Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:11][C:12]=2[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:37][C:38]1[CH:43]=[CH:42][C:41]([P:44](=[O:51])([O:48][CH2:49][CH3:50])[O:45][CH2:46][CH3:47])=[CH:40][CH:39]=1>O.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[O:11][C:12]=2[CH2:13][CH2:14][C:15]([NH:37][C:38]2[CH:43]=[CH:42][C:41]([P:44]([O:48][CH2:49][CH3:50])([O:45][CH2:46][CH3:47])=[O:51])=[CH:40][CH:39]=2)=[O:17])=[CH:6][CH:7]=1
Reactant: CCOP(=O)(OCC)c1ccc(N)cc1
Reactant: O=C(O)CCc1oc(-c2ccccc2)nc1-c1ccc(Cl)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(OCC)c1ccc(NC(=O)CCc2oc(-c3ccccc3)nc2-c2ccc(Cl)cc2)cc1
Reaction time: 1 h
Yield: 35.9 %

Procedure:
To a mixture of 4-(4-chlorophenyl)-2-phenyl-5-oxazolepropionic acid (500 mg), triethylamine (230 mg) and tetrahydrofuran (10 ml) was added ethyl chlorocarbonate (250 mg) at −40° C., and the mixture was stirred for 1 hr. Diethyl 4-aminophenylphosphonate (420 mg) was added, and the mixture was stirred at room temperature for 5 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography and 3-[4-(4-chlorophenyl)-2-phenyl-5-oxazolyl]-N-[4-(diethylphosphono)phenyl]propionamide (295 mg, yield 36%) was obtained as colorless prism crystals from a fraction eluted with ethyl acetate-chloroform (1:1, volume ratio). melting point: 139–140° C. (recrystallized from dichloromethane-isopropyl ether).
Reaction SMILES: [Br:1][C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:25]([C:27]1C=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[OH:26].[Li+].CC([N-:38]C(C)C)C.ClC1C=CC(C=O)=NC=1>C1COCC1.CC(=O)OCC.O>[Br:1][C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:25]([C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][N:38]=1)[OH:26]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Br)cnc21
Reactant: CC(C)[N-]C(C)C
Agent: O=Cc1ccc(Cl)cn1
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cn3)c(Br)cnc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 138.9 %

Procedure:
To a solution of 6-bromo-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 20, step 4, 398 mg, 0.10 mmol) in THF (10 mL) at −78° C. was added LDA (2M in THF, 2.50 mL, 5.00 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then 5-chloropicolinaldehyde (211 mg, 1.50 mmol) in THF (2 mL) was added. The reaction was stirred at −78° C. for 40 min then diluted with EA (20 mL) and water (10 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (8:1) to give 6-bromo-5-((5-chloropyridin-2-yl)(hydroxy)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (75 mg, 13.9% yield) as a solid. LCMS: MH+ 541 and TR=1.773 min.
Reaction SMILES: [CH2:1]([CH:4]1[C:8]([OH:10])([CH3:9])[CH:7]=[CH:6][C:5]1=[O:11])[CH:2]=[CH2:3].[C:12](OC(=O)C)(=[O:14])[CH3:13]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:12]([O:10][C:8]1([CH3:9])[CH:7]=[CH:6][C:5](=[O:11])[CH:4]1[CH2:1][CH:2]=[CH2:3])(=[O:14])[CH3:13]
Reactant: C=CCC1C(=O)C=CC1(C)O
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C=CCC1C(=O)C=CC1(C)OC(C)=O
Yield: 95.9 %

Procedure:
lnto a flask equipped with a stirrer and a thermometer, dl-2-allyl-3-hydroxy-3-methyl-4-cyclopentenone (152 g), p-toluenesulfonic acid (1 g) and acetic anhydride (320 g) were charged, and the resultant mixture was stirred at 100° C. for 2 hours. After completion of the reaction, acetic anhydride was removed under reduced pressure, and the residue was extracted with toluene. The toluene layer was washed with 1% sodium bicarbonate solution and water in order. Toluene was removed from the toluene layer to give dl-3-acetoxy-2-allyl-3-methyl-4-cyclopentenone (186 g). Yield, 96%. B.P., 72°-75° C./0.2-0.3 mmHg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH:12]=[C:13]([CH3:17])[C:14]([OH:16])=[O:15].[CH:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[C:20](O)[CH:19]=1.CN(C1C=CC=CN=1)C.Cl.C(N=C=NCCCN(C)C)C>CCCCCC.C(OCC)(=O)C.ClCCl>[N+:24]([C:23]1[CH:18]=[CH:19][C:20]([O:15][C:14](=[O:16])[C:13]([CH3:17])=[CH:12][C:3]2[CH:4]=[C:5]([O:10][CH3:11])[C:6]([O:8][CH3:9])=[CH:7][C:2]=2[NH2:1])=[CH:21][CH:22]=1)([O-:26])=[O:25]
Reactant: COc1cc(N)c(C=C(C)C(=O)O)cc1OC
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(N)c(C=C(C)C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1OC

Procedure:
Into 20 ml of dichloromethane, 0.82 g (3.5 mmol) of (E) 3-(2-amino-4,5-dimethoxyphenyl)-2-methyl-2-propenoic acid and 0.97 g (7 mmol) of p-nitrophenol (manufactured by Wako Pure Chemical Industries, Ltd.) were dissolved, and 40 mg of dimethylaminopyridine (manufactured by Wako Pure Chemical Industries, Ltd.) were added thereto. While this mixture was stirred under cooling with ice, 0.81 g (4.2 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC/HCl) (manufactured by Wako Pure Chemical Industries, Ltd.) were added thereto in portions. The mixture was returned to room temperature and then was stirred for 20 hours. After the end point of the reaction was verified by TLC, the reaction liquid was concentrated under a reduced pressure and then was dissolved in 100 ml of ethyl acetate. After this solution was washed and dried, the solvent was evaporated, whereby a syrupy crude product was obtained. This product was refined by a silica gel column chromatography (n-hexane/ethyl acetate=2/1), whereby 0.15 g of the aimed compound was obtained as a yellow crystal (yield: 12%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:34])([CH3:33])[C@@H:11]([O:23]CC1C=CC(OC)=CC=1)[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:13])(=[O:7])=[O:6].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl.O>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:33])([CH3:34])[C@@H:11]([OH:23])[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:13])(=[O:7])=[O:6]
Reactant: CCOC(=O)OCCOC(=O)[C@H](OCc1ccc(OC)cc1)C(C)(C)COS(=O)(=O)CCCCl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)OCCOC(=O)[C@H](O)C(C)(C)COS(=O)(=O)CCCCl
Yield: 19 %

Procedure:
Following the general procedure for the oxidative cleavage of (4-methoxy)benzyl ethers of Description 19, (ethoxycarbonyloxy)ethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-2-[(4-methoxyphenyl)methoxy]-3,3-dimethylbutanoate (36a) (0.77 g max.) dissolved in a mixture of dichloromethane (DCM) and water (10:1) (10 mL) was treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (0.68 g, 3.0 mmol). After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 0.2 g (19% yield over two steps) of the title compound (36b) as a colorless oil. Rf=0.57 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3, both diastereomers): δ=0.99-1.01 (2s, 3H), 1.12-1.14 (2s, 3H), 1.32-1.37 (m, 3H), 1.59-1.62 (m, 3H), 2.31-2.38 (m, 2H), 2.89-2.94 (2d, J=6.0, 6.8 Hz, 1H), 3.31-3.35 (m, 2H), 3.69-3.72 (m, 2H), 3.97-4.02 (m, 1H), 4.06-4.08 (m, 1H), 4.10-4.22 (m, 1H), 4.21-4.28 (m, 2H), 6.83-6.89 (m, 1H) ppm. MS (ESI) m/z: 426.94 (M+H)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[CH:4]=[N:3]1.C(N(CC)CC)C.[N:44]1([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.O>CN(C)C=O>[CH3:1][N:2]1[C:6]([NH:7][C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:5]([NH:27][C:28]([N:47]2[CH2:48][CH2:49][N:44]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:45][CH2:46]2)=[O:29])[CH:4]=[N:3]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cn1ncc(NC(=O)Oc2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1ncc(NC(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 85.6 %

Procedure:
To a suspension of phenyl [1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]carbamate (4.6 g) in N,N-dimethylformamide (32 ml) were added triethylamine (1.08 g) and tertbutyl 1-piperazinecarboxylate (1.99 g). The reaction mixture was stirred for 3 hours and poured into water. The mixture was extracted with ethyl acetate, and the organic layer was concentrated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate→ethyl acetate:ethanol=20:1) to give tert-butyl 4-({[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}carbonyl)-1-piperazinecarboxylate (4.7 g)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1COCC(O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN([C@@H](C(=O)NC)CC1C=CC=CC=1)C(=O)[C@H](NC)CC1C=CC2C(=CC=CC=2)C=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)NC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S)-2-(((carboxy)methoxy)methyl)-pyrrolidin-1-carboxylic acid tert-butylester (1.2 g, 4.5 mmol) in dichloromethane (20 ml) were added 1-hydroxy-7-azabenzotriazole (612 mg, 4.5 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (950 mg, 4.95 mmol) and the mixture was stirred for 30 min. (2R)-N-Methyl-2-methylamino-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide (605 mg, 1.5 mmol) in dichloromethane (10 mL) was added followed by diisopropylethylamine (0.33 ml, 2.0 mmol) and the mixture was stirred for 2 hours at room temperature. The mixture was washed with water (10 ml), aqueous sodium bicarbonate (10 ml), water (2×10 ml), brine (10 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (40 g) with ethyl acetate/heptane 4:1 to give 760 mg of (2S)-2-([N-methyl-N(1R)-1-(N-methyl-N-[(1R)-1-(methylcarbamoyl)-2-phenylethyl]carbamoyl)-2-(2-naphthyl)ethyl}carbamoyl]methoxymethyl)pyrrolidine-1-carboxylic acid tert-butylester. The obtained product was taken up in 50% trifluoroacetic acid in methylene chloride (5 ml) and stirred for 10 min. Then saturated sodium bicarbonate was added until pH 8 and the phases were separated. The aqueous phase was extracted with dichloromethane (2×10 ml) and the combined organic phases were washed with brine (5 ml), dried over magnesium sulfate and concentrated in vacuo. The product was redissolved in water (30 ml) and acetic acid (2 ml) was added and the mixture was liophilized to give 720 mg of the acetate salt of the title compound as an amorphous powder.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.[C:18](Cl)(=[O:21])[CH:19]=[CH2:20]>ClCCl.O>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:18](=[O:21])[CH:19]=[CH2:20]
Reactant: c1ccc2c(c1)CCNC2
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)N1CCc2ccccc2C1
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 56817.1 %

Procedure:
To a stirred solution of 1,2,3,4-tetrahydroisoquinoline (1 g, 7.52 mmol) in anhydrous dichloromethane (10 ml) was added triethylamine (4.17 ml, 30.00 mmol) and acryloyl chloride (0.73 ml, 9.02 mmol) at 0° C. The reaction mixture was stirred at 20-35° C. for 16 h. The progress of the reaction was monitored by TLC. After 16 h of stirring, the reaction mixture was diluted with water (50 ml) and extracted with dichloromethane (2×50 ml). The combined organic layers were washed with brine (50 ml), followed by drying over anhydrous Na2SO4 and filtering. The filtrate was rotary evaporated to get residue which was purified by column chromatography using a mixture of 40% ethyl acetate/pet ether as an eluent to get the desired compound as a pale brown liquid (800 g, 57%). 1H NMR (400 MHz, DMSO-d6) δ 7.24-7.06 (m, 4H), 6.70-6.60 (m, 1H), 6.33 (dd, J=16.6, 1.5 Hz, 1H), 5.73 (dd, J=10.5, 1.7 Hz, 1H), 4.80 (s, 1H), 4.73 (s, 1H), 3.89 (t, J=5.8 Hz, 2H), 3.78 (t, J=5.8 Hz, 2H).
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:25]=[CH:24][C:16]3[N:17]([CH2:20][CH:21]4[CH2:23][CH2:22]4)[N:18]=[N:19][C:15]=3[C:14]=2[C:26]([F:29])([F:28])[F:27])=[CH:9][CH:8]=1)(=O)=O.Cl.[NH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH:21]1([CH2:20][N:17]2[C:16]3[CH:24]=[CH:25][C:13]([C:10]4[CH:11]=[CH:12][C:7]([CH2:6][NH:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:8][CH:9]=4)=[C:14]([C:26]([F:29])([F:27])[F:28])[C:15]=3[N:19]=[N:18]2)[CH2:23][CH2:22]1
Reactant: CCOC(=O)CN
Reactant: CS(=O)(=O)OCc1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)CNCc1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-[1-(Cyclopropylmethyl)-4-(trifluoromethyl)-1H-benzotriazol-5-yl]benzyl methanesulfonate (0.12 mg, 0.28 mmol) was dissolved in acetonitrile (2.8 mL) and treated the mixture with ethyl aminoacetate hydrochloride (150 mg, 1.1 mmol), cesium carbonate (270 mg, 0.824 mmol) and tetra-n-butylammonium iodide (51 mg, 0.14 mmol). The mixture was placed into an oil bath preheated to 85° C. and stirred for 2 h, at which time the mixture was cooled to ambient temperature, diluted with ethyl acetate and washed with sodium bicarbonate (2×30 mL, aqueous saturated). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC (85:15 to 42:58; water with 0.05% trifluoroacetic acid:acetonitrile with 0.05% trifluoroacetic acid) to afford the titled compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:15])[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[N+:35]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([NH2:44])[C:39]=1[NH2:45])([O-:37])=[O:36].C([O-])(O)=O.[Na+]>C(Cl)Cl.C(Cl)CCl>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][CH2:11][C:12](=[O:14])[NH:44][C:40]1[CH:41]=[CH:42][CH:43]=[C:38]([N+:35]([O-:37])=[O:36])[C:39]=1[NH2:45])[CH3:15])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(CCCC(=O)O)C(=O)OC(C)(C)C
Reactant: Nc1cccc([N+](=O)[O-])c1N
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: CN(CCCC(=O)Nc1cccc([N+](=O)[O-])c1N)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 96 h
Yield: 37 %

Procedure:
To a solution of 9 g of 4-(tert-butoxycarbonyl-methyl-amino)-butyric acid (prepared from 4-(methylamino)butyric acid and BOC anhydride) in 159 mL DCM were added 14.2 mL of DIPEA, 8 g of HOBt and 9.1 g of EDC. After stirring for 5 min 6.1 g of 3-nitro-benzene-1,2-diamine were added and the mixture was stirred for 4 days at rt. Saturated aq. NaHCO3 solution was added, the phases were separated and the organic phase washed with brine. The combined organic phases were dried over MgSO4, and concentrated in vacuo. Purification by CC using EtOAc/heptane 1/4 to 3/1 yielded 5.2 g of [3-(2-Amino-3-nitro-phenylcarbamoyl)-propyl]methyl-carbamic acid tert-butyl ester as orange foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([OH:11])=[CH:6][C:5]=1[OH:12].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([O:11][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:6][C:5]=1[OH:12]
Reactant: COC(=O)c1cc(Br)c(O)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(OCc2ccccc2)cc1O
Temperature: 70 °C
Yield: 45.5 %

Procedure:
To a solution of 5-Bromo-2,4-dihydroxy-benzoic acid methyl ester (1.0 g, 4.04 mmol) in DMF (7 mL) was added Cs2CO3 (1.58 g, 4.85 mmol) and benzylbromide (0.69 g, 4.04 mmol) and heated at 70° C. for 6 h. Reaction mixture was diluted with EtOAc (10 mL) and filtered, filtrate was washed with water, brine and dried over Na2SO4. Solvent was removed under reduced pressure and silicagel column chromatography (EtOAc:Hex, 1:3) gave pure 4-benzyloxy-5-bromo-2-hydroxy-benzoic acid methyl ester (0.62 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[F:10].[I:11]I>C(Cl)Cl.FC(F)(F)S([O-])(=O)=O.[Ag+]>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([I:11])=[CH:4][C:3]=1[F:10]
Reactant: COc1ccc(F)c(Br)c1
Reactant: II
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: COc1cc(Br)c(F)cc1I
Reaction time: 0.33 h
Yield: 89.2 %

Procedure:
To a solution of 2-bromo-1-fluoro-4-methoxybenzene (500.0 g, 2.44 mol, 1.0 equiv) in DCM (5.0 L) was added silver trifluoromethane sulfonate (686.0 g, 2.68 mol, 1.1 equiv, Angene) and the reaction mixture was stirred for 20 mins. Iodine (678.0 g, 2.68 mol, 1.1 equiv) was added to the reaction and the mixture was stirred at room temperature for 16 h. The mixture was diluted with DCM (3.0 L) and filtered through celite. The celite bed was washed with DCM (2×1.0 L) and the filtrate was washed with 20% aqueous sodium thiosulfate (3.0 L) and saturated aqueous sodium bicarbonate solution (3.0 L). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude material which was purified by chromatography (silica gel; mesh size 60-120, elution 0-5% ethyl acetate and petroleum ether) to get 1-bromo-2-fluoro-4-iodo-5-methoxybenzene (720 g, 87%), as off-white solid. TLC solvent system: 100% hexanes. Product's Rf: 0.6. MS (ESI, positive ion) m/z: 331.0 (M+1). 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J=7.2 Hz, 1H), 6.95 (d, J=5.6 Hz, 1H), 3.89 (s, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[C:11]([O:15][C:16]([N:18]1[CH:23]2[CH2:24][CH2:25][CH:19]1[CH2:20][C:21](=[O:26])[CH2:22]2)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(O)(=O)C>C1COCC1>[C:11]([O:15][C:16]([N:18]1[CH:23]2[CH2:24][CH2:25][CH:19]1[CH2:20][C:21]([OH:26])([C:2]1[O:1][CH:5]=[CH:4][N:3]=1)[CH2:22]2)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Reactant: c1cocn1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1ncco1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
Borane-THF complex (1M, 4.5 mL, 4.5 mmol) was added to a solution of oxazole (0.3 mL, 4.5 mmol) in THF (5 mL) and stirred for 1 hour under nitrogen before cooling to −78° C. n-Butyl lithium (2.5M, 1.8 mL, 4.5 mmol) was added and the reaction mixture stirred for a further 30 minutes. A solution of 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.675 g, 3.0 mmol) in THF (5 mL) was added and the reaction mixture stirred for 30 minutes. 10% acetic acid in IMS (10 mL) was added and the reaction mixture warmed to room temperature and then further to 40° C. for 30 minutes. The solvent was removed by evaporation under vacuum, water and ethyl acetate were added to the residues, the organics extracted, dried over magnesium sulphate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica eluting with 25-60% ethyl acetate/cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.3 g) as a colourless oil. LCMS m/z 295.2 [M+H]+. R.T.=3.07 min (Analytical Method 3).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:15])=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.[C:16]([N:24]=[C:25]=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCCCCC>CC(C)=O>[C:16]([NH:24][C:25]([NH:15][C:4]1[C:3]([O:2][CH3:1])=[CH:8][N:7]=[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=1)=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1cnc(N2CCOCC2)cc1N
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CCCCCC
Solvent: CC(C)=O
Product: COc1cnc(N2CCOCC2)cc1NC(=S)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66.1 %

Procedure:
To a stirred solution of 27.5 g (132 mmol) 5-methoxy-2-morpholin-4-yl-pyridin-4-ylamine in 400 ml acetone was added dropwise 19.5 ml (145 mmol) benzoyl isothiocyanate at room temperature. The reaction mixture then heated at reflux for 90 min before being cooled to room temperature and poured onto 400 ml hexane and stirred for 5 min. The resulting crystals were collected by filtration, washed with hexane and dried to afford 32.5 g (66%) 1-benzoyl-3-(5-methoxy-2-morpholin-4-yl-pyridin-4-yl)-thiourea as a brown crystalline solid. ES-MS m/e (%): 373 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1C[CH2:15][CH2:14][CH2:13]1>>[C:2]1([CH2:1][O:8][CH2:9][C@@H:10]([OH:11])[CH2:15][CH:14]=[CH2:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: O=CCOCc1ccccc1
Product: C=CC[C@H](O)COCc1ccccc1

Procedure:
The optically active tetrahydrofuran derivatives are prepared according to Scheme V. Benzyloxyacetaldehyde is reacted with optically active 2-allyl-1,3,2-dioxaborolane-4,5-dicarboxylic acid ester, XVII, to give optically pure (S)-1-phenylmethoxy-4-penten-2-ol, XVIII. Cyclization of alcohol, XVIII, with iodine in the presence of sodium bicarbonate gives a mixture of optically pure 2,5-anhydro-1,3-dideoxy-1-iodo-D-threopentitol, XIX, ##STR111## and 2,5-anhydro-1,3-dideoxy-1-iodo-D-erythro-pentitol, XX, which is separated by flash chromatography using silica gel. ##STR112##
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:27][NH2:28].Cl>C(#N)C>[CH3:27][NH:28][CH2:12][CH:13]1[O:18][C:17]2[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: CN
Agent: Cl
Solvent: CC#N
Product: CNCC1COc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 5 using [7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.4 g, 0.9 mmol), methanamine (33% in EtOH, 1 ml) and ACN (3 ml). Yield: 0.2 g, 76%. The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 273° C. MS m/z (rel. intensity, 70 eV) 257 (M+, 79), 79 (bp), 70 (70), 63 (59), 51 (83).