Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2](F)(F)[CH:3]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[C:14]([NH:16][C:17]3[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=3)[CH:13]=[C:12]([CH3:27])[CH:11]=2)=[CH:8][N:9]=1)[OH:4].C(O)(=O)C(C)(C)C.C(=O)([O-])[O-].[K+].[K+].OC(C(F)(F)F)=O.[OH:50][CH2:51][C@@H:52]1[CH2:57][CH2:56][C@](C2SC=CN=2)(O)[CH2:54][C:53]1(C)[CH3:64]>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>[OH:50][CH2:51][C@@H:52]1[CH2:57][CH2:56][C@:3]([C:5]2[S:6][C:7]([C:10]3[CH:15]=[C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=4)[CH:13]=[C:12]([CH3:27])[CH:11]=3)=[CH:8][N:9]=2)([OH:4])[CH2:2][C:53]1([CH3:64])[CH3:54]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(O)C(F)(F)F)s2)c1
Reactant: CC1(C)C[C@](O)(c2nccs2)CC[C@H]1CO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)C(=O)O
Agent: O=C([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc([C@]3(O)CC[C@@H](CO)C(C)(C)C3)s2)c1
Temperature: 120 °C
Yield: 20.4 %

Procedure:
A 4-mL screw-cap pressure vial was charged with N-(3-bromo-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine (INTERMEDIATE 2, 74.8 mg, 0.225 mmol), stir bar, pivalic acid (2.61 μl, 0.023 mmol), potassium carbonate (46.7 mg, 0.338 mmol), (1S,4R)-4-(hydroxymethyl)-3,3-dimethyl-1-(thiazol-2-yl)cyclohexanol TFA salt (40 mg, 0.113 mmol), and Pd(PPh3)4 (13.01 mg, 0.011 mmol). The vial was closed, evacuated and back-filed with nitrogen 3 times. DMA (0.5 ml) (dry, over molecular sieves, Fluka) was added and the reaction mixture heated to 120° C. for 16 hours, LCMS showed product formation and some remaining starting materials. Filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC (10-60% acetonitrile gradient with water+0.1% TFA) to afford (1S,4R)-4-(hydroxymethyl)-3,3-dimethyl-1-(5-(3-methyl-5-(4-(trifluoromethyl)pyrimidin-2-ylamino)-phenyl)thiazol-2-yl)cyclohexanol (14 mg, 0.023 mmol, 20.51% yield over 2 steps) as a yellow solid.
Reaction SMILES: [CH3:1][CH2:2][C:3]([CH2:5][CH2:6]/[CH:7]=[C:8](/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])\[CH3:9])=[CH2:4].[CH:16]([CH:18]=[CH2:19])=[O:17]>>[CH:16]([CH:18]1[CH2:19][CH:4]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:14])[CH3:15])[CH2:2][CH2:1]1)=[O:17]
Reactant: C=C(CC)CC/C=C(\C)CCC=C(C)C
Reactant: C=CC=O
Product: CC(C)=CCCC(C)=CCCC1=CCC(C=O)CC1
Temperature: 100 °C
Yield: 50 %

Procedure:
The (E)-β-farnesene-containing product of Example 1 (5.0 g) and acrolein (3.0 g) are heated together at 100° C. for two hours. The mixture is then distilled under reduced pressure to give 1-formyl-4-(4,8-dimethyl-3,7-nonadienyl)-cyclohex-4-ene as a yellow oil (2.2 g, 50%); b.p. 140°-150°/0.5τ; nD20 1.5033; M+ (m/z as % base peak): 260 (3.6); δ (CCl4) 1.70 (M, 9H), 1.90-2.30 (m, 15H), 5.16 (m, 2H), 5.50 (br, t, 1H), 9.84 (br, s, 1H).
Reaction SMILES: Br[C:2]([CH3:6])([CH3:5])[CH:3]=[O:4].[N:7]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1>CCOCC>[CH3:5][C:2]([N:10]1[CH2:9][CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11]1)([CH3:6])[CH:3]=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(Br)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(C(C)(C)C=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of 2-bromo-2-methylpropanal (5 g, 33.11 mmol, 1.00 equiv) and tert-butyl piperazine-1-carboxylate (18.6 g, 99.87 mmol, 3.02 equiv) in ether (80 mL). The resulting solution was stirred overnight at 25° C. The solids were filtered out. The organic filtrate was washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum to give 6 g of tert-butyl 4-(2-methyl-1-oxopropan-2-yl)piperazine-1-carboxylate as a white solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][CH:25]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].C1C(=O)N([Br:40])C(=O)C1>C(#N)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([Br:40])=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CCOC(=O)c1csc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCOC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To compound 34A in acetonitrile was added 1.05 eq of NBS. The reaction mixture was stirred at rt for 2 hours. The solvent was removed, and the residue was purified by column chromatography on silica gel eluting with 3:2 hexanes/EtOAc to provide the desired product: MS (ESI(+)): 544 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][N:9]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.O>C1(C)C=CC=CC=1.Cl.Cl.[Pd+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:8]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][N:9]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: OCc1ccnc(Br)c1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: OCc1ccnc(-c2ccccc2C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 9083 %

Procedure:
16.5 ml (0.3 mmol) of an aqueous solution of potassium carbonate having a concentration of 2M and 0.4 g (0.1 mmol) of 1,1′-bis(diphenylphosphino)ferrocene palladium(II) dihydrochloride are added under a stream of nitrogen to a solution containing 2.0 g (0.1 mmol) of 2-bromopyridine-4-methanol and 2.2 g (0.1 mmol) of 2-(trifluoromethyl)phenylboronic acid in 30 ml of toluene. The mixture is stirred at 80° C. for 5 hours then 20 ml of water are added. After extraction with ethyl acetate, the organic phase is dried over sodium sulphate, filtered and evaporated. The residue obtained is purified by chromatography over silica gel eluted with a 60/40 heptane/ethyl acetate mixture. 2.3 g (85%) of [2-(2-trifluoromethylphenyl)pyridin-4-yl]methanol are obtained in the form of a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:52])[C@@H:7]([NH:31][C:32](=[O:51])[NH:33][C@@H:34]([CH2:42][CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:30])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](ON1C(=O)CCC1=O)=[O:21])([CH3:4])([CH3:3])[CH3:2].[NH2:53][C@@H:54]([CH2:58][CH2:59][CH2:60][CH2:61][N:62]([CH2:70][C:71]1[N:72]([CH3:76])[CH:73]=[CH:74][N:75]=1)[CH2:63][C:64]1[N:65]([CH3:69])[CH:66]=[CH:67][N:68]=1)[C:55]([OH:57])=[O:56].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:69][N:65]1[CH:66]=[CH:67][N:68]=[C:64]1[CH2:63][N:62]([CH2:70][C:71]1[N:72]([CH3:76])[CH:73]=[CH:74][N:75]=1)[CH2:61][CH2:60][CH2:59][CH2:58][C@@H:54]([C:55]([OH:57])=[O:56])[NH:53][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13](=[O:30])[NH:12][CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:52])[NH:31][C:32](=[O:51])[NH:33][C@H:34]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:42][CH2:43][C:44](=[O:45])[O:46][C:47]([CH3:49])([CH3:50])[CH3:48]
Reactant: Cn1ccnc1CN(CCCC[C@H](N)C(=O)O)Cc1nccn1C
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)CCCCCCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccnc1CN(CCCC[C@H](NC(=O)CCCCCCC(=O)NCCCC[C@H](NC(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)O)Cc1nccn1C
Yield: 17.6 %

Procedure:
A solution of (S)-di-tert-butyl 2-(3-((S)-1-tert-butoxy-6-(8-(2,5-dioxopyrrolidin-1-yloxy)-8-oxooctanamido)-1-oxohexan-2-yl)ureido)pentanedioate (0.356 g, 0.48 mmol), the compound of Compound 13 (0.16 g, 0.48 mmol) and DIPEA (1.0 mL) in DMF (5.0 mL) was stirred at room temperature for overnight. The solvent was evaporated to give a residue, which was purified by Biotage eluting with DCM/MeOH to give (7S,11S,26S)-26-(4-(bis((1-methyl-1H-imidazol-2-yl)methyl)amino)butyl)-7,11-bis(tert-butoxycarbonyl)-2,2-dimethyl-4,9,17,24-tetraoxo-3-oxa-8,10,16,25-tetraazaheptacosan-27-oic acid (81 mg, 18%). MS (ESI), 481 (M/2+H)+.
Reaction SMILES: C(Cl)(=O)C.C(OC(=O)[NH:11][C@H:12]1[C@H:21]([O:22][CH3:23])[CH2:20][C:19]2[C:14](=[CH:15][C:16]([C:24](=[O:26])[NH2:25])=[CH:17][CH:18]=2)[C:13]1([CH2:29][CH3:30])[CH2:27][CH3:28])(C)(C)C>C(O)C>[NH2:11][C@@H:12]1[C:13]([CH2:27][CH3:28])([CH2:29][CH3:30])[C:14]2[CH:15]=[C:16]([C:24]([NH2:25])=[O:26])[CH:17]=[CH:18][C:19]=2[CH2:20][C@H:21]1[O:22][CH3:23]
Reactant: CCC1(CC)c2cc(C(N)=O)ccc2C[C@@H](OC)[C@@H]1NC(=O)OC(C)(C)C
Solvent: CCO
Solvent: CC(=O)Cl
Product: CCC1(CC)c2cc(C(N)=O)ccc2C[C@@H](OC)[C@@H]1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 112.9 %

Procedure:
Acetyl chloride (278.8 mL, 3920 mmol) was added dropwise to ethanol (382 mL, 6530 mmol) at −5° C. over 2 h keeping the internal temperature below 20° C. The resulting solution was added portion wise over 15 min, keeping the internal temperature below 30° C., to a slurry of trans-(7-carbamoyl-1,1-diethyl-3-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid tert-butyl ester (123.0 g, 327 mmol) and ethanol (500 mL) that had been cooled to 10° C. The reaction mixture was stirred at room temperature for 2 h, and concentrated to ˜200 mL by rotary evaporation. Ethyl acetate (200 mL) was added and the resulting slurry was stirred at 0° C. for 30 min, filtered and dried to yield the hydrochloride salt of the title compound (102 g, >98% purity) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][CH2:5][NH:6][C:7](=[O:37])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=3)=[C:22]([CH:35]=[O:36])[CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.[BH4-].[Na+]>CO.C(OCC)(=O)C>[OH:36][CH2:35][C:22]1[CH:21]=[C:20]([O:19][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:38])=[O:2])=[O:37])=[CH:9][CH:10]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])[CH:25]=[CH:24][C:23]=1[C:26]1[CH:27]=[CH:28][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:30][CH:31]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Oc2ccc(-c3ccc(C(C)C)cc3)c(C=O)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)CC(Oc1ccc(-c2ccc(C(C)C)cc2)c(CO)c1)c1ccc(C(=O)NCCC(=O)O)cc1
Reaction time: 2 h
Yield: 263.8 %

Procedure:
To the solution of 3-{4-[1-(2-formyl-4′-isopropyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-propionic acid methyl ester (36 mg, 0.07 mmol) in methanol (5 ml) is added NaBH4 (3 mg, 0.07 mmol). After 2 h, the mixture is diluted with ethyl actate, washed with 1N HCl, water, brine, dried over MgSO4, and concentrated. The residue is taken into methanol (20 mL), followed by the addition of sodium hydroxide (5 N aqueous, 1 mL), stirred for 4 h. The reaction mixture is concentrated and acidified by 5 N HCl (1 mL), extracted with ethyl acetate. Combined organic layers are washed with water and brine, dried over sodium sulfate. Concentration gives the title compound (93 mg) as a white solid. MS (ES): 502.2 [M−H]−.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)(O)[CH3:21])=[CH:16][CH:15]=1.FC1C=CC(C(C2C=CC(F)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=CC=1>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([C:9]2[C:8]3[C:12](=[C:4]([CH2:3][S:2][CH3:1])[CH:5]=[CH:6][CH:7]=3)[NH:11][CH:10]=2)([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH3:21])=[CH:18][CH:19]=1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: CC(O)(c1ccc(F)cc1)c1ccc(Cl)cc1
Agent: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3)c[nH]c12
Product: CSCc1cccc2c(C(C)(c3ccc(F)cc3)c3ccc(Cl)cc3)c[nH]c12
Temperature: 80 °C
Reaction time: 4 h

Procedure:
The title compound was prepared starting from 1.00 g (5.64 mmol) of the compound from Example 8A and 1.41 g (5.64 mmol) of the compound from Example 182A in analogy to the synthesis of the compound from Example 278. A difference was that stirring at 80° C. was for only 4 h. 1.31 g (56% of theory) of the target compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[CH:12](=O)[CH2:13][CH3:14].C(O)(C)C.Cl>C(OCC)(=O)C>[CH2:13]([CH:14]1[NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[S:8](=[O:10])(=[O:9])[NH:11]1)[CH3:12]
Reactant: CCC=O
Reactant: Nc1ccncc1S(N)(=O)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCC1Nc2ccncc2S(=O)(=O)N1

Procedure:
0.5 g of 4-aminopyridine-3-sulfonamide (Preparation 2) and 0.34 g (2 equivalents) of propionaldehyde are introduced into 5 cm3 of isopropanol to which 10 drops of a saturated solution of hydrochloric acid in ethyl acetate have been added. After refluxing for 2 h, the solution obtained is concentrated to dryness and the residue is recrystallized from a 1/3 isopropanol/petroleum ether (40°-60° C.) mixture.
Reaction SMILES: Br[CH2:2][C:3]([CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])([C:5]1[CH:6]=[N:7][C:8]([Cl:11])=[CH:9][CH:10]=1)[OH:4].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2([CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])[CH2:2][O:4]2)=[CH:6][N:7]=1
Reactant: OC(CBr)(CC(Cl)(Cl)Cl)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1ccc(C2(CC(Cl)(Cl)Cl)CO2)cn1
Reaction time: 0.08 h
Yield: 66 %

Procedure:
To a solution of 7.0 g (19 mmoles) of α-(bromomethyl)-6-chloro-α-(2,2,2-trichloroethyl)-3-pyridinemethanol in 200 ml of acetonitrile was added 10 g (0.07 mole) of powdered anhydrous K2CO3. The slurry was stirred for five minutes, filtered and the filtrate concentrated in vacuo, giving 5 g of crude product. Recrystallization from hexane yielded 3.6 g (66%) of product, m.p. 65°-67° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH:12][C:13](=[O:27])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[C:23]([F:26])([F:25])[F:24])[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].[OH:28][C:29]1[CH:44]=[CH:43][C:32]([CH2:33][NH:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:31][CH:30]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[OH:28][C:29]1[CH:44]=[CH:43][C:32]([CH2:33][N:34]([CH2:35][C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])[C:5](=[O:6])[C:4]2[CH:8]=[CH:9][C:10]([NH:12][C:13](=[O:27])[CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[C:23]([F:26])([F:25])[F:24])=[CH:11][C:3]=2[O:2][CH3:1])=[CH:31][CH:30]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)O)c(OC)c2)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)CNCc1ccc(O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(O)cc3)c(OC)c2)c(C(F)(F)F)c1
Yield: 99 %

Procedure:
Prepared using General Procedure 6: To a stirred solution of 2-methoxy-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzoic acid INT-23 (404 mg, 1.05 mmol), tert-butyl 2-((4-hydroxybenzyl)amino)acetate INT-22 (250 mg, 1.05 mmol) and TEA (367 μL, 2.63 mmol) in DMF (5 mL) was added HATU (421 mg, 1.11 mmol). After 2 h the reaction mixture was diluted with EA (100 mL) and washed with brine (2×150 mL). The organics were pre-absorbed onto silica gel and then purified by chromatography (EA/isohexanes) to afford 633 mg (99%) of tert-butyl 2-(N-(4-hydroxybenzyl)-2-methoxy-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate INT-24 as a waxy solid. LCMS-ESI (m/z) calculated for C31H33F3N2O7: 602 found 601 [M−H]−, tR=2.29 min (Method 10). 1H NMR (400 MHz, DMSO 100° C.) δ 10.25 (s, 1H), 9.28 (s, 1H), 7.52-7.41 (m, 2H), 7.27-7.04 (m, 5H), 6.95 (d, J=8.0 Hz, 1H), 6.72 (dd, J=20.5, 7.9 Hz, 2H), 4.52 (br s, 1H), 4.22 (s, 1H), 3.81 (m, 9H), 3.62 (s, 1H), 1.40 (d, J=2.1 Hz, 4.5H), 1.30 (d, J=2.1 Hz, 4.5H).
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C[Si](Cl)C>>[Cl:1][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(O)CCl
Agent: C[Si](C)Cl
Product: CCOC(=O)CC(=O)CCl

Procedure:
The quantitation of ethyl 4-chloro-3-hydroxybutyrate was carried out by gas chromatography. Thus, using a glass column (ID 3 mm×1 m) packed with PEG-20M Chromosorb WAW DMCS 10%, 80/100 mesh (product of GL Sciences Inc.), chromatography was carried out at 150° C. The detection was made by FID.
Reaction SMILES: O[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH2:7][C:6]1=[O:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:41]I>C(Cl)(Cl)Cl>[I:41][CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH2:7][C:6]1=[O:15]
Reactant: II
Reactant: C[C@H](CO)CN1C(=O)CSc2ccccc21
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: C[C@H](CI)CN1C(=O)CSc2ccccc21
Yield: 75.4 %

Procedure:
The compound (S)-4-(3-Hydroxy-2-methylpropyl]-4H-benzo[1,4]thiazin-3-one (108LM34-31) (2.33 g, 9.82 mmol), triphenylphosphine (5.15 g, 19.7 mmol), imidazole (1.67 g, 24.6 mmol) and iodine (7.48 g, 29.5 mmol) in CHCl3 (30 mL) were reacted according to GP4 to give the title compound (108LM37-34) (2.57 g, 75%). 1H NMR (CDCl3) δ 7.37 (d, J=7.8 Hz, 1H), 7.24 (t, J=7.8 Hz, 1H), 7.16 (d, J=7.8 Hz, 1H), 7.02 (t, J=7.8 Hz, 1H), 4.02 (d, J=6.8 Hz, CH2), 3.37 (s, CH2), 3.15-3.05 (m, CH2), 1.95 (m, 1H), 0.97 (d, J=6.2 Hz, CH3).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[CH3:12][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([Cl:11])=[N:10][C:2]=1[Cl:1]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)c1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.3 %

Procedure:
To the mixture of 2,6-dichloro-nicotinic acid (4.7 g, 22 mmol) and acetone (22 ml), potassium carbonate (4.6 g, 33 mmol) and dimethylsulfate (2.4 ml, 24 mmol) were sequentially added at room temperature, and the obtained reaction mixture was stirred at room temperature for 16 hours. Impurities were removed by filtration, and the solvents were evaporated under reduced pressure from the filtrate. Dichloromethane was added to the obtained residue, followed by washing with a saturated sodium bicarbonate aqueous solution. The obtained organic layer was dried using anhydrous sodium sulfate, and the solvents were evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography (heptane:ethyl acetate=10:1 to 1:1), thereby obtaining the entitled compound (4.0 g, 87%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[C:29]2[N:28]=[C:26]([NH2:27])[NH:25][C:23](=O)[C:22]=2[N:21]=[CH:20]1)(=[O:3])[CH3:2].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:55])=O>[Cl-].C([N+](CC)(CC)CC)C.C(#N)C>[NH2:27][C:26]1[N:28]=[C:29]2[C:22]([N:21]=[CH:20][N:19]2[C@@H:6]2[O:7][C@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:5]2[O:4][C:1](=[O:3])[CH3:2])=[C:23]([Cl:55])[N:25]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC[N+](CC)(CC)CC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 47.5 °C
Reaction time: 0.25 h

Procedure:
An 8-liter, 3-neck, round bottom flask equipped with a mechanical stirrer, a condenser, a thermometer, and an argon inlet is charged with dry acetonitrile (2.2 liters) and 2′,3′,5′-tri-O-acetyl-guanosine (550 g, 1.344 moles). Tetraethylammonium chloride (423 g, 2.55 moles), previously dried for 18 hours over P2O5 at 110° C./high vacuum is added to afford a clear, green solution. After heating to 45-50° C., N,N-dimethylaniline (179 g, 1.48 moles) is added, followed by phosphorus oxychloride (825 g, 5.38 moles) over 15 minutes, during which the temperature rose to 75±3° C. The mixture was kept at 75±3° C. for 15 minutes, flash evaporated (TBath<40° C.), and the dark red residue taken up in dichloromethane (4 liters). With vigorous stirring, the mixture is washed with ice water (2.5 L), the organic phase is collected, and the aqueous phase extracted with additional dichloromethane (2×1 L). The combined organic phases are washed with cold water (2×2 liters), saturated aqueous NaHCO3 (2×2 L), dried (Na2SO4), filtered, and concentrated to approximately 1.5 liters. Absolute ethanol (1.5 L) is added and the mixture concentrated to approximately 2 liters. Upon cooling to room temperature, the product crystallizes as a colorless solid (321 g, 56%) after drying in vacuo at 40° C. for 17 hours.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].Br[C:12]1[C:13](=[O:25])[N:14]([C:18]([CH:22]([CH3:24])[CH3:23])([CH3:21])[C:19]#[N:20])[C:15](=[O:17])[CH:16]=1.C(O)(C)C.C([O-])(=O)C.[Na+]>CCOCC>[C:19]([C:18]([N:14]1[C:13](=[O:25])[CH:12]=[C:16]([NH:4][C:3]2[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]([OH:10])=[O:9])[C:15]1=[O:17])([CH3:21])[CH:22]([CH3:23])[CH3:24])#[N:20]
Reactant: CC(C)C(C)(C#N)N1C(=O)C=C(Br)C1=O
Reactant: Nc1ccccc1C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)O
Product: CC(C)C(C)(C#N)N1C(=O)C=C(Nc2ccccc2C(=O)O)C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.5 %

Procedure:
A mixture of anthranilic acid, (13.7 g, 0.1 mol), 3-bromo-α-isopropyl-α-methyl-2,5-dioxo-3-pyrroline-1-acetonitrile (27 g, 0.1 mol), isopropanol (200 ml) and sodium acetate (8.2 g) is stirred at room temperature 3 days and then is heated at reflux 1 hour. On cooling, and with the addition of ether, a yellow solid 31.6 g, (97.7%) is obtained, mp 262°-266° C. after crystallizing from acetic acid. Anal. calcd. for C17H17N3O4 : C, 62.37; H, 5.24; N, 12.84. Found: C, 62.24; H, 5.19; N, 12.70.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]2[C:5]([C:6]([NH:24][C@H:25]([CH3:28])[CH2:26][OH:27])=[N:7][C:8]([S:12]([CH2:15][C:16]3C=[CH:20][CH:19]=[C:18](F)[C:17]=3F)(=O)=O)=[N:9]2)=[N:4][CH:3]=1.CC1[O:34]C(CS)=CC=1.CC(C)([O-])C.[K+]>CS(C)=O.C1COCC1>[NH2:1][C:2]1[N:11]=[C:10]2[C:5]([C:6]([NH:24][C@H:25]([CH3:28])[CH2:26][OH:27])=[N:7][C:8]([S:12][CH2:15][C:16]3[O:34][C:19]([CH3:20])=[CH:18][CH:17]=3)=[N:9]2)=[N:4][CH:3]=1
Reactant: Cc1ccc(CS)o1
Reactant: C[C@H](CO)Nc1nc(S(=O)(=O)Cc2cccc(F)c2F)nc2nc(N)cnc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(CSc2nc(N[C@H](C)CO)c3ncc(N)nc3n2)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the product from example 10, step (a) (0.18 g) and 5-methyl-2-furanmethanethiol (75 mg) in anhydrous DMSO (3 ml) was treated with potassium t-butoxide solution in THF (1.0 M, 0.44 ml) and stirred at room temperature for 1 hour. The solution was purified directly by preparative reversed phase HPLC on a Waters 19×50 mm Symmetry C8 silica column eluted with 0.1% aqueous ammonium acetate:acetonitrile (70:30) to give an off-white solid that was dried under reduced pressure at 40° C. (8 mg).