Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[C:2]([SiH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:5])([CH3:4])[CH3:3].[C@H:19]1([N:27]2[CH:34]=[CH:33][C:31](=[O:32])[NH:30][C:28]2=[O:29])[O:24][C@@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[CH2:20]1>N1C=CC=CC=1>[Si:6]([O:26][CH2:25][C@@H:23]1[O:24][C@H:19]([N:27]2[CH:34]=[CH:33][C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:20][C@@H:21]1[OH:22])([C:2]([CH3:5])([CH3:3])[CH3:4])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=c1ccn([C@@H]2C[C@H](O)[C@H](CO)O2)c(=O)[nH]1
Reactant: CC(C)(C)[SiH](c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: c1ccncc1
Product: CC(C)(C)[Si](OC[C@@H]1O[C@H](n2ccc(=O)[nH]c2=O)C[C@@H]1O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.8 %

Procedure:
Tert-butyldiphenylsilane chloride (0.9 ml; 3.50 mmol) is added to a solution of 7a (0.6 g; 2.63 mmol) in anhydrous pyridine (8 ml). The solution is stirred for 4 h at room temperature and then the solvent is evaporated under reduced pressure. Water and dichloromethane are added. The organic phase is separated, washed successively with a saturated aqueous sodium hydrogen carbonate solution and water, dried over sodium sulfate and filtered. After evaporation to dryness, the residue is chromatographed on a silica gel column [eluent: step gradient of methanol (0-2%) in dichloromethane] to give 1.2 g (98%) of 8a in the form of a foam: 1H NMR (DMSO-d6) δ ppm: 11.26 (s, 11H, 3-NH), 7.78 (d, 1H, H-6; J=8.2 Hz), 7.65-7.35 (m, 10 H, 2 C6H5), 6.09 (dd, 1H, H-1′; J=1.9 and 6.4 Hz), 5.55 (d, 1H, H-5; J=8.2 Hz), 5.30 (d, 1H, OH-3′: J=3.1 Hz), 4.25 (m, H, H-3′), 4.05-3.95 (m, 2H, H-4′ and 5′), 3.85-3.80 (m, 1H, H-5″), 2.6-2.5 (m, 1H, H-2′ partially obscured by DMSO-d5), 1.85 (dd, 1H, H-2″; J=1.9 and 16.5 Hz), 0.93 [s, 9H, (CH3)3C]; mass spectrum (matrix: glycerol-thioglycerol: 50:50, v/v): FAB<0 465 [M−H]− and 111 [B]−.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:25])[C:7]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)=[C:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:38][S:39]([NH2:42])(=[O:41])=[O:40].C1CCN2C(=NCCC2)CC1>C1COCC1>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:25])[C:7]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH:42][S:39]([CH3:38])(=[O:41])=[O:40])=[O:21])=[CH:18][CH:17]=3)=[C:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1ccc(-c2c(C(F)(F)F)oc3cc(O)ccc3c2=O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CS(=O)(=O)NC(=O)c1ccc(-c2c(C(F)(F)F)oc3cc(O)ccc3c2=O)cc1
Reaction time: 2 h

Procedure:
Synthesis: To a solution of 4-(7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-chromen-3-yl)benzoic acid (synthesis is described in PCT/US2010/024035) (100 mg, 0.28 mmol) in THF (10 ml) was added CDI (139 mg, 0.86 mmol) at room temperature. The mixture was stirred for 2 hours. MeSO2NH2 (280 mg, 2.86 mmol) was added in one portion, followed by DBU (394 mg, 2.86 mmol). The mixture was stirred for 4 hours and partitioned between 1N HCl (30 ml) and ethyl acetate (100 ml). The organic phase was separated, washed with brine (50 ml), dried over Na2SO4 and concentrated to give the desired product contaminated with the acid starting material. The mixture was difficult to purify and the acid contaminant was converted into the methyl ester by treatment with SOCl2 (91 mg, 0.77 mmol) in MeOH (4 ml) at 0° C. When the addition was complete, the mixture was stirred for 3 days. The volatiles were removed under reduced pressure and the residue was purified by prep-HPLC to afford the desired product in Example 10 as a white powder (25 mg, 20.5%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH:7]=1>CC(C)=O.[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:7][CH2:8][C:9](=[O:12])[CH2:10][CH2:11]1
Reactant: O=C1CC=C(CCCCO)CC1
Agent: [Pd]
Solvent: CC(C)=O
Product: O=C1CCC(CCCCO)CC1
Reaction time: 3 h

Procedure:
To a solution of 4.63 g of 4-(4-hydroxybutyl)-cyclohex-3-ene-1-one in 130 ml acetone is added 0.46 g of 10% palladium on carbon and the suspension is then hydrogenated at 3 atmospheres (=3.04 bar) pressure for 3 h. The catalyst is evaporated to dryness to give 4-(4-hydroxybutyl)-cyclohexanone as an oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[C:6]=2[O:5]1.C(N(C(C)C)CC)(C)C.Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>>[Cl:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[C:12]1[C:6]2[O:5][CH:4]([CH2:3][N:2]([CH3:1])[C:31](=[O:32])[O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:8][C:7]=2[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNCC1Cc2cccc(-c3c(Cl)cccc3Cl)c2O1
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC1Cc2cccc(-c3c(Cl)cccc3Cl)c2O1)C(=O)OCc1ccccc1
Yield: 101.3 %

Procedure:
Treatment of (±)-[(N-methyl-1-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (1.1 g, 3.57 mmol) with diisopropylethylamine (0.69 g, 5.35 mmol) and benzyl chloroformate (0.0.82 g, 4.28 mmol) generally according to the procedure described for Intermediate 12 provided 1.6 g (99%) of (±)-benzyl {[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylcarbamate as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Cl:20])[N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:8]=12)(=[O:3])[NH2:2].C(OCC)(=O)C.[Br:27]N1C(=O)CCC1=O.O>ClCCl>[Br:27][C:5]1[C:4]([C:1](=[O:3])[NH2:2])=[C:8]2[CH2:9][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:11][CH2:12][N:7]2[C:6]=1[Cl:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCn2c(Cl)cc(C(N)=O)c2C1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCn2c(Cl)c(Br)c(C(N)=O)c2C1
Temperature: 0 °C
Reaction time: 5 h
Yield: 37.6 %

Procedure:
To a solution of 10.5 g (35.1 mmol) of tert-butyl 8-carbamoyl-6-chloro-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in 1 l of a mixture of 50% ethyl acetate in dichloromethane precooled to 0° C. is added slowly a solution of 6.90 g (38.6 mmol) of N-bromosuccinimide in 200 ml of dichloromethane. The reaction is stirred for 5 hours at 0° C. and then for 12 hours while allowing the temperature to return to room temperature. 300 ml of water are then added, the organic phase is separated out by settling and the aqueous phase is then washed with twice 200 ml of ethyl acetate. The organic phases are combined and partially concentrated under reduced pressure. The solution is taken up in 60 ml of water and the organic solvents are removed by evaporation under reduced pressure. The insoluble matter suspended in water is isolated by filtration, washed with water and then dried under reduced pressure in the presence of phosphorus pentoxide. The residue obtained is chromatographed on a column of silica gel, eluting with a mixture of 5 to 50% ethyl acetate in dichloromethane, to give 5.0 g of tert-butyl 7-bromo-8-carbamoyl-6-chloro-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in the form of a white solid after triturating in ethyl acetate and drying at 60° C. under reduced pressure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH:6]=[CH:5]2.[Li]CCCC.[CH2:19]([O:26][C:27]1[C:32]([O:33][CH3:34])=[CH:31][C:30]([CH2:35][CH:36]=[O:37])=[CH:29][C:28]=1[O:38][CH3:39])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:19]([O:26][C:27]1[C:32]([O:33][CH3:34])=[CH:31][C:30]([CH2:35][C:36]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[O:8][C:7]([CH3:13])([CH3:12])[CH:6]=[CH:5]3)=[O:37])=[CH:29][C:28]=1[O:38][CH3:39])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1cc(CC=O)cc(OC)c1OCc1ccccc1
Reactant: CC1(C)C=Cc2cc(Br)ccc2O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(CC(=O)c2ccc3c(c2)C=CC(C)(C)O3)cc(OC)c1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 20 %

Procedure:
To a cooled (−78° C.) stirring solution of 6-bromo-2,2-dimethyl-2H-chromene, which was prepared according to Chemistry and Biology, 2000, Vol. 7, p. 979, (567.7 mg, 2.38 mmol) in THF (7 mL) was added n-BuLi (2.88 M, 0.94 mL, 2.71 mmol). After completion of addition, the reaction mixture continued to stir at −78° C. After 25 minutes, (4-benzyloxy-3,5-dimethoxy-phenyl)-acetaldehyde (619.6 mg, 2.17 mmol) dissolved in THF (7.0 mL) was added. After completion of addition the reaction continued to stir for 15 minutes and was then quenched with saturated ammonium chloride. The aqueous layer was separated and extracted with ethyl acetate. All Combined organic layers were dried over sodium sulfate, filtered, and concentrated to yield a crude oil. The crude material was purified by silica gel chromatography (3:1 ethyl acetate:hexanes) to yield the desired product (200.5 mg, 20% yield).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[C:13]([OH:18])[CH:12]=1>CN(C)C=O>[N+:8]([C:7]1[C:2]([NH:17][C:16]2[CH:11]=[CH:12][C:13]([OH:18])=[CH:14][CH:15]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: Nc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccnc1Nc1ccc(O)cc1
Temperature: 100 °C
Reaction time: 0.67 h
Yield: 81.3 %

Procedure:
8.17 g (50 mmol) of 2-chloro-3-nitropyridine and 16.70 g (150 mmol) of p-aminophenol were added to 50 ml of dimethylformamide and the mixture was stirred at 100° C. for 40 min. The solvent was distilled off under reduced pressure, the same treatment as that of Production Example 1 was repeated and the product was recrystallized from ethanol to obtain 9.4 g of the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[C:7]([CH3:12])[CH:6]=1)[CH:2]=[CH2:3].C([Li])CCC.C[O:19][C:20](=O)[O:21]C>C1COCC1>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:20]([OH:21])=[O:19])=[C:7]([CH3:12])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(Br)c(C)c1
Reactant: COC(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCOc1ccc(C(=O)O)c(C)c1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
To a solution of 4-allyloxy-1-bromo-2-methyl-benzene (10.87 g, 47.9 mmol) in THF (125 mL), a solution of n-butyl lithium (45 mL, 1.5 M in diethyl ether) is added at −75° C. The mixture is stirred at −75° C. for 30 min before it is transferred via a double-tip needle into a cooled (0° C.) solution of dimethylcarbonate (12.93 g, 144 mmol) in THF (45 mL). The mixture is stirred at 0° C. for 2 h, then at rt for 20 h before the solvents are removed in vacuo. The remaining oil is evaporated twice from ethanol (100 mL) before it is dissolved in 2 M aq. LiOH solution (75 mL) and ethanol (100 mL). The mixture is stirred at rt for 2 days and at 60° C. for 1 h. The org. solvent is evaporated and the remaining solution is diluted with 0.5 M aq. NaOH solution and extracted with diethyl ether (100 mL). The org. extract is washed with 1 M aq. NaOH solution (150 mL). The combined basic aq. extracts are washed with diethyl ether (100 mL), acidified with 25% aq. HCl and extracted with DCM (2×100 mL). The DCM extracts are combined, dried over MgSO4, filtered, concentrated and dried under high vacuum to give 4-allyloxy-2-methyl-benzoic acid (5.83 g) as an orange solid; LC-MS: tR=0.87 min; [M+1]+=not detectable; 1H NMR (CDCl3): δ 2.66 (s, 3H), 4.62 (dt, J=5.3, 1.5 Hz, 2H), 5.34 (dq, J=10.5, 1.5 Hz, 1H), 5.45 (dq, J=17.1, 1.5 Hz, 1H), 6.03-6.13 (m, 1H), 6.79-6.83 (m, 2H), 8.08 (d, J=9.5 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:14])[CH3:13])[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[NH:25][CH:26]=[N:27]2.[Na]>C(O)CCC>[F:1][C:2]1[CH:11]=[C:10]([CH:12]([NH:14][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][NH:27]3)[CH3:13])[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(N)c1cc(F)c2cccnc2c1-c1cccc(F)c1
Reactant: Clc1ncnc2nc[nH]c12
Agent: [Na]
Solvent: CCCCO
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(F)c2cccnc2c1-c1cccc(F)c1
Temperature: 110 °C

Procedure:
A mixture of 1-[5-fluoro-8-(3-fluorophenyl)quinolin-7-yl]ethanamine (0.39 g, 1.4 mmol, 6-chloropurine (0.27 g, 1.8 mmol) and sodium hydrogenecarbonate (0.17 g, 2.0 mmol) in 1-butanol (4 mL) was heated at 110° C. overnight. The mixture was filtered and purified on a preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the desired product. LCMS calculated for C22H17F2N6 (M+H)+: m/z=403.1; Found: 403.1. The racemic N-{1-[5-fluoro-8-(3-fluorophenyl)quinolin-7-yl]ethyl}-9H-purin-6-amine (70 mg, 0.2 mmol) was submitted for chiral resolution (column: ChiralPak IA, 20×250 mm, 5 μm; mobile phase: 15% ethanol/85% hexanes; flow rate: 15 mL/min) to give two enantiomers. retention times: 8.7 and 13.5 minutes, respectively.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[C:18]([N+:27]([O-])=O)=[C:19]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=2)[CH2:9][CH2:8]1.O.NN>CO.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[C:18]([NH2:27])=[C:19]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=2)[CH2:11][CH2:12]1
Reactant: NS(=O)(=O)c1cccc(CCCCN2CCN(c3ncccn3)CC2)c1[N+](=O)[O-]
Agent: [Pd]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1c(CCCCN2CCN(c3ncccn3)CC2)cccc1S(N)(=O)=O
Reaction time: 0.5 h

Procedure:
0.06 mol of N-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl-2-nitrobenzenesulphonamide is dissolved in 500 ml of MeOH, 2.4 g of 5% Pd-C are added, the mixture is heated to boiling and 0.17 mol of hydrazine hydrate in 50 ml of MeOH is added dropwise within 15 minutes. After boiling for a further 30 minutes, the mixture is filtered, the filtrate is evaporated, the residue is taken up in diethyl ether, washed with water, evaporated again and crystallised from isorpopanol/isopropyl ether.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:18])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].CCN(C(C)C)C(C)C.C(N[C@H:36]([C:47](O)=[O:48])[CH2:37]C1C=CC([N+]([O-])=O)=CC=1)(OC(C)(C)C)=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl>C(#N)C>[C:47]([NH:1][C:2]1[C:3](=[O:18])[N:4]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[CH3:8])(=[O:48])[CH2:36][CH3:37]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: COc1ccc(Cn2ccc(C)c(N)c2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)Nc1c(C)ccn(Cc2ccc(OC)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 157.3 %

Procedure:
To a solution of 3-amino-1-(4-methoxybenzyl)-4-methyl-2-pyridone (5.03 g, 20.6 mmol), DIEA (3.76 mL, 21.6 mmol) and N-Boc-p-nitrophenylalanine (6.71 g, 21.6 mmol) in acetonitrile (100 mL) cooled on ice was added TBTU (7.94 g, 24.7 mmol). The mixture was stirred at rt overnight. Additional DIEA (3.76 mL, 21,6 mmol) was added, and the slurry was stirred for another 6 hours. 1N HCl (50 mL) was added, and the acetonitrile was removed under reduced pressure. Ethyl acetate (300 mL) was added, and the organic suspension was separated and washed with 1N HCl, 2.5N NaOH and brine. Ethyl acetate (50 mL) and THF (100 mL) were added to the suspension to dissolve all solids, and the organic phase was washed with brine, and dried (MgSO4/silica gel/charcoal). Evaporation of the solvent gave 3-2′-(S)-tbutoxycarbonylamino-3′-(4″-nitro)benzene]propanoylamino-1-(4-methoxybenzyl)-4-methyl-2-pyridone as a brown solid (9.73 g, 88%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.COP([O:18][CH3:19])OC.[CH2:20]([C@@H:27]1[N:30]([Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[C:29](=[O:38])C1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O=O>C1COCC1>[CH2:20]([C@@H:27]1[N:30]([Si:31]([C:34]([CH3:36])([CH3:35])[CH3:37])([CH3:32])[CH3:33])[C:29](=[O:38])[C@H:19]1[OH:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C[C@@H]1Cc1ccccc1
Reactant: COP(OC)OC
Agent: O=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](O)[C@@H]1Cc1ccccc1
Reaction time: 0.25 h
Yield: 60.6 %

Procedure:
To a solution of diisopropylamine (800 μL, 5.7 mmol) in anhydrous THF (40 mL) at −20° was added butyllithium (3.56 mL, 5.7 mmol, 1.6 M in hexane). After 15 min., the reaction was cooled to −78°, and freshly distilled trimethylphosphite (1.12 mL, 7.6 mmol) was added followed by a solution of 4(S)-benzyl-1-(tert-butyldimethylsilyl)azetidin-2-one (from example 1, step C, 1.05 g, 3.8 mmol) in THF (10 mL). A constant stream of oxygen was introduced and the mixture was stirred at −78° for 3 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (120 mL). The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (SiO2, 10% EtOAc-hexane to 30% EtOAc in hexane) to give 4(S)-benzyl-1-(tert-butyldimethylsilyl)-3(S)-hydroxyazetidin-2-one (671 mg , 60% yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ7.25-7.21 (m, 5H), 4.51 (d, J=2 Hz, 1H), 3.75-3.71 (m, 1H), 3.26 (bs, 1H), 3.20 (dd, J=14, 3.8 Hz, 1H), 2.66 (dd, J=14, 11.1 Hz, 1H), 1.00 (s, 9H), 0.30 (d, J=3.5 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:13]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]([Cl:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(O)cc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)c(O)cc1Cl
Yield: 8.7 %

Procedure:
To a solution of methyl 2-chloro-4-hydroxybenzoate (13.6 g, 73.1 mmol) in acetic acid (300 mL) was added N-chlorosuccinimide (9.8 g, 73.7 mmol). The solution was refluxed for 24 h and the solvent was evaporated under vacuo. The residue was taken up in chloroform, washed with water, brine, dried over magnesium sulfate, filtered and concentrated. Methyl 2,3-dichloro-4-hydroxybenzoate precipitated out of ethyl acetate. Chromatography of the residue using ethyl acetate/hexane (1/9 to 3/7) afforded methyl 2,5-dichloro-4-hydroxybenzoate (1.4 g, 60%) as well as an additional batch of methyl 2,3-dichloro-4-hydroxybenzoate isomer (total of 8.4 g, 10%).
Reaction SMILES: [I:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([S:9]([CH3:12])(=[O:11])=[O:10])[N:3]=1.Br[CH2:14][CH:15]1[CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[CH:15]1([CH2:14][O:8][C:7]2[C:2]([I:1])=[N:3][C:4]([S:9]([CH3:12])(=[O:10])=[O:11])=[CH:5][CH:6]=2)[CH2:17][CH2:16]1
Reactant: BrCC1CC1
Reactant: CS(=O)(=O)c1ccc(O)c(I)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(OCC2CC2)c(I)n1
Temperature: 80 °C
Reaction time: 4 h
Yield: 84.8 %

Procedure:
A mixture of 2-iodo-6-methylsulfonylpyridin-3-ol (500.0 mg, 1.67 mmol), bromomethylcyclopropane (248.4 mg, 1.84 mmol) and K2CO3 (461.3 mg, 33.4 mmol) in ACN (15 mL) was stirred at 80° C. for 4 hrs. Water (30 mL) was added and the mixture was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to give the title compound (500.0 mg, 84.8%). 1H NMR (CDCl3, 400 MHz) δ 7.96 (d, J=8.8 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 4.09 (d, J=6.8 Hz, 2H), 3.22 (s, 3H), 1.36-1.22 (m, 1H), 0.69-0.57 (m, 2H), 0.43-0.37 (m, 2H). LCMS: 354.0 (M+1)+
Reaction SMILES: BrB(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([N:16]([CH3:18])[CH3:17])(=[O:15])=[O:14].CO>ClCCl>[OH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([N:16]([CH3:18])[CH3:17])(=[O:15])=[O:14]
Reactant: COc1ccccc1S(=O)(=O)N(C)C
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1ccccc1O
Temperature: -70 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
200 ml (200 mmol, 4.9 eq) of a 1 M solution of tribromoborane in dichloromethane were added dropwise to a solution of 8.78 g (40.8 mmol, 1 eq) of 2-methoxy-N,N-dimethylbenzenesulfonamide in 250 ml of dichloromethane at −70° C. under nitrogen. The reaction medium was left at −70° C. for one hour and was then left to return to 10° C. for one and a half hours. The reaction medium was then cooled to −70° C. and approximately 100 ml of methanol were added dropwise (approximately one hour of addition). The reaction medium was then left to return to ambient temperature and was concentrated. The residue obtained was filtered off on silica with the eluent 6/4 heptane/ethyl acetate. 7.81 g of product were obtained in the form of a beige solid. Yield=95%.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[N:21]([CH2:27][CH2:28][CH3:29])[S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])C1C=CC=CC=1>C1COCC1.CO>[CH3:20][C:14]1([CH3:19])[CH2:13][CH:12]([N:21]([CH2:27][CH2:28][CH3:29])[S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=2)[O:15]1
Reactant: CCCN(C1CC(C)(C)Oc2ccc(OCc3ccccc3)cc21)S(=O)(=O)CC
Solvent: C1CCOC1
Solvent: CO
Product: CCCN(C1CC(C)(C)Oc2ccc(O)cc21)S(=O)(=O)CC

Procedure:
6.0 g of N-[6-benzyloxy-2,2-dimethylchroman-4-yl]-N-(1-propyl)ethanesulfonamide were dissolved in 150 ml of THF/methanol (1:1) and hydrogenated in a shaking duck using Pdlcarbon, 4.4 g of product, m.p. 173-175° C. (from petroleum ether).
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([O:22][CH2:23]Cl)[CH3:21]>CN(C=O)C>[Br:1][C:2]1[N:10]([CH2:23][O:22][CH2:20][CH3:21])[C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Reactant: CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To a stirring suspension of 8-bromo-3-methylxanthine (7.06 g, 28.8 mmol) and potassium carbonate (3.98 g, 28.8 mmol) in DMF (150 ml) was added chloromethyl ethyl ether (2.72 g, 28.8 mmol). After stirring overnight at room temperature, the reaction mixture was poured into ice-cold water (650 ml). After stirring at 0-5° C. for 1 hour, the cloudy mixture was filtered, washed with water (3×15 ml) and dried under vacuum to provide 8-bromo-7-ethoxymethyl-3-methylxanthine (6.15 g, 70% yield) as a white solid.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH2:8][CH2:7]1)=O)=C.Cl.CO>>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1/[CH:13]=[CH:12]/[CH:9]1[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]1
Reactant: C=COC(=O)N1CCC(/C=C/c2ccccc2F)CC1
Agent: Cl
Solvent: CO
Product: Fc1ccccc1/C=C/C1CCNCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.9 %

Procedure:
904 mg of 1-(vinyloxycarbonyl)-4-[(E)-2-(2-fluorophenyl)-1-ethenyl]piperidine was suspended in 5 ml of a 10% hydrogen chloride-methanol solution. After stirring for 15 minutes at room temperature, the mixture was heated at 70° C. for one hour. The solvent was evaporated, and water and ethyl acetate were added to the residue, to separate the aqueous layer. The aqueous layer was basified with a diluted ammonia, and extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, to give 660 mg of the title compound as a colorless oil.