Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][CH2:7][C:6]1=NO)(=[O:3])[CH3:2].C(Cl)(Cl)Cl.[O:26]1CCOCC1>>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][CH2:7][C:6]1=[O:26])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1OCC(=NO)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CC(=O)OC[C@H]1OCC(=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
[litt=P. Jarglis, Thesis, Darmstadt-Eberstadt 1980] 3,4,6-Tri-O-acetyl-1,5-anhydro-D-fructose oxime (2) (5.00 g, 16.5 mmol) was dissolved in dioxane (100 mL) and NH4OAc (13.0 g, 169 mmol) was added. The mixture was cooled on ice, 15% TiCl3 (44 mL, 54 mmol) was added and the reaction mixture was stirred at rt for 3 h. The mixture was extracted with CHCl3 (5×30 mL) and the combined organic phase was washed with saturated aqueous NaHCO3 (70+50 mL). The combined aqueous phase was extracted with CHCl3 (30 mL) and the combined organic phase was washed with H2O (30 mL). The organic phase was dried (MgSO4) and evaporated to a syrup of 3 (3.54 g, 75%). Upon addition of Et2O, the product crystallises (1.29 g, mp 81-85° C.). Two recrystallisation from Et2O afforded an analytical sample: mp 93-95° C.; [α]D−7.2 (c 1.5. CHCl3) [Lit. mp 86-88° C., [α]D−10 (c 0.5, CHCl3)]. 1 H NMR (CDCl3 at 727, 300 MHz) δ 2.08 (s, 3H, OCOCH3) 2.10 (s, 3H, OCOCH3), 2.16 (s, 3H, OCOCH3), 3.99 (ddd, J=2.5, 5.0 and 9.0, 1H, H-5), 4.10 (d, J=15.5, 1H, H-1), 4.23 (dd, J=2.5 and 12.5, 1H, H-6), 4.27 (d, J=15.5. 1H, H-1′), 4.32 (dd, J=5.0 and 12.5, 1H, H-6′), 5.34 (t, J=9.5, 1H, H-4), 5.42 (d, J=10.0, 1H, H-3). 13C NMR (CDCl3 at 77.0. 75.5 MHz) δ 20.4, 20.7 (3×OCOCH3), 62.1 (C-6), 69.4 (C-4), 72.9 (C-1), 76.5 (C-5), 76.8 (C-3), 169.1, 169.8, 170.5 (3×OCOCH3), 196.3 (C-2).
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6](=[O:34])[C:7]([C:29]([O:31]CC)=[O:30])=[CH:8][N:9]2[C:13]2[CH:18]=[C:17]([NH:19]C(OC(C)(C)C)=O)[C:16]([F:27])=[CH:15][C:14]=2[F:28])=[CH:4][C:3]=1[F:35]>C(O)(=O)C.Cl>[NH2:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6](=[O:34])[C:7]([C:29]([OH:31])=[O:30])=[CH:8][N:9]2[C:13]2[CH:18]=[C:17]([NH2:19])[C:16]([F:27])=[CH:15][C:14]=2[F:28])=[CH:4][C:3]=1[F:35]
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Cl)c(N)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N)c(Cl)c32)c(F)cc1F
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Ethyl 7-amino-1-(5-tert-butoxycarbonylamino-2,4-difluorophenyl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate was dissolved in a mixed liquid of acetic acid (10 ml) and 2N hydrochloric acid (8 ml), and the solution was stirred at 100° C. for 2 hours. After the solution was cooled back to room temperature, the solvent was distilled off under reduced pressure. The residue was washed with ethanol and then dissolved in N,N-dimethylformamide (3 ml). Ethanol (3 ml) was further added to the solution, and the mixture was left to stand overnight at room temperature. Crystals deposited were collected by filtration and washed with ethanol to obtain the title compound (740 mg) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@:11]([CH2:14][N:15]=[N+]=[N-])([F:13])[CH2:10][C@H:9]1[C:18](=[O:29])[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[F:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].P(C)(C)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@:11]([CH2:14][NH2:15])([F:13])[CH2:10][C@H:9]1[C:18](=[O:29])[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[F:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@](F)(CN=[N+]=[N-])C[C@H]1C(=O)NCc1cccc(Cl)c1F
Agent: CP(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@](F)(CN)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Reaction time: 16 h

Procedure:
To a solution of (2S,4R)-4-azidomethyl-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (380 mg, 0.884 mmol) in THF (25 mL) under N2 atmosphere at RT was added 1M PMe3 in THF (1.06 mL, 1.06 mmol). The reaction mixture was stirred for 16 h then quenched with water and extracted twice with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (CH2Cl2/MeOH 8:2) to give the desired material. MS (LC/MS): 404/406 [M+H]+, 402 [M−H]−; tR (HPLC conditions f): 1.57 min, 19F NMR (100 MHz, DMSO-d6) δ (ppm): −120, −154.
Reaction SMILES: [Si:1]([O:8]CC(Cl)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:13]([OH:17])(=[O:16])[CH2:14]O.[Si](OCl)(C(C)(C)C)(C)C.N1C=CN=C1>>[Si:1]([O:8][O:17][C:13](=[O:16])[CH3:14])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCC(=O)Cl
Reactant: O=C(O)CO
Agent: CC(C)(C)[Si](C)(C)OCl
Agent: c1c[nH]cn1
Product: CC(=O)OO[Si](C)(C)C(C)(C)C

Procedure:
Scheme I shows the preparation of tert-butyldimethylsilyloxy acetyl chloride. Glycolic acid on reaction with TBDMS-Cl (tert-butyldimethylsilyloxy chloride) in the presence of imidazole provided O-tert-butyldimethylsilyloxy acetic acid, which on reaction with oxalyl chloride gave the desired acid chloride derivative.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O-:9])=[O:8])=[C:5]([OH:12])[C:4]=1[CH2:13][NH:14][C:15](=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21]C(OC(C)(C)C)=O)[CH3:2].[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>ClCCl>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([OH:12])[C:4]=1[CH2:13][NH:14][C:15](=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH3:2]
Reactant: CCc1ccc(C(=O)[O-])c(O)c1CNC(=O)CCCCCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C(=O)O)c(O)c1CNC(=O)CCCCCN
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl(N-tert-butoxycarbonyl-6-aminohexanoyl)aminomethyl-2-hydroxybenzoate (0.58 g, 1.41 mmoles) was dissolved in dichloromethane (5 mL) and the solution was cooled in an ice/water bath. Trifluoroacetic acid (5 mL) was added, and the reaction was allowed to warm to room temperature. After 2 hours, the reaction mixture was evaporated to dryness to give the product as an oil, which was dried in vacuo over potassium hydroxide pellets to afford 0.59 g (99% yield) of ethyl (6-aminohexanoyl)aminomethyl-2-hydroxybenzoate trifluoroacetate.
Reaction SMILES: [Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=O)=[C:4]([F:11])[CH:3]=1.[CH3:12][C:13]([S@:16]([NH2:18])=[O:17])([CH3:15])[CH3:14]>S([O-])([O-])(=O)=O.[Cu+2].ClCCCl>[Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5](/[CH:6]=[N:18]/[S@@:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[O:17])=[C:4]([F:11])[CH:3]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1cc(F)c(Br)cc1F
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1cc(F)c(Br)cc1F
Temperature: 60 °C
Yield: 92.5 %

Procedure:
To a round bottom flask with stir bar was added 4-bromo-2,5-difluorobenzaldehyde (5.3 g, 24.0 mmol), (R)-2-methylpropane-2-sulfinamide (3.2 g, 26.4 mmol) and DCE (80 mL). To this mixture was then added copper (II) sulfate (5.74 g, 36.0 mmol). The reaction mixture was heated in a preheated oil bath at 60° C. for 18 hours. The reaction mixture was filtered through a pad celite, washing the solids with DCE. The filtrate was concentrated to afford a viscous green oil of (R,E)-N-(4-bromo-2,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide (7.2 g, 22.2 mmol, 93% yield). Material was taken onto next step without further purification. LCMS m/z 326.0 (M+H)+, Rt 1.04 min.
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8].[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].C(COC)OC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7]#[N:8])=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1Br
Reactant: N#Cc1ccsc1I
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: N#Cc1ccsc1-c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A solution of 2-iodothiophene-3-carbonitrile (20 g, 85 mmol, preparation 23), 4 bromobenzeneboronic acid (18.8 g. 94 mmol), potassium carbonate (26 g, 187 mmol) and tetrakis(triphenylphosphine)-palladium (0) (10 g, 8.5 mmol) in a mixture of anhydrous dimethoxyethane (300 mL) and absolute ethanol (150 mL) is degassed with Ar or N2 for 15 min and stirred for 12 hours at 80° C. The reaction mixture is cooled to room temperature, water (100 ml) is then added and the crude product is extracted with methylene chloride (3×150 mL). The crude material is purified by column chromatography (hexane-ethyl acetate 10/1) to provide the title compound as a white solid. 1H NMR (CDCl3): 7.32 (m, 2H), 7.62 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[N:16]=[CH:15][C:14]([CH2:17][C:18]([NH2:20])=[O:19])=[C:13]([NH:21][CH2:22][C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=2)[CH:12]=1.N[C:32]1C=CC(C#N)=CC=1NC1N=CC(CC(N)=O)=C(NCC2C=C(F)C=C(F)C=2)C=1.C(OC)(OC)OC>>[C:8]([C:6]1[CH:5]=[CH:4][C:3]2[N:10]([C:11]3[N:16]=[CH:15][C:14]([CH2:17][C:18]([NH2:20])=[O:19])=[C:13]([NH:21][CH2:22][C:23]4[CH:24]=[C:25]([F:30])[CH:26]=[C:27]([F:29])[CH:28]=4)[CH:12]=3)[CH:32]=[N:1][C:2]=2[CH:7]=1)#[N:9]
Reactant: N#Cc1ccc(Nc2cc(NCc3cc(F)cc(F)c3)c(CC(N)=O)cn2)c(N)c1
Reactant: N#Cc1ccc(N)c(Nc2cc(NCc3cc(F)cc(F)c3)c(CC(N)=O)cn2)c1
Solvent: COC(OC)OC
Product: N#Cc1ccc2c(c1)ncn2-c1cc(NCc2cc(F)cc(F)c2)c(CC(N)=O)cn1

Procedure:
From the mixture of 6-[(2-amino-4-cyanophenyl)amino]-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxyamide and 6-[(2-amino-5-cyanophenyl)amino]-4-[(3,5-difluorobenzyl) amino]pyridine-3-carboxyamide (1H-NMR integral ratio 3:1) and trimethyl orthoformate in a manner similar to step 2 of Example 365, the title compound was obtained as a white solid (yield 45%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[CH3:25][O:26][C:27]1[CH:40]=[CH:39][C:30]([CH2:31][N:32]2[CH2:36][C@@H:35]([CH3:37])[NH:34][C:33]2=[O:38])=[CH:29][CH:28]=1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:34]4[C@H:35]([CH3:37])[CH2:36][N:32]([CH2:31][C:30]5[CH:39]=[CH:40][C:27]([O:26][CH3:25])=[CH:28][CH:29]=5)[C:33]4=[O:38])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: COc1ccc(CN2C[C@@H](C)NC2=O)cc1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: COc1ccc(CN2C[C@@H](C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)c(F)c3)C2=O)cc1
Yield: 81.3 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (157 mg) described in Preparation Example 114 and (R)-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (106 mg) described in Preparation Example 202 and by the reaction and treatment in the same manner as in Example 1, (R)-3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (173 mg) was obtained. Using the obtained (R)-3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (173 mg) and by the reaction and treatment in the same manner as in Example 421, the title compound (106 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[NH:17][C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].S(OC)(O[CH3:31])(=O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[N:17]([CH3:31])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
using isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl]-benzoate and dimethyl sulphate in dimethylformamide there is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-3-methyl-4-trifluoromethyl-2,6-dioxo-1(2H)-pyrimidinyl]benzoate, 1H-NMR (CDCl3, 400 MHz) 7.84 ppm (d, 1H), 7.37 ppm (d, 1H), 6.38 ppm (s, 1H), 5.25 ppm (m, 1H), 3.57 ppm (d, 3H), 1,36 ppm (d, 6H),
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[NH2:18][C:19]1[C:27]2[NH:26][CH:25]=[N:24][C:23]=2[CH:22]=[CH:21][CH:20]=1>>[NH:24]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:18][C:2]3[CH:7]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=4)[N:5]=[CH:4][N:3]=3)[C:27]=2[N:26]=[CH:25]1
Reactant: Nc1cccc2nc[nH]c12
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Product: FC(F)(F)c1ccc(-c2cc(Nc3cccc4[nH]cnc34)ncn2)cc1

Procedure:
Analogous to the procedure used to prepare Example 5(b), 4-chloro-6-(4-trifluoromethylphenyl)pyrimidine, Example 5(a), (690 mg, 2.67 mmol) and 4-aminobenzimidazole (296 mg, 2.22 mmol, Astatech) afforded after purification by silica gel chromatography with gradient from 1% to 10% solution of (2 M NH3 in MeOH) in CH2Cl2, the title compound as a yellow solid. MS (ESI, pos. ion.) m/z: 356 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[CH2:4][NH:5][C:6](=[NH:14])[CH:7](OCC)OCC.ClCCl.OS(O)(=O)=O>CCOC(C)=O>[Br:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]2[C:3]=1[CH:4]=[N:5][C:6]([NH2:14])=[CH:7]2
Reactant: CCOC(OCC)C(=N)NCc1cc(F)ccc1Br
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Nc1cc2c(F)ccc(Br)c2cn1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a mixture of N-(2-bromo-5-fluorobenzyl)-2,2-diethoxyacetimidamide (1.6 g, 4.80 mmol) and dichloromethane (2 mL) was added H2SO4 (1.280 mL, 24.01 mmol). The reaction mixture was stirred at 80° C. for 16 hours, cooled to rt., diluted with EtOAc (100 mL), quenched with ice-water, and neutralized with NaHCO3 solution. The organic phase was washed with water, dried over Na2SO4, and evaporated. The residue was purified on an 80 g Thompson silica cartridge (3% to 100% EtOAc in Hexanes, 1200 mL). The desired product was obtained as a pale yellow solid (0.47 g, 1.950 mmol, 40.6% yield).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C:19]1([CH2:24][OH:25])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([NH:18][C:19]3([CH2:24][OH:25])[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: NC1(CO)CCCC1
Product: O=C(NC1(CO)CCCC1)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and 1-amino-cyclopentanemethanol (CAN 10316-79-7) as starting materials, LC-MS (UV peak area/ESI) 100%, 331.2014 (M+H)+.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[OH:9][C@@H:10]1[C:15](=[O:16])[CH:14]=[CH:13][C@@H:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:11]1.N1C=CN=C1>CN(C)C=O>[Si:5]([O:9][C@@H:10]1[C:15](=[O:16])[CH:14]=[CH:13][C@@H:12]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:11]1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(CO[C@@H]2C=CC(=O)[C@@H](O)C2)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc(CO[C@@H]2C=CC(=O)[C@@H](O[Si](C)(C)C(C)(C)C)C2)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 66.7 %

Procedure:
tert-Butyldimethychlorosilane (26 mg, 0.18 mmol, 1.5 equiv) was added to an ice-cooled solution of (4S,6S)-6-hydroxy-4-(4-methoxybenzyloxy)cyclohex-2-enone (29 mg, 0.12 mmol, 1 equiv) and imidazole (24 mg, 0.35 mmol, 3 equiv) in dimethylformamide (0.5 mL). After 45 min, the reaction mixture was partitioned between water (15 mL), saturated aqueous sodium chloride solution (15 mL), and ethyl acetate (20 mL). The layers were separated. The organic layer was washed with water (2×20 mL) and the washed solution was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by flash-column chromatography to provide 29 mg of the product, (4S,6S)-6-(tert-butyldimethylsilyloxy)-4-(4-methoxybenzyloxy)cyclohex-2-enone, as a colorless oil (87%).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].BrCC1OC(C(F)(F)F)=CC=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:20]1=[O:40].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1>>[O:40]=[C:20]1[C:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]1[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CBr
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using ethyl bromoacetate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, ethyl (2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetate was obtained (90%): mp 58-59° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.29-7.23 (m, 1H), 7.18-7.15 (m, 1H), 7.08-7.02 (m, 1H), 6.77-6.74 (m, 1H), 6.47 (s, 1H), 6.34 (s, 1H), 4.89-4.39 (m, 4H), 4.25-4.15 (m, 4H), 4.11-4.08 (m, 2H), 1.26 (t, J=9.0 Hz, 3H); MS (ES+) m/z 381.8 (M+1).
Reaction SMILES: [OH:1][C:2]1(C)[CH2:7][CH:6]([OH:8])CC(C)(C)[CH:3]1C=CC(O)CCC.C([O:22][C:23](=[O:25])[CH3:24])(=O)C>C(N(CC)CC)C.CN(C)C1C=CN=CC=1>[CH3:3][C:2]([CH2:7][C:6]([CH2:24][C:23]([OH:22])=[O:25])=[O:8])=[O:1]
Reactant: CCCC(O)C=CC1C(C)(C)CC(O)CC1(C)O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)CC(=O)O
Reaction time: 8 h

Procedure:
To a solution of 1.28 g of 1-(2,4-dihydroxy-2,6,6-trimethylcyclohexyl)hex-1-en-3-ol in 50 ml of triethylamine was slowly added 1.2 ml of acetic anhydride under ice-cooling. To the mixture was further added 120 mg of p-dimethylaminopyridine. The mixture was allowed to stand at room temperature overnight. The reaction mixture was poured onto ice and extracted with diethyl ether. The extract was washed successively with a 0.5N hydrochloric acid aqueous solution and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate, followed by filtration. The filtrate was concentrated under reduced pressure to obtain 1.25 g of a triacetate compound as an oily product. The resulting triacetate compound (1.21 g) was dissolved in 130 ml of carbon tetrachloride, followd by cooling to -5° C. to 0° C. with ice-cold sodium chloride. To the solution was slowly added dropwise 8.3 ml of bromine. After completion of the addition, the mixture was allowed to stand at 0° C. for 1 hour, washed successively with a 10% aqueous solution of sodium hydrogen carbonate and a saturated sodium chloride aqueous solution, and dried over ahhydrous magnesium sulfate. After filtration, the filtrate was concetrated under reduced pressure to obtain 1.95 g of an oily product.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:15]([NH:17][C@H:18]([C:23]([NH:25][C@H:26]([C:32]([NH:34][C@H:35]([C:40]([OH:42])=[O:41])[CH2:36][C:37](=[O:39])[NH2:38])=[O:33])[CH2:27][CH2:28][C:29](=[O:31])[NH2:30])=[O:24])[C@H:19]([CH2:21][CH3:22])[CH3:20])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=1>C(O)(=O)C.[C].[Pd]>[NH2:1][C@H:2]([C:15]([NH:17][C@H:18]([C:23]([NH:25][C@H:26]([C:32]([NH:34][C@H:35]([C:40]([OH:42])=[O:41])[CH2:36][C:37](=[O:39])[NH2:38])=[O:33])[CH2:27][CH2:28][C:29](=[O:31])[NH2:30])=[O:24])[C@H:19]([CH2:21][CH3:22])[CH3:20])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:6][CH:5]=1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)O

Procedure:
A solution of 1.2 g of the tetrapeptide derivative obtained sub (3) in 50 ml of 90% acetic acid is hydrogenated in the presence of 0.5 g of palladium carbon (10% Pd). On completion of the hydrogenation the catalyst is suctioned off, the filtrate evaporated to dryness under vacuum and the residue dried at 40° C. under a high vacuum.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[C:9]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C.CCOC(C)=O>[I:1][C:2]1[CH:7]=[CH:6][N:5]([CH3:9])[C:4](=[O:8])[CH:3]=1
Reactant: O=c1cc(I)cc[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1ccc(I)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
To a solution of 4-iodopyridin-2(1H)-one (3 g, 0.013 mol) and K2CO3 (3.55 g, 0.026 mol) in DMF (30 mL) was added iodomethane (4.7 g, 0.033 mmol). The mixture was stirred at room temperature overnight. Water and EtOAc were added. The organic phase was dried over Na2SO4 and concentrated to give 4-iodo-1-methylpyridin-2(1H)-one (1.6 g, 53%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1>CN(C)C=O>[N+:19]([C:18]1[C:13]([O:3][C:4]2[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=2[CH:6]=[O:7])=[N:14][CH:15]=[CH:16][CH:17]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: O=Cc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1Oc1ncccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 22.5 %

Procedure:
Sodium hydride (60%) (0.0899 mol) was added portionwise under N2 at room temperature to a mixture of 2-hydroxybenzaldehyde (0.0818 mol) in N,N-dimethyl-formamide and the mixture was stirred under N2 for 15 minutes. 2-Chloro-3-nitro-pyridine (0.0818 mol) in N,N-dimethylformamide was added and the mixture was stirred at 100° C. for 2 hours. The mixture was poured into ice/water, extracted with diethylether and the solvent was evaporated, yielding 4.5 g (23%) of 2-[(3-nitro-2-pyridinyl)oxy]benzaldehyde (interm. 1).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[O:4]=[S:5]1(=[O:29])[C:10]2[CH:11]=[C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23](O)=[O:24])=[CH:18][CH:17]=3)[CH:13]=[CH:14][C:9]=2[N:8]2[CH2:26][CH2:27][CH2:28][CH:7]2[NH:6]1>C1COCC1>[O:4]=[S:5]1(=[O:29])[C:10]2[CH:11]=[C:12]([O:15][C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23]([N:2]([CH3:3])[CH3:1])=[O:24])=[CH:20][CH:21]=3)[CH:13]=[CH:14][C:9]=2[N:8]2[CH2:26][CH2:27][CH2:28][CH:7]2[NH:6]1
Reactant: O=C(O)Cc1ccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)Cc1ccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)cc1

Procedure:
The procedure is as in Step A of Example 3 but replacing the ammonia gas with 2M dimethylamine in THF and 3-{4-[5,5-dioxo-2,3-dihydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl)oxy]phenyl}propanoic acid by the compound obtained in Step B. Purification is carried out by chromatography on a silica column, eluting with a mixture of CH2Cl2/MeOH 99/1, followed by crystallisation from water.