there are used in the manner described under (a), instead of 942 g (3.79 mols) of 3,12-dipropyl-1,2-diaza-1,5,9-cyclododecatriene, 74.8 g (0.2 mol) of 3,12-di-(3-heptyl)-1,2-diazacyclododecane (diastereoisomeric mixture) and correspondingly reduced amounts of catalyst and solvent, using otherwise the same procedure, there is obtained, after chromatographic purification and distillation, 29.9 g (40% of theory) of 6,15-diamino-5,16-diethyleicosane as colourless oil [b.p. 170° C./0.01 Torr; nD20 =1.4662; IR (liquid) inter alia bands at 3278 and 1613 cm-1 ].
Reaction SMILES: [ClH:1].FC1C=C(NC(NC(=O)CC2C=CC=CC=2)=S)C=CC=1OC1C=CN=C2C=C(C(N3CCCCC3)=O)SC=12.FC1C=C(NC(NC(=O)CC2C=CC=CC=2)=S)C=CC=1OC1C=CN=C2C=C(C(N3CCCCC3)=O)SC=12.C([O:82][C:83]([C@@H:85]1[CH2:89][CH2:88][CH2:87][N:86]1[C:90]([C:92]1[S:100][C:99]2[C:94](=[N:95][CH:96]=[CH:97][C:98]=2[O:101][C:102]2[CH:107]=[CH:106][C:105]([NH:108][C:109]([NH:111][C:112](=[O:120])[CH2:113][C:114]3[CH:119]=[CH:118][CH:117]=[CH:116][CH:115]=3)=[S:110])=[CH:104][C:103]=2[F:121])[CH:93]=1)=[O:91])=[O:84])(C)(C)C>>[ClH:1].[F:121][C:103]1[CH:104]=[C:105]([NH:108][C:109]([NH:111][C:112](=[O:120])[CH2:113][C:114]2[CH:115]=[CH:116][CH:117]=[CH:118][CH:119]=2)=[S:110])[CH:106]=[CH:107][C:102]=1[O:101][C:98]1[CH:97]=[CH:96][N:95]=[C:94]2[CH:93]=[C:92]([C:90]([N:86]3[CH2:87][CH2:88][CH2:89][C@H:85]3[C:83]([OH:84])=[O:82])=[O:91])[S:100][C:99]=12
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)c1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Agent: Cl
Agent: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(C(=O)N4CCCCC4)sc23)c(F)c1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(C(=O)N4CCC[C@H]4C(=O)O)sc23)c(F)c1

Procedure:
Following the procedure described above for the synthesis of compound 136a (Example 93) but substituting compound 135d (example 92, table 11) for the compound 135a (Example 89, Table 11), title compound 136c was obtained. Characterization of this material is provided in Table 12.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][O:7][C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K]>CN(C=O)C>[C:17]1(=[O:27])[N:21]([CH2:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[C:11]2[C:5]([C:6]([OH:7])=[O:16])=[CH:4][CH:3]=[CH:2][CH:1]=2)[C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C1OCc2ccccc2-c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1-c1ccccc1CN1C(=O)c2ccccc2C1=O
Temperature: 170 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
A mixture of 35 g (0.17 mol) of 7H-dibenzo[c,e]oxepin-5-one and 30.8 g (0.17 mol) of potassium phthalimide in 330 ml of DMF was heated at 170° C. for 18 h. After cooling, the deposited precipitate was filtered off with suction and introduced into 160 ml of glacial acetic acid. After stirring for 1 h, the mixture was diluted with 650 ml of ice water and the deposited product was filtered off with suction and dried in vacuo. 44.8 g of 2′-phthalimidomethylbiphenyl-2-carboxylic acid were obtained; m.p. 198° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[Cl:21][C:22]1[N:27]=[C:26]([Cl:28])[CH:25]=[CH:24][N:23]=1.[CH:29](=[O:33])[CH:30]([CH3:32])[CH3:31]>O1CCCC1>[Cl:21][C:22]1[N:27]=[C:26]([Cl:28])[C:25]([CH:29]([OH:33])[CH:30]([CH3:32])[CH3:31])=[CH:24][N:23]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)C(O)c1cnc(Cl)nc1Cl
Reaction time: 0.67 h

Procedure:
A solution of diisopropylamine (1.1 mL; 7.85 mmol) (Aldrich) and freshly distilled tetrahydrofuran (15 mL) was cooled to −78° C. n-Butyllithium (2.5M in hexanes; 3.1 mL; 7.75 mmol) (Aldrich) was added dropwise and stirring continued for 40 minutes to prepare a LDA solution. 2,4-Dichloropyrimidine (0.50 g; 3.37 mmol) (Aldrich) in tetrahydrofuran (3 mL) was then added dropwise to this freshly prepared LDA solution over 15 minutes. After stirring for 40 minutes, isobutyraldehyde (0.61 mL; 6.72 mmol) (Aldrich) was added over 6 minutes and stirring continued for another 30 minutes. The reaction was quenched with the addition of 25% aqueous ammonium chloride solution (20 mL) and then diluted with ethyl acetate and water. The organic phase was washed with a second portion of aqueous ammonium chloride solution and then brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (Biotage 40S; 10:90 to 15:85 ethyl acetate-hexanes gradient) to give (±)-1-(2,4-dichloro-pyrimidin-5-yl)-2-methyl-propan-1-ol. (Yield 0.25 g; 33.4%).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[N:13]1([CH2:19][CH2:20][NH2:21])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[NH2:22][C:23]1[C:24]([C:30](O)=[O:31])=[N:25][C:26]([Br:29])=[CH:27][N:28]=1.O.ON1C2C=CC=CC=2N=N1>C(#N)C>[NH2:22][C:23]1[C:24]([C:30]([NH:21][CH2:20][CH2:19][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:31])=[N:25][C:26]([Br:29])=[CH:27][N:28]=1
Reactant: NCCN1CCOCC1
Reactant: Nc1ncc(Br)nc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: Nc1ncc(Br)nc1C(=O)NCCN1CCOCC1
Reaction time: 7 h
Yield: 68.6 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.68 g, 3.5 mmol) was added in one portion to a stirred suspension of 2-morpholin-4-ylethanamine (0.422 g, 3.2 mmol), 3-amino-6-bromopyrazine-2-carboxylic acid (0.64 g, 3.0 mmol; described in: Ellingson, R. C.; Henry, R. L. J. Am. Chem. Soc. 1949, 2798-2800), and 1-hydroxybenzotriazole hydrate (0.48 g, 3.5 mmol) in acetonitrile (25 mL) at 0° C. The cooling bath was removed and stirring was continued at room temperature for 7 h. The solid was filtered off, washed with acetonitrile and purified by column chromatography on silica using methylene chloride/methanol/triethyl amine, (95:5:0.1), to give 0.68 g (69% yield) of the title compound: 1H NMR (DMSO-d6, 400 MHz) δ 8.53 (m, 1H), 8.34 (s, 1H), 8.68 (br s, 2H), 3.57 (t, J=5 Hz, 4H), 3.37 (q, J=7 Hz, 2H), 2.47 (q, J=7 Hz, 2H), 2.40 (m, 4H); MS (ES) m/z 330 and 332 (M++1).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH2:5])=[O:4].C(N(CC)CC)C.[C:16]1([CH2:22][S:23](Cl)(=[O:25])=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl.O>[C:16]1([CH2:22][S:23]([N:1]2[CH2:8][CH2:7][CH2:6][C@H:2]2[C:3]([NH2:5])=[O:4])(=[O:25])=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: NC(=O)[C@@H]1CCCN1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)[C@@H]1CCCN1S(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Yield: 55.9 %

Procedure:
To a solution of L-prolinamide (2.28 g, 20 mmol) and triethylamine (5.76 ml, 42 mmol) in 40 ml methylene chloride was added 3.92 g (20 mmol) α-toluenesulfonyl chloride at 0° C. with stirring. The reaction was gradually warmed up to room temperature and stirred overnight. The mixture was diluted with water, and extracted into 200 ml methylene chloride. The organic extract was concentrated and further purified by silica gel to give 3.0 g product as a white solid (55.7% yield). 1H NMR (CDCl3): d 01.89 (m, 3H); 2.25 (m, 1H); 3.40 (m, 1H); 3.50 (m, 1H); 3.96 (m, 1H); 4.35 (s, 2H); 7.39-7.45 (m, 5H, aromatic).
Reaction SMILES: [C:1]([C:4]1[CH:8]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2F)[C:6](=[O:23])[C:5]=1[OH:24])(=[O:3])[CH3:2].[C:25]([O:35][CH3:36])(=[O:34])[C@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([C:4]1[CH:8]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:6](=[O:23])[C:5]=1[O:24][C@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25]([O:35][CH3:36])=[O:34])(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(O)C(=O)N(c2ccc(Cl)cc2F)C1C1CCCCC1
Reactant: COC(=O)[C@@H](O)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](OC1=C(C(C)=O)C(C2CCCCC2)N(c2ccc(Cl)cc2)C1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a cooled (0° C.) mixture of 4-acetyl-1-(4-chloro-2-fluorophenyl)-5-cyclohexyl-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one (2.05 g, 5.84 mmol), methyl (S)-mandelate (1.36 g, 8.18 mmol) and triphenylphosphine (2.0 g, 7.6 mmol) in THF (50 ml) is added dropwise DIAD (1.6 ml, 7.6 mmol). The reaction is then left to warm to room temperature and is stirred for 12 hours. The solvent is removed under vacuum and the oily residue is plugged through a pad of silica gel (eluent 1/1 hexanes/ethyl acetate). The solvent is removed and the residual oil is purified by radial chromatography (eluent 9/1 hexanes/ethyl acetate) to yield each diastereomer (1 g) as a white foam.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:11](=[O:13])[CH3:12])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23]>C(OCC)(=O)C.CN(C)C=O>[Cl:27][C:26]([Cl:29])([Cl:28])[CH2:25][O:24][C:22]([CH2:21][O:1][N:2]=[C:3]([C:11](=[O:13])[CH3:12])[C:4]([O:6][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:5])=[O:23]
Reactant: O=C(CCl)OCC(Cl)(Cl)Cl
Reactant: CC(=O)C(=NO)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)C(=NOCC(=O)OCC(Cl)(Cl)Cl)C(=O)OC(C)(C)C
Reaction time: 3.5 h
Yield: 90.2 %

Procedure:
To a suspension of tert-butyl 2-hydroxyimino-3-oxobutyrate (46.8 g) and potassium carbonate (51.8 g) in ethyl acetate (70 ml) and N,N-dimethylformamide (70 ml) was added 2,2,2-trichloroethyl chloroacetate (56.5 g), and the mixture was stirred at 45° to 48° C. for 3.5 hours. After the insoluble inorganic substance was filtered off, to the filtrate were added water and ethyl acetate. The separated ethyl acetate solution was washed with water and a saturated aqueous sodium chloride, followed by drying over magnesium sulfate. Removal of the solvent gave tert-butyl 2-(2,2,2-trichloroethoxycarbonylmethoxyimino)-3-oxobutyrate (84.9 g).