Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=O)[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2].C(=O)(O)[O-].[Na+].Cl.[CH2:20]([O:23][NH2:24])[CH:21]=[CH2:22].Cl>O.C(OCC)(=O)C>[CH2:20]([O:23][N:24]=[C:9]([C:7]1[N:8]=[C:4]([NH:3][CH:1]=[O:2])[S:5][CH:6]=1)[C:10]([OH:12])=[O:11])[CH:21]=[CH2:22]
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Reactant: C=CCON
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 66.1 %

Procedure:
To a solution of 2-(2-formamidothiazol-4-yl)-glyoxylic acid (30 g) and sodium bicarbonate (12.6 g) in water (1300 ml) was added allyloxyamine hydrochloride (19.8 g), and the mixture was stirred for 7 hours at ambient temperature at pH 6. To the reaction mixture was added ethyl acetate (500 ml). After the mixture was adjusted to pH 1.9 with 10% hydrochloric acid, the ethyl acetate layer was separated. The ethyl acetate layer was washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and then the solvent was distilled off. The residue was pulverized in diisopropyl ether, collected by filtration and then dried to give 2-allyloxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (25.3 g).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH:7]([C:9]1[CH:10]=[CH:11][C:12]2[S:16][CH:15]=[C:14]([CH2:17][CH2:18][NH:19][C:20]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[C:13]=2[CH:28]=1)=C>CC(O)(C)C.O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH:7]([C:9]1[CH:10]=[CH:11][C:12]2[S:16][CH:15]=[C:14]([CH2:17][CH2:18][NH:19][C:20]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[C:13]=2[CH:28]=1)=[O:2]
Reactant: C=Cc1ccc2scc(CCNC(=O)C3CCCCC3)c2c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1ccc2scc(CCNC(=O)C3CCCCC3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.10 g of osmium tetroxide in 2-methyl-2-propanol and then 8.70 g of sodium periodate are added at room temperature to a solution of 10 mmol of the product obtained in Step D in a mixture of 50 ml of dioxane and 25 ml of water. After stirring overnight at room temperature, the suspension is filtered and the filtrate is concentrated under reduced pressure. The resulting residue is taken up in dichloromethane. The organic phase is washed with water, dried and evaporated. The residue is purified by chromatography over silica gel to yield the title product.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.Cl.[NH2:30][CH2:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([OH:38])[CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:38][C@H:35]1[CH2:36][CH2:37][C@H:32]([CH2:31][NH:30][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:14][C:15]4[S:16][C:17]5[CH:23]=[C:22]([O:24][C:25]([F:27])([F:26])[F:28])[CH:21]=[CH:20][C:18]=5[N:19]=4)=[N:4][C:5]=3[CH:10]=2)=[O:13])[CH2:33][CH2:34]1
Reactant: NC[C@H]1CC[C@H](O)CC1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NC[C@H]3CC[C@H](O)CC3)ccc21
Yield: 62.9 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (trans-4-hydroxy-cyclohexylmethyl)-amide (60 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (75 mg), trans-4-aminomethyl-cyclohexanol hydrochloride (34 mg), HBTU (84 mg), and DIEA (48 uL). LC/MS: m/z 521.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.40 (bs, 1H), 8.47-8.35 (m, 1H), 8.08 (s, 1H), 7.92 (s, 1H), 7.80-7.65 (m, 2H), 7.49 (d, 1H), 7.36 (d, 1H), 4.49 (s, 1H), 3.63 (s, 3H), 3.11 (t, 2H), 1.92-1.68 (m, 3H), 1.66-1.18 (m, 4H), 1.17-0.88 (m, 3H).
Reaction SMILES: [Na].[CH3:2][O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Br[CH2:14][CH2:15][Cl:16]>C(O)C>[CH3:2][O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:14][CH2:15][Cl:16])=[CH:7][CH:6]=1
Reactant: ClCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: [Na]
Solvent: CCO
Product: COC(=O)c1ccc(OCCCl)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 56.6 %

Procedure:
To 35 mL of ethanol was added sodium pellets (2.27gm, 98.6 mmol). After all the sodium had disappeared methyl-4-hydroxybenzoate (15 gm, 98 mmol) was added in one portion at room temperature. The reaction mixture was then heated to 60° C. and treated dropwise with 1-bromo-2-chloroethane (10.2 gm, 123 mmol) in 15 mL of ethanol. The reaction was stirred for 16 hrs then cooled to room temperature and concentrated. The residue was taken up in ethyl acetate and washed with water, 2N NaOH, and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was chromatographed on silica gel using 1:10 Ethyl acetate:Hexanes to 1:6 Ethyl acetate:Hexanes as the gradient eluant to yield 11.9 gm of the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:48](=[O:52])[CH:49]([CH3:51])[CH3:50].O>O1CCCC1>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)[C:49]([CH3:51])([CH3:50])[CH:48]2[OH:52])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(N=Cc2cccc([N+](=O)[O-])c2)cc1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)C(O)c2cc(S(C)(=O)=O)ccc2NC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.5 %

Procedure:
To a mixture of (4-methanesulfonyl-phenyl)-(3-nitro-benzylidene)-amine (10 g, 33 mmol) and ytterbium(III) triflate hydrate (2.05 g, 3.3 mmol) in dry tetrahydrofuran (100 mL) at 25° C. was added isobutyraldehyde (3.3 mL, 36.3 mmol) and water (0.6 mL, 33 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 6-methanesulfonyl-3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinolin-4-ol (10 g, 92%) as a light yellow oil: LC/MS m/e calcd for C18H20N2O5S (M+H)+: 377.43, observed: 376.8.
Reaction SMILES: N[C@H:2]([C:7](O)=[O:8])[CH2:3]C(C)C.[NH2:10][C@H:11]([C:20]([OH:22])=[O:21])[CH2:12][CH2:13][CH2:14][CH2:15]NC(=N)N>>[NH2:10][C@H:11]([C:20]([OH:22])=[O:21])[CH2:12][C:13]1[CH:3]=[CH:2][C:7]([OH:8])=[CH:15][CH:14]=1
Reactant: N=C(N)NCCCC[C@H](N)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)O
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
0.98 Leu: 1.00 Har: 0.97 Pro: 0.96
Reaction SMILES: [NH2:1][C:2]1[C:5](=[O:6])[C:4](=[O:7])[C:3]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(O)=O.O>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:5](=[O:6])[C:4](=[O:7])[C:3]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:14]=1
Reactant: C1CCNCC1
Reactant: Nc1c(NCCCOc2cccc(C=O)c2)c(=O)c1=O
Solvent: O
Solvent: O=CO
Solvent: Cc1ccccc1
Product: Nc1c(NCCCOc2cccc(CN3CCCCC3)c2)c(=O)c1=O
Temperature: 65 °C
Yield: 62.8 %

Procedure:
A suspension of 1-amino-2-[3-(3-formylphenoxy)propylamino]-1-cyclobutene-3,4-dione (6.0 g, 21.8 mmole) in 150 mL of toluene was treated with piperidine (4.3 mL, 3.7 g, 43.6 mmole) and the mixture was heated to 65° C., and then cooled to about 30° C. Formic acid (2.2 mL of 95% aqueous formic acid containing 2.5 g formic acid, 55.4 mmole) was added. The mixture was heated to reflux temperature and the water formed was collected by azeotropic distillation. When the distillate became clear and gas evolution had ceased (about 30 minutes at reflux), the mixture was cooled and the solids were collected by filtration, washed with toluene, methanol and dried to yield 4.7 g (62.8%) of the title compound; mp=223°-228° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1.Cl>C(O)C.O>[Cl:8][C:7]1[C:2]([NH2:1])=[C:3]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)[N:4]=[CH:5][N:6]=1
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: c1ccc2c(c1)CCN2
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1c(Cl)ncnc1N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
To a stirring slurry of 5-amino-4,6-dichloropyrimidine (3 g, 18.29 mmol) and indoline (2.057 mL, 18.29 mmol) in ethanol (7 mL) and water (43 mL) was added concentrated aqueous HCl (600 μL) and the mixture was refluxed for 3 h and left to stir at room temperature overnight. The reaction mixture was extracted with ethyl acetate, washed with water, brine, dried over MgSO4 and solvent evaporated. The resulting residue was triturated in 25% ethyl acetate in hexanes for 1 h then filtered to afford title compound 105 (1.55 g, 34%) as a tan solid. LRMS (ESI): (calc) 246.07. (found) 247.2 (MH)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:14]2[N:15]=[C:16]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:23][CH:22]=3)[C:17]([C:18]([NH2:20])=[O:19])=[C:13]2[NH:12][CH2:11][CH2:10]1.[C:34](Cl)(=[O:37])[CH:35]=[CH2:36]>>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:14]2[N:15]=[C:16]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:23][CH:22]=3)[C:17]([C:18]([NH2:20])=[O:19])=[C:13]2[NH:12][CH2:11][CH2:10]1)[C:34](=[O:37])[CH:35]=[CH2:36]
Reactant: CNc1ccccc1C1CCNc2c(C(N)=O)c(-c3ccc(Oc4ccccc4)cc3)nn21
Reactant: C=CC(=O)Cl
Product: C=CC(=O)N(C)c1ccccc1C1CCNc2c(C(N)=O)c(-c3ccc(Oc4ccccc4)cc3)nn21

Procedure:
The desired product was prepared from 7-(2-(methylamino)phenyl)-2-(4-phenoxy phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide and acryloyl chloride using the procedure similar to that for compound 8. 1H NMR (DMSO-d6) δ 7.45-7.37 (m, 6H), 7.29-7.24 (m, 1H), 7.15 (t, J=7.6 Hz, 1H), 7.06-7.00 (m, 5H), 6.81 (d, J=7.6 Hz, 1H), 6.25-6.16 (m, 2H), 5.94-5.87 (m, 1H), 5.63-5.51 (m, 1H), 5.41-5.35 (m, 1H), 3.41-3.22 (m, 5H), 2.41-1.97 (m, 2H). MS (ESI) m/e [M+1]+ 493.9.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4](Br)=[CH:5][CH:6]=1.[Li]CCCC.[CH:13]([C@@H:15]1[N:19]([CH3:20])[C:18](=[O:21])[CH2:17][C@@H:16]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:14].[NH4+].[Cl-]>C1C=CC=CC=1.C1COCC1>[Br:1][C:2]1[S:3][C:4]([C@@H:13]([OH:14])[C@@H:15]2[N:19]([CH3:20])[C:18](=[O:21])[CH2:17][C@@H:16]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:5][CH:6]=1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1C=O
Reactant: Brc1ccc(Br)s1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)c1ccc(Br)s1
Reaction time: 2.5 h
Yield: 58.2 %

Procedure:
To a −78° C. solution of 2,5-dibromothiophene (7.2 g, 29.6 mmol, 1.02 equiv) in anhyd. THF (100 mL) was added dropwise a solution of n-BuLi (1.6M in hexane, 18.5 mL, 29.6 mmol, 1.02 equiv) keeping the reaction temperature below −70° C. The resulting brown solution was stirred for 2.5 h. A solution of (±)-(4R*,5R*)-5-formyl-1-methyl-4-phenylpyrrolidin-2-one (Intermediate Z, 5.9 g, 29.1 mmol) in benzene (30 mL) was added, keeping the reaction temperature below −70° C. The reaction mixture was diluted with THF (30 mL) and after 30 min was treated with a saturated NH4Cl solution (150 mL). The resulting mixture was extracted with EtOAc (200 mL) and CH2Cl2 (2×200 mL) and dried (Na2SO4). The combined organic layers were concentrated under reduced pressure. The crude product was triturated (MeOH) to give (±)-(4R*,5R*)-5-[(1S*)(5-bromo(2-thienyl))hydroxymethyl]-1-methyl-4-phenyl-pyrrolidin-2-one (6.2 g) as a white solid. The filtrate was treated with silica gel (15 g), concentrated under reduced pressure and purified by flash chromatography to afford an additional 0.92 g of product (total 7.12 g, 67%) as an off-white solid: TLC (60% EtOAc/hex) Rf 0.39; 1H NMR (CDCl3) δ 2.24 (dd, J=6.2, 15.1 Hz, 1H), 2.42 (s, 3H), 2.95 (t, J=13.8 Hz, 1H), 3.76-3.85 (m, 1H), 4.15 (d, J=8.0 Hz, 1H), 4.36 (d, J=4.5 Hz, 1H), 6.06 (d, J=5.6 Hz, 1H), 6.70-7.15 (m, 1H), 7.02 (dd, J=1.9, 4.0 Hz, 1H), 7.22-7.44 (m, 5H).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].[CH2:16]([O:18][C:19](=[O:48])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([O:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:25]=[CH:24][C:23]=1[O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]OS(C)(=O)=O)[CH3:17]>>[CH2:16]([O:18][C:19](=[O:48])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([O:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:25]=[CH:24][C:23]=1[O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][O:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15])[CH3:17]
Reactant: CCOC(=O)CCCOc1ccc(OCCCCCOS(C)(=O)=O)c(CCC(=O)OCC)c1
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Product: CCCc1c(OCCCCCOc2ccc(OCCCC(=O)OCC)cc2CCC(=O)OCC)ccc2c1OCCC2=O
Yield: 83.6 %

Procedure:
Using the procedure of example 11 and starting with 0.28 g (1.4 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one and 0.7 g (1.4 mmol) of 2-[5-(methylsulfonyl)oxypentyloxy]-5-(3-ethoxycarbonylpropoxy)benzenepropanoic acid ethyl ester (from example 46), 5-(3-ethoxycarbonylpropoxy)-2-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid ethyl ester was obtained in 83.6% yield (0.7 g) as a solid. This diester (1.17 mmol) was saponified with 3 mL of 3N aqueous lithium hydroxide in 25 mL of tetrahydrofuran, at room temperature, for 37 hr. Work-up as in example 4gave a light-brown oily acid which was flash-chromatographed on silica gel, eluting with 95:5:1 chloroform-methanol-acetic acid. There was obtained 0.39 g (61.5%) of pure 5-(3-carboxypropoxy)-2-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy] benzenepropanoic acid. Recrystallization from hexane-ethyl acetate gave a colorless solid, mp 119°-124° C.
Reaction SMILES: Cl[C:2]([O-:4])=[O:3].[NH2:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][NH2:11]>C1(C)C=CC=CC=1.CCCCCC>[C:2](=[O:3])([OH:4])[NH2:5].[NH2:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][NH2:11]
Reactant: O=C([O-])Cl
Agent: NCCNCCN
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: NC(=O)O

Procedure:
A 988 g (1:04 mole) portion of polyisobutyl-24 chloroformate prepared according to the procedure outlined in Example 2, which had been diluted to 1800 ml with toluene was combined with 1800 ml of a solution containing 870 ml (8.05 moles) of diethylenetriamine in toluene using a Kenics static mixer (11 inches×3/8 inch); the reaction mixture was discharged into a 5 liter receiver. The reaction mixture was stripped, and then diluted with 8 1 hexane. A lower layer containing excess diethylene triamine was removed. The upper layer was washed twice with 3 l 5% aqueous sodium hydroxide; phase separation was assisted by the addition of salt, NaCl (to give brine in situ). After a final wash with basic brine, the organic layer was dried (over Na2SO4 ), filtered and stripped to give the above-identified product as a viscous yellow liquid (AV=64).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH2:13])[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:23]([O:26][CH2:27][C:28](Cl)=[O:29])(=[O:25])[CH3:24]>C(Cl)Cl.C(OCC)(=O)C>[C:23]([O:26][CH2:27][C:28]([NH:13][C:10]1[S:11][CH:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[N:9]=1)=[O:29])(=[O:25])[CH3:24]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Nc1nc(-c2ccc(Br)cc2)cs1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(=O)OCC(=O)Nc1nc(-c2ccc(Br)cc2)cs1
Temperature: 0 °C
Reaction time: 2 h
Yield: 41.7 %

Procedure:
4-(4-Bromophenyl)-1,3-thiazol-2-ylamine (2.00 g, 7.84 mmol) was dissolved in methylene chloride, diisopropylethylamine (1.50 mL, 8.62 mmol) was added and the mixture was cooled to 0° C. Acetoxy acetyl chloride (0.920 mL, 8.62 mmol) was added dropwise, the mixture was stirred for 2 h and then diluted with ethyl acetate. The mixture was washed with NaHCO3, water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (20% acetone/hexane) followed by recrystallization from acetone/hexane afforded 1.16 g of 2-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}-2-oxoethyl acetate (1.16 g, 42%) as a white solid. HRMS: calcd for C13H, BrN2O3S+H+, 354.97465; found (ESI, [M+H]+), 354.9738. Analytical HPLC: retention time 9.8 min, 210-370 nm the Xterra® RP18 column, 3.5%, 150×4.6 mm 40° C. 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min, 1.2 mL/min 5 μL injection.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH:5]([C:12]1[N:13]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[N:14]=[C:15]2[C:20]=1[CH:19]=[CH:18][CH:17]=[CH:16]2)[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)C.[OH-].[Na+]>CO>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([N:13]2[C:12]([CH:5]([CH:6]3[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)[C:4]([OH:28])=[O:3])=[C:20]3[C:15]([CH:16]=[CH:17][CH:18]=[CH:19]3)=[N:14]2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)C(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Yield: 117.9 %

Procedure:
A solution of [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-acetic acid ethyl ester (9 mg, 23 μmol) in MeOH (0.5 ml) and 4 N aqueous NaOH (90 μl, 345 μmol) was heated for 14 h under reflux conditions. The solvent was removed under reduced pressure, ice water/1 N aqueous NaOH solution/TBME 1/1/2 was added and the layers were separated. The aqueous layer was extracted one more time with TBME. The aqueous layer was acidified with 1 N aqueous HCl solution and extracted two times with iPrOAc. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give the title compound (10 mg; quant.) as off-white solid which was sufficiently pure to be used in the next step. MS: m/e=369.1 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[Br:25]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:10]([Br:25])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cn2ncnc(N)c2c1-c1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: CCOC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)c2c(N)ncnn2c1Br
Temperature: 60 °C
Yield: 83 %

Procedure:
Ethyl 4-amino-5-(4-nitrophenyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (2.0 g, 6.11 mmol) was suspended in ACN and treated with N-bromosuccinimide (1.20 g, 6.72 mmol). The dark suspension was heated to 60° C. for 1 h. The suspension was cooled and filtered. The brown solid was washed with ACN and MeOH. The product was collected by filtration to give 2.06 g of a yellow brown solid (83%). 1H-NMR (DMSO-d6) δ 8.26 (d, J=8.8, 2H), 8.07 (s, 1H), 7.64 (d, J=8.8, 2H), 4.02 (q, J=7.0, 2H), 0.95 (t, J=7.0, 3H); MS [M+H]+=406.1, 408.0; LCMS RT=2.93.
Reaction SMILES: [I-].[CH2:2]([O:4][CH:5]([O:13][CH2:14][CH3:15])[C:6]1[CH:11]=[CH:10][N+:9]([CH3:12])=[CH:8][CH:7]=1)[CH3:3].[OH-:16].[K+].C1(C)C=CC=CC=1>O.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[CH3:12][N:9]1[CH:8]=[CH:7][C:6]([CH:5]([O:4][CH2:2][CH3:3])[O:13][CH2:14][CH3:15])=[CH:11][C:10]1=[O:16]
Reactant: [OH-]
Reactant: CCOC(OCC)c1cc[n+](C)cc1
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(OCC)c1ccn(C)c(=O)c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
4-(Diethoxymethyl)-1-methylpyridinium iodide (3.43 g, 10.6 mmol) was dissolved in water (70 mL). To this, a solution of potassium ferricyanide (38.4 g, 117 mmol) in water (85 mL) was added dropwise under a nitrogen atmosphere at 0° C. over 1 hour. To this, an aqueous solution (16 mL) of potassium hydroxide (9.40 g, 167 mmol) was added dropwise at the same temperature over 30 minutes. To this, toluene (100 mL) was added and the mixture was stirred at 40° C. for 30 minutes. Then, extraction with dichloromethane was performed, followed by drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to give 1-methyl-4-(diethoxymethyl)-2(1H)-pyridone (1.20 g, yield: 53%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[O:17][C@H:14]([O:15][CH3:16])[C@H:13]([O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:12]([O:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:11]1O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:40])(=O)=O>N1C=CC=CC=1>[CH2:1]([O:8][CH2:9][C@H:10]1[O:17][C@H:14]([O:15][CH3:16])[C@H:13]([O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:12]([O:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@H:11]1[Cl:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](O)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: c1ccncc1
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@H](Cl)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of crude methyl 6-O-benzyl-2,3-di-O-benzoyl-α-D-glycopyranoside (compound 66) (from previous step) in 300 mL of pyridine at -40° C. was added sulfuryl chloride (15 mL). After 1 hour, the cooling bath was removed and stirring was continued at room temperature for 3 hours. Dichloromethane was then added and the resulting solution was washed with saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and evaporated. The residue was chromatographed on a silica gel, eluting with dichloromethane, to provide methyl 6-O-benzyl-2,3-di-O-benzoyl-4-chloro-4-deoxy-α-D-galactopyranoside (compound 67) (15.3 g, 90.0% --based on compound 65) as a syrup.
Reaction SMILES: [F:1][C:2]1[CH:39]=[CH:38][C:5]([CH2:6][O:7][C:8]2[C:17]3[C:16]([CH3:19])([CH3:18])[CH2:15][CH2:14][C:13]([CH3:21])([CH3:20])[C:12]=3[CH:11]=[C:10]([C:22]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[CH:30]=[C:29]([C:34]([O:36]C)=[O:35])[CH:28]=[CH:27]4)=[O:23])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>>[F:1][C:2]1[CH:39]=[CH:38][C:5]([CH2:6][O:7][C:8]2[C:17]3[C:16]([CH3:19])([CH3:18])[CH2:15][CH2:14][C:13]([CH3:20])([CH3:21])[C:12]=3[CH:11]=[C:10]([C:22]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[CH:30]=[C:29]([C:34]([OH:36])=[O:35])[CH:28]=[CH:27]4)=[O:23])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2cc(C(=O)c3cc(OCc4ccc(F)cc4)c4c(c3)C(C)(C)CCC4(C)C)ccc2c1
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)CCC(C)(C)c2c(OCc3ccc(F)cc3)cc(C(=O)c3ccc4cc(C(=O)O)ccc4c3)cc21

Procedure:
In a manner similar to that of Example 1g, by reacting 250 mg (0.5 mmol) of methyl 6-{1-[4-(4-fluorobenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]methanoyl}-2-naphthalenecarboxylate with 40 mg of sodium hydroxide. A white crystallized solid is obtained (m=235 mg; yield=66%; m.p.=277° C.).