Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([O-])(C)C.[K+].[F:7][C:8]([F:24])([F:23])[C:9]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[CH2:22])=[CH:17][CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>C1COCC1>[F:7][C:8]([F:23])([F:24])[C:9]([C:10]([F:12])([F:11])[F:13])([C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[CH2:22])=[CH:17][CH:16]=1)[O:14][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]
Reactant: C=Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1ccc(C(OCC(=O)OC(C)(C)C)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102 %

Procedure:
A 1M solution of t-BuOK in THF (25.00 mL, 25.00 mmol) was slowly added to a solution of 1,1,1,3,3,3-Hexafluoro-2-(4-vinylphenyl)-2-propanol (5.48 g, 20.30 mmol) in THF (25 mL). The reaction mixture was allowed to stir at room temperature for 30 min, then cooled to −78° C. using a dry ice /acetone bath followed by the addition of t-butyl bromoacetate (3.75 mL, 25.40 mmol). The reaction mixture was allowed to slowly warm to room temperature overnight, concentrated, diluted with hexane, filtered through celite, and concentrated to provide 7.96 g of a reddish-yellow oil. This material was purified by column chromatography on silica gel using 50:1 hexane/ethyl acetate to provide 6.44 g (82%) of a colorless oil; 1H NMR (CDCl3) δ 7.60 (d, 2ArH), 7.50 (d, 2ArH), 6.75 (dd, CH═), 5.85 (dd, ═CHH), 5.40 (dd, ═CHH), 4.05 (s, CH2), 1.50 (s, t-Bu).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][OH:10])[CH2:4][CH2:3]1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C.Cl>ClCCl>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:10][CH2:9][CH2:8][CH:5]2[CH2:4][CH2:3][C:2]([CH3:11])([CH3:1])[CH2:7][CH2:6]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: CC1(C)CCC(CCO)CC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CCC(CCOS(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 13.3 %

Procedure:
To a solution of 2-(4,4-dimethylcyclohexyl)-1-ethanol (Preparation 15, 1.45 g, 9 mmol) and 4-bromobenzenesulfonyl chloride (2.53 g, 10 mmol) in dichloromethane (30 ml) was added triethylamine (1.9 ml, 13.5 mmol), and the reaction mixture was allowed to stir at room temperature for 24 h. After a further addition of 4-bromobenzenesulfonyl chloride (2.53 g, 10 mmol) and triethylamine (1.9 ml, 13.5 mmol), the reaction mixture was heated under reflux for 1 h. After allowing the reaction mixture to cool to room temperature, the mixture was treated with 2N aqueous hydrochloric acid (100 ml) and the phases were separated. The organic extract was dried (MgSO4), filtered and concentrated in vacuo to afford the crude product. The residue was purified by silica (80 g) column chromatography eluting with diethyl ether:hexane (1:20) to give the title compound as a colourless oil (450 mg, 13%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.[N+:18]([O-])([O-:20])=[O:19].[K+]>OS(O)(=O)=O.[OH-].[K+]>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([C:14]([F:16])([F:17])[F:15])[C:3]=1[N+:18]([O-:20])=[O:19]
Reactant: O=c1[nH]c2cc(F)cc(C(F)(F)F)c2[nH]c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: O=c1[nH]c2cc(F)c([N+](=O)[O-])c(C(F)(F)F)c2[nH]c1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 76.8 %

Procedure:
To a solution of 7-fluoro-5-trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione (60 mg, 0.24 mmol) in concentrated H2SO4 (1 mL) at 0° C. was added KNO3 (27 mg, 0.26 mmol, Baker). The mixture was stirred at 90°-100° C. for 14 h, then cooled to room temperature and poured into ice water (2 g). The precipitate was collected by filtration, affording 64 mg (90%) of crude title compound. It was dissolved in 1N KOH (2 mL) and filtered. The filtrate was acidified to pH=2 with 4N HCl to give a yellow precipitate, which was collected by filtration, then was dried in the air at 50° C. for 4 h, affording pure title compound (54 mg, 76%) as a yellow powder. Mp: 305°-307° C.; IR (KBr, cm-1): 3418, 3124, 2971, 1717, 1624, 1556; 1H NMR (DMSO-d6): δ 7.422 (d, 1H, J=10.2 Hz), 11.765 (br, 1H), 12.532 (s, 1H). HRMS: calcd for C9H3F4N3O4 (M+) m/z: 293.0086, found: 293.0071.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:18]=[CH:17][C:13]([N:14]([CH3:16])[CH3:15])=[CH:12][CH:11]=1.[C@@H:19]1([NH2:26])[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]1[NH2:25]>[Cu]I.O1CCOCC1>[CH3:15][N:14]([CH3:16])[C:13]1[CH:17]=[CH:18][C:10]([NH:25][C@@H:20]2[CH2:21][CH2:22][CH2:23][CH2:24][C@H:19]2[NH2:26])=[CH:11][CH:12]=1
Reactant: CN(C)c1ccc(Br)cc1
Reactant: N[C@@H]1CCCC[C@H]1N
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CN(C)c1ccc(N[C@@H]2CCCC[C@H]2N)cc1
Temperature: 110 °C
Reaction time: 70 h
Yield: 59.3 %

Procedure:
An oven-dried resealable Schlenk tube was charged with CuI (190 mg, 0.998 mmol), K3PO4 (2.10 g, 9.89 mmol), 4-bromo-N,N-dimethylaniline (1.00 g, 5.00 mmol), evacuated and backfilled with argon. trans-1,2-Cyclohexanediamine (0.60 L, 5.00 mmol) and dioxane (3.0 mL) were added under argon. The Schlenk tube was sealed and the reaction mixture was stirred magnetically at 110° C. for 70 h. The resulting dark brown suspension was cooled to room temperature and filtered through a 2×1 cm pad of Celite eluting with 50 mL of dichloromethane. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×20 cm; dichloromethane saturated with aq NH3— methanol 40:1; 20 mL fractions). Fractions 12–16 provided 692 mg (59% yield) of the product as a brown solid. 1H NMR (400 MHz, CDCl3): δ 6.75–6.63 (m, 4H), 3.00 (br s, 1H), 2.87–2.77 (m, 7H), 2.53–2.45 (m, 1H), 2.17–2.04 (m, 1H), 2.02–1.94 (m, 1H), 1.78–1.16 (m, 7H), 1.04–0.92 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 144.7, 140.9, 116.2, 116.1, 62.0, 56.5, 42.6, 35.7, 33.0, 25.8, 25.5.
Reaction SMILES: C[O:2][P:3]([CH2:7][NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])(=[O:6])[O:4]C.Br[Si](C)(C)C>C(Cl)Cl>[F:18][C:15]1[CH:14]=[CH:13][C:12]([S:9]([NH:8][CH2:7][P:3](=[O:2])([OH:6])[OH:4])(=[O:11])=[O:10])=[CH:17][CH:16]=1
Reactant: COP(=O)(CNS(=O)(=O)c1ccc(F)cc1)OC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: O=P(O)(O)CNS(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97.2 %

Procedure:
A solution of diester 35 (0.58 g, 1.95 mmol) in dry CH2Cl2 (10 mL) and bromotrimethylsilane (1.5 mL, 11.7 mmol) was stirred at room temperature for 5 hours and then concentrated. The resulting residue was dissolved in anhydrous CH3OH (10 mL) and stirred at room temperature for 20 minutes. Insolubles were filtered, and the filtrate was concentrated. Purification by trituration with CH2Cl2 gave the phosphonic acid (iv) (0.51 g, 97%) as a white solid: 1H NMR (300 MHz, CD3OD) δH 3.17 (d, J=13.5 Hz, 2 H), 7.35 (m, 2 H), 7.97 (m, 2 H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:31][CH2:32][O:33][CH3:34])=[C:7]([CH:30]=1)[C:8]([NH:10][C:11]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:12]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:9].[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][NH:39][CH3:40]>CC(C)=O>[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][N:39]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:31][CH2:32][O:33][CH3:34])=[C:7]([CH:30]=1)[C:8]([NH:10][C:11]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:12]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:9])[CH3:40]
Reactant: CNCCN(C)C
Reactant: COCOc1ccc(CBr)cc1C(=O)Nc1cc(-c2ccccc2)ccc1C(=O)OC(C)(C)C
Solvent: CC(C)=O
Product: COCOc1ccc(CN(C)CCN(C)C)cc1C(=O)Nc1cc(-c2ccccc2)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under ice-cooling, tert-butyl 2-(5-(bromomethyl)-2-(methoxymethoxy)benzamido)-4-phenylbenzoate (0.12 g) was added to an acetone (1.8 mL) solution of N,N,N′-trimethylethylenediamine (0.089 mL), followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and a saturated aqueous solution of sodium bicarbonate and chloroform were added to the residue. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-90% chloroform/methanol] to obtain 0.070 g of tert-butyl 2-(5-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)-2-(methoxymethoxy)benzamido)-4-phenylbenzoate.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[C:4]([C:10]([OH:12])=O)=[N:3]1.C1N=C[N:15](C(N2C=NC=C2)=O)[CH:14]=1.CN>C1COCC1>[CH3:14][NH:15][C:10]([C:4]1[C:5]([N+:7]([O-:9])=[O:8])=[CH:6][N:2]([CH3:1])[N:3]=1)=[O:12]
Reactant: Cn1cc([N+](=O)[O-])c(C(=O)O)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)c1nn(C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To 1-methyl-4-nitropyrazole-3-carboxylic acid (2.0 g) in THF (30 ml) was charged carbonyl-1,1′-diimidazole (1.9 g) over 1 hour at room temperature. The reaction was stirred overnight before cooling to 0° C. A solution of methylamine in THF (12 ml of a 2M solution) was added and the reaction stirred for 1 hour. The THF layer was separated and concentrated in vacuo. The crude oil was purified by column chromatography on silica (25 g), eluting with 100% EtOAc (500 ml) to give N,1-dimethyl-4-nitropyrazole-3-carboxamide, 976 mg.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([OH:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:9]([O:17][C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCO
Reactant: Brc1cnc(Br)nc1
Product: CCCCCCCCOc1ncc(Br)cn1

Procedure:
Analogously to the above procedure, 5.95 g of 2,5-dibromopyrimidine are reacted with 7.9 g of 1-octanol to give 2-octyloxy-5-bromopyrimidine. The product is purified by chromatography on silica gel.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][C@@H:40]([CH3:44])[C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([F:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:41](=[O:42])[C@@H:40]([OH:39])[CH3:44])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)cc1F
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f27) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH:11]=O.[Cl-].[CH2:14]([O:21][C:22]1[CH:47]=[CH:46][CH:45]=[CH:44][C:23]=1[CH2:24][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N12CCCN=C1CCCCC2>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH:11]=[CH:24][C:23]1[CH:44]=[CH:45][CH:46]=[CH:47][C:22]=1[O:21][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(COc2ccccc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccccc1CCC=O
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1ccccc1CCC=Cc1ccccc1OCc1ccccc1

Procedure:
Following a procedure similar to that described in the first part of Preparation 3, the whole of the 3-(2-methoxyphenyl)propanal prepared as described above, 1.65 g of 2-benzyloxybenzyltriphenylphosphonium chloride (prepared as described in Preparation 1) and 1.01 g of 1,8-diazabicyclo[5,4,0]undec-7-ene were reacted in 30 ml of acetonitrile. The crude product, extracted as described in Preparation 3, was purified by column chromatography through silica gel, using a 9:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.98 g of benzyl 2-[4-(2-methoxyphenyl)-1-butenyl]phenyl ether as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[N:5]=[C:4]2[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:15](=[O:18])[NH:16][CH2:17][C:3]=12.O.C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:42]2[CH:50]=[CH:49][C:45]([C:46]([OH:48])=[O:47])=[CH:44][CH:43]=2)O1>O1CCOCC1.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>[F:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[N:14]1[C:4]2[N:5]=[C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[N:7]=[C:2]([C:42]3[CH:50]=[CH:49][C:45]([C:46]([OH:48])=[O:47])=[CH:44][CH:43]=3)[C:3]=2[CH2:17][NH:16][C:15]1=[O:18]
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Reactant: CN(C)CCNc1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CN(C)CCNc1nc(-c2ccc(C(=O)O)cc2)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Yield: 77.7 %

Procedure:
To a solution of 5-chloro-1-(2,6-difluorophenyl)-7-{[2-(dimethylamino)-ethyl]-amino}-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (150 mg, 0.39 mmol) in dioxane (12 mL)/water (4 mL) were added potassium carbonate (325 mg, 2.36 mmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.019 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (146 mg, 0.59 mmol). The reaction mixture was bubbled with N2 for about 5 mins, then microwaved at about 150° C. for about 30 mins. The reaction mixture was concentrated. To the concentrated mixture were added DMSO (2 mL), H2O (0.5 mL) and AcOH (0.05 mL). Separation via a HPLC then provided the title compound as a white solid (142 mg, 77%). LC-MS m/z 469 (M+H)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[N:16]([CH2:17][CH2:18][OH:19])[N:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH:1]([NH:11][C:12]1[N:16]([CH2:17][CH2:18][OH:19])[N:15]=[CH:14][CH:13]=1)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccnn1CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=CO
Product: O=CNc1ccnn1CCO
Temperature: 25 °C

Procedure:
A mixture of acetic anhydride (44.5 ml) and formic acid (22.3 ml) was stirred at room temperature for an hour. To this mixture was added 5-amino-1-(2-hydroxyethyl)pyrazole (30 g) at 0°-10° C., and the mixture was stirred under ice-cooling for 30 minutes. The mixture was poured into ice-cooled water, adjusted to pH 10.5 with 40% potassium carbonate solution, and stirred under ice-cooling for 30 minutes. The mixture was extracted with a mixture of tetrahydrofuran and ethyl acetate 6 times. The organic layer was dried over magnesium sulfate, and evaporated in vacuo to give 5-formamido-1-(2-hydroxyethyl)pyrazole (30.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH2:17][OH:18])[N:14]=[CH:13]1)[N:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6](=[O:24])[NH:5]2.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH2:17][O:18][C:32](=[O:33])[NH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:14]=[CH:13]1)[N:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6](=[O:24])[NH:5]2
Reactant: O=C=Nc1ccccc1
Reactant: CCOC(=O)c1nc2cc(-n3cnc(CO)c3)c(Cl)cc2[nH]c1=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc2cc(-n3cnc(COC(=O)Nc4ccccc4)c3)c(Cl)cc2[nH]c1=O
Yield: 56.6 %

Procedure:
To a suspension of the compound (100 mg, 287 μmol) of Example 41 in ethyl acetate (3 ml) were added phenyl isocyanate (68.4 mg, 574 μmol) and triethylamine (58.1 mg, 574 μmol), and the mixture was refluxed for 24 hours. After cooling, the insolubles were filtered off and solvent was distilled off. The residue obtained was purified by means of silica gel column chromatography [ethyl acetate], thereby obtaining 76.0 mg of title compound as light brown powder. Yield 57%.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][C:3]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[CH:14](N)=[O:15].N>C(O)=O.O>[Cl:1][C:2]1[S:6][C:5]([NH:7][CH:14]=[O:15])=[N:4][C:3]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: Nc1nc(-c2cccnc2)c(Cl)s1
Reactant: NC=O
Agent: N
Solvent: O=CO
Solvent: O
Product: O=CNc1nc(-c2cccnc2)c(Cl)s1

Procedure:
5-Chloro-4-(pyridin-3-yl)-thiazol-2-amine (20 g) was dissolved in formic acid (40 ml) and formamide (20 ml) and the mixture was heated at 90° C. for six hours. After cooling, the mixture was diluted with water (240 ml) and basified with aqueous ammonia solution. The resulting solid was isolated by filtration, and dried in vacuo at 60° C. to give N-[5-chloro-4-(pyridin-3-yl)-thiazol-2-yl]-formamide, (22,8 g) Mp 229° C.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@@H:17]([O:38][Si](C(C)(C)C)(C)C)[CH2:18][C@@H:19]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([NH:8][C@H:9]([C@@H:17]([OH:38])[CH2:18][C@@H:19]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[O:29])[CH2:20][C:21]1[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@H](Cc1ccncc1)NC(=O)OCc1cccnc1)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccncc1)NC(=O)OCc1cccnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.4 %

Procedure:
A solution of 74.5 mg (0.117 mmol) of (2S,3S,5S)-2-(Boc-amino)-5-(N-((3-pyridinyl)methoxycarbonyl)amino)-1-phenyl-6-(4-pyridinyl)-3-(tert-butyldimethylsilyloxy)-hexane in 4 ml of tetrahydrofuran was treated with 102 μl of 1M solution of tetrabutylammonium fluoride in tetrahydrofuran. After being stirred at ambient temperature for 24 h, the solvent was removed in vacuo, and the residue was purified by silica gel chromatography using 10% methanol in dichloromethane to provide 51.4 mg (84%) of the desired compound as a white solid. 1H NMR (CDCl3) δ1.37 (s, 9H), 1.65 (t, 2H), 2.82-3.01 (m, 5H), 3.70 (m, 2H), 4.03 (m, 1H), 4.78 (d, 1H), 5.03 (s, 2H), 5.18 (br d, 1H), 7.06 (d, 2H, 7.16-7.31 (m, 6H), 7.61 (d, 1H), 8.44 (d, 2H), 8.57 (s , 2H). Mass spectrum: (M+H)+ =521.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:15]2[NH:16][C:17](=[O:19])[O:18][C@H:14]2[CH2:13][C@H:12]([CH2:20][O:21][Si](C(C)(C)C)(C)C)[C@H:11]1[O:29][C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CCOC(C)=O.CO>CO>[C:1]([O:9][C@@H:10]1[C@H:15]2[NH:16][C:17](=[O:19])[O:18][C@H:14]2[CH2:13][C@H:12]([CH2:20][OH:21])[C@H:11]1[O:29][C:30](=[O:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H]2OC(=O)N[C@@H]2[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1N[C@@H]2[C@@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@@H](CO)C[C@@H]2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
To a suspension of (3 aS,4R,5R,6R,7aS)-6-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxooctahydrobenzo[d]oxazole-4,5-diyl dibenzoate (3.29 g, 6.27 mmol) in dry MeOH (50 mL) at room temperature was added a solution of HCl in 4:1 EtOAc-MeOH (1.5 M, 28 mL, 41.8 mmol). The mixture was stirred at room temperature for 2 h. The solvents were evaporated to give the crude product. This was purified by SiO2 column, eluted with 60-80% EtOAc in hexanes to give (3aS,4R,5R,6R,7aS)-6-(hydroxymethyl)-2-oxooctahydrobenzo[d]oxazole-4,5-diyl dibenzoate (1.87 g, 73%). MS m/z 434.1 (M+23, 100%); 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J=7.8 Hz, 2H), 7.87 (d, J=7.8 Hz, 2H), 7.49 (t, J=7.8 Hz, 2H), 7.33 (t, J=7.8 Hz, 4H), 6.37 (s, 1H), 5.45 (dd, J=9.7 Hz, 6.8 Hz, 1H), 5.31 (t, J=10.0 Hz, 1H), 4.90-4.92 (m, 1H), 3.88 (t, J=6.8 Hz, 1H), 3.74 (dd, J=12.1 Hz, 2.5 Hz, 1H), 3.57 (dd, J=12.1 Hz, 2.0 Hz, 1H), 2.39 (d, J=13.8 Hz, 1H), 2.19-2.32 (m, 2H).
Reaction SMILES: [F:1]/[C:2](=[C:5](/[C:8]1[C:17]([O:18][CH2:19][CH2:20][CH3:21])=[CH:16][C:15]2[C:14]([CH3:23])([CH3:22])[CH2:13][CH2:12][C:11]([CH3:25])([CH3:24])[C:10]=2[CH:9]=1)\[CH2:6]C)/[CH2:3][OH:4].C[N+]1([O-])CCOCC1>C(Cl)Cl.CC#N.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[F:1]/[C:2](=[C:5](/[C:8]1[C:17]([O:18][CH2:19][CH2:20][CH3:21])=[CH:16][C:15]2[C:14]([CH3:23])([CH3:22])[CH2:13][CH2:12][C:11]([CH3:24])([CH3:25])[C:10]=2[CH:9]=1)\[CH3:6])/[CH:3]=[O:4]
Reactant: CCCOc1cc2c(cc1/C(CC)=C(/F)CO)C(C)(C)CCC2(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: CCCOc1cc2c(cc1/C(C)=C(/F)C=O)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 88.1 %

Procedure:
A mixture of (E)-2-fluoro-3-(5,5,8,8-tetramethyl-3-propoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-pent-2-en-1-ol (Intermediate 7, 1.01 g, 3.04 mmol), NMO (0.89 g, 7.60 mmol), TPAP (catalytic amount), and 4 Å molecular sieves (200 mg) in CH2Cl2—CH3CN (40 mL, 8 mL) was stirred at ambient temperature for 45 min. The mixture was loaded onto a pad of silica gel and eluted with 10% EtOAc-hexane to give the tide compound as a pale yellow solid (890 mg, 89%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[NH:11][C:10]([CH3:17])([CH3:16])[CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:20](Br)[CH2:21][CH2:22][CH3:23]>C(O)C>[CH2:20]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][C:10]([CH3:17])([CH3:16])[NH:11][C:12]([CH3:15])([CH3:14])[CH2:13]2)=[CH:4][CH:3]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCBr
Reactant: CC1(C)CC(c2ccc(O)cc2)CC(C)(C)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCOc1ccc(C2CC(C)(C)NC(C)(C)C2)cc1

Procedure:
1 Part of 4-(4-hydroxyphenyl)-2,2,6,6-tetramethylpiperidine was dissolved in warm ethanol and treated with 0.172 parts of sodium hydroxide dissolved in ethanol. The solution was stirred and heated to reflux whilst 0.65 parts of n-butyl bromide dissolved in ethanol was added. The solution was heated at reflux overnight and then evaporated under reduced pressure. The residue was dissolved in ether and washed with water, sodium hydroxide solution (3%) and further water. The organic layer was dried (MgSO4) and evaporated under reduced pressure. The residue was distilled to yield the desired product having b.p. 160°/0.2 mm. and the following elemental analysis: