Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([OH:15])[C@H:10]([C:16]([O:18]CC)=[O:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>COC(C)(C)C.[OH-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([OH:15])[C@H:10]([C:16]([OH:18])=[O:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCC[C@@H]1O
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H](O)[C@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.3 %

Procedure:
A mixture of 28.7 g of the compound prepared in Example 13 in 200 ml of tert-butyl methyl ether and 200 ml of 2N NaOH was stirred vigorously at room temperature for 4 hours and then at 50° C. for 20 hours. After cooling, the aqueous phase was extracted twice with 100 ml of tert-butyl methyl ether each time. The organic phases were discarded. The aqueous phase was acidified cautiously with about 70 ml of 6N HCl and extracted once with 200 ml of tert-butyl methyl ether and twice with 100 ml of tert-butyl methyl ether each time. All three organic phases were washed once with 50 ml of 10% sodium chloride solution, combined and dried over sodium sulphate. After removal of the solvent under reduced pressure (40° C./25 mbar) the brown viscous oil was dissolved in 60 ml of isopropyl ether at 60° C. and left to crystallize at -20° C. for 16 hours. The crystals were filtered off, washed with a small amount of isopropyl ether, cooled to -20° C. and dried at 40° C. for hours and 25 mbar, yielding 12.0 g of (3R,4S)-4-hydroxy-azepan-1,3-dicarboxylic acid 1-tert-butyl ester of melting point 98.5-101.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[CH3:15][Mg]Br.O1CCCC1.O>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH3:15])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Clc1nc(Cl)nc(-c2ccccc2)n1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(Cl)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(Step 2) In 85 ml of dry tetrahydrofuran was dissolved 17 g of 2,4-dichloro-6-phenyl-1,3,5-triazine. To this solution on an ice-water bath was added 135 ml of 1M methylmagnesium bromide-tetrahydrofuran dropwise over about 30 minutes. After completion of dropwise addition, the mixture was stirred at room temperature for 2 hours. This reaction mixture was poured into iced water and extracted with ethyl acetate. The extract was washed with water, dried over MgSO4, and concentrated. The residue was purified with silica gel column chromatography to provide 3.6 g of the title compound as white crystals.
Reaction SMILES: [OH-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1>C(O)C>[N:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:25]=[CH:24][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1ccc(N2CCN(c3ccncc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(N2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.9 %

Procedure:
1M sodium hydroxide solution (103 ml) was added to a suspension of ethyl 4-[4-(4pyridyl)-1-piperazinyl]benzoate (10.3 g) in ethanol (200 ml) and the mixture was stirred at ambient temperature for 16 hours. The solution was evaporated to dryness. The residue was stirred in water (515 ml) for 15 minutes and any insoluble material was filtered off. The filtrate was treated with ice-cooled 1 M hydrochloric acid (103 ml). The precipitate was filtered off, slurry washed with water, sucked dry and dried over phosphorus pentoxide, at 50° C. for 2 days to give 4-[1-(4-pyridyl)piperazin-4-yl]-benzoic acid (5.24 g) as an off-white solid, mp>300° C.
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[C:5]1=[O:14]>C(O)(=O)C>[Br:1][C:12]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]([CH3:3])[CH:13]=1
Reactant: Cn1ccc2ccncc2c1=O
Reactant: BrBr
Solvent: CC(=O)O
Product: Cn1cc(Br)c2ccncc2c1=O
Temperature: 15 °C
Reaction time: 1 h
Yield: 27.4 %

Procedure:
Bromine (1.1 g, 6.87 mmol) in acetic acid (10 mL) was added dropwise to 2-methyl-2,7-naphthyridin-1-one (1.1 g, 6.87 mmol) in acetic acid (60 mL) at 10-15° C. After stirring at 15° C. for 1 h, the mixture was concentrated under vacuum. Purification by silica gel chromatography (DCM: MeOH=50:1 to 10:1) gave the title compound (0.45 g, 27.4%) as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@H:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][Mg]Br.O>C(OCC)C.Cl>[CH2:15]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]1[CH2:13][CH2:12][CH2:11][C@@:10]1([CH3:22])[OH:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[Mg]Br
Reactant: O=C1CCC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: C[C@@]1(O)CCC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Temperature: -78 °C
Reaction time: 4 h
Yield: 39.8 %

Procedure:
To a solution of (2S)-2-(dibenzylamino)cyclopentanone (8.31 g, 29.7 mmol) in diethyl ether (149 mL) at −78° C. is added methyl magnesium bromide (29.7 mL, 89.1 mmol, 3 M in diethyl ether) slowly. The mixture is stirred at −78° C. for 4 h and then the reaction is allowed to warm to room temperature. Water is added to the reaction, resulting in an emulsion. Aqueous 1 M hydrochloric acid is added to break up the emulsion while keeping the aqueous phase basic. The aqueous phase is extracted twice with EtOAc. The combined organic portions are dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by silica gel chromatography (10% EtOAc/hexanes) to obtain the product. The material is dissolved in 1 M hydrochloric acid and extracted four times with EtOAc. The combined organic layers are dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound as an orange solid (3.49 g, 40%). ES/MS m/z 296 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.[NH2-].[Na+].Br[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[C:15]1([CH2:14][CH2:13][CH:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:8]#[N:9])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N#CCc1cccnc1
Reactant: BrCCc1ccccc1
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(CCc1ccccc1)c1cccnc1
Temperature: -35 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
A solution of 3-pyridylacetonitrile (23 g) in tetrahydrofuran (75 ml) was added dropwise to a stirred suspension of sodium amide (8 g) in tetrahydrofuran (175 ml) under a nitrogen atmosphere at 0° C. After complete addition of the solution, the resultant mixture was stirred at 0-10° C. for 1 hour, then cooled to -35° C. and a solution of 2-(bromoethyl)benzene (36 g) in tetrahydrofuran (100 ml) was added dropwise over 30 minutes. The resultant new mixture was stirred between -35° C. to ambient temperature overnight, then quenched with water and neutralized with 10% hydrochloric acid. After the removal of of tetrahydrofuran, the residue was dissolved in methylene chloride and washed with saturated sodium bicarbonate solution. The organic extract was then dried over magnesium sulfate, filtered and evaporated to give an oil. The oil was then distilled to provide 30 g of α-(2-phenylethyl)-3-pyridineacetonitrile, b.p.=170-173° C./0.5 mmHg.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8]>>[C:1]([O:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: O=C(O)C(O)Cc1ccccc1
Product: CC(=O)OC(Cc1ccccc1)C(=O)O
Yield: 100.4 %

Procedure:
4.83 g (61.53 mmol) of acetyl chloride are added to 8.88 g (53.49 mmol) of (RS)-2-hydroxy-3-phenyl propanoic acid. The mixture is refluxed for 30 minutes. The excess acetyl chloride is evaporated. 11.18 g of (RS)-2-acetyloxy-3-phenyl propanoic acid are obtained.
Reaction SMILES: ClC(OCC)=O.C([N:9]([CH2:12][CH3:13])CC)C.[CH3:14][S:15]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=1)(=[O:17])=[O:16].N1CC1>CC(C)=O>[CH3:14][S:15]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([N:9]2[CH2:12][CH2:13]2)=[O:25])=[CH:26][CH:27]=1)(=[O:16])=[O:17]
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)Nc1ccc(C(=O)O)cc1
Agent: C1CN1
Agent: CCOC(=O)Cl
Solvent: CC(C)=O
Product: CS(=O)(=O)Nc1ccc(C(=O)N2CC2)cc1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
To a solution of 0.343 g (3.16 mmol) of ethyl chloroformate in 0.6 mL of acetone cooled to -10° C. under a nitrogen atmosphere add dropwise a solution of 1.0 g (3.16 mmol) of 4-[(methylsulfonyl)amino]benzoic acid triethylamine salt in 25 mL of acetone. Stir the mixture at -10° C. for 2 h then add slowly a solution of 0.136 g (3.16 mmol) of aziridine in 10 mL of acetone. Stir the reaction mixture for 30 min at ambient temperature after the addition is completed then remove the solvent in vacuo. Flash chromatograph the residue on silica gel with diethyl ether: methylene chloride (2:1), evaporate the solvent from the product containing fractions to obtain the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:23][S:24](Cl)(=[O:26])=[O:25].O[Li].O>C(Cl)Cl.CCOC(C)=O.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH:15][S:24]([CH3:23])(=[O:26])=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cnccc1OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)Nc1cnccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
To a solution of 4-(benzyloxy)pyridin-3-amine (40 g, 0.2 mol) and Et3N (60.6 g, 0.6 mol) in DCM (600 mL), MsCl (45.8 g, 0.4 mol) was added dropwise at 0° C. The mixture was allowed to warm up to room temperature and stirred overnight. The reaction mixture was quenched with NaHCO3 and extracted with DCM. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was dissolved in THF:H2O=5:1 (500 mL) and LiOH.H2O (16.8 g, 0.4 mmol) was added. The mixture was stirred for 4 hours at room temperature. EtOAc (300 mL) was added, and the organic phase washed with NaHCO3 (sat., a.q.), brine, dried over Na2SO4, filtrated and concentrated to give pure N-(4-(benzyloxy)pyridin-3-yl)methanesulfonamide (30.0 g, yield: 54.0%). 1H-NMR (CDCl3, 400 MHz) δ 8.67 (s, 1H), 8.34 (d, J=5.6 Hz, 1H), 7.35˜7.42 (m, 5H), 6.91 (d, J=5.6 Hz, 1H), 6.61 (br, 1H), 5.15 (s, 2H), 2.96 (s, 3H). MS (M+H)+: 279.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:16]3[CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH2:28]([N:30]=[C:31]=[O:32])[CH3:29]>>[CH2:28]([NH:30][C:31]([N:20]1[CH2:21][C:16]2[C:15]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[N:14][C:13]([C:10]3[CH:11]=[CH:12][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:8][CH:9]=3)=[N:18][C:17]=2[CH2:19]1)=[O:32])[CH3:29]
Reactant: CCN=C=O
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CN(C(=O)NCC)C3)cc1

Procedure:
Method as described for example 33 using 1-ethyl-3-(4-(4-morpholino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 14) and ethyl isocyanate as starting materials.
Reaction SMILES: CS(C1C=CC([N:11]2C(=O)C=CC(C([O-])=O)=N2)=CC=1)(=O)=O.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([O:34][C:35]2[C:36]([C:51]([O:53]C)=O)=[N:37][N:38]([C:42]3[CH:47]=[CH:46][C:45]([C:48]#[N:49])=[C:44]([F:50])[CH:43]=3)[C:39](=[O:41])[CH:40]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(C)(C)C>>[C:51]([C:36]1[C:35]([O:34][CH:31]2[CH2:32][CH2:33][N:28]([C:26]([O:25][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:27])[CH2:29][CH2:30]2)=[CH:40][C:39](=[O:41])[N:38]([C:42]2[CH:47]=[CH:46][C:45]([C:48]#[N:49])=[C:44]([F:50])[CH:43]=2)[N:37]=1)(=[O:53])[NH2:11]
Reactant: COC(=O)c1nn(-c2ccc(C#N)c(F)c2)c(=O)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(=O)[O-])ccc2=O)cc1
Agent: CC(C)C
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(C#N)c(F)c3)nc2C(N)=O)CC1
Yield: 91 %

Procedure:
tert-Butyl 4-(3-carbamoyl-1-(4-cyano-3-fluorophenyl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate was prepared in 91% yield according to procedures described in Example 31 (Step A) substituting methyl 441-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-(methylsulfonyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate for methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-cyano-3-fluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate (example 29). MS (ESI) 402 (M+H-tBu).
Reaction SMILES: [OH:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:8]([Mg]Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[NH4+]>ClCCl.O=[Mn]=O>[CH2:8]([CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][N:2]1[OH:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: ON1CCCCC1
Agent: O=[Mn]=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: ON1CCCCC1Cc1ccccc1
Reaction time: 1 h
Yield: 32.6 %

Procedure:
Activated MnO2 (1.29 g, 14.8 mmol) was added to a solution of N-hydroxypiperidine (0.50 g, 4.95 mmol) in dichloromethane (25 mL) at 0° C. and the mixture was stirred for 1 h. The reaction mixture was filtered through a pad of Celite™ and Na2SO4. The filtrate was added dropwise to a solution of benzylmagnesium chloride (2.0 M in tetrahydrofuran, 4.95 mL, 9.90 mmol) at −10° C. The reaction mixture was stirred at 0° C. for 0.5 h and then saturated aqueous ammonium chloride solution (25 mL) and dichloromethane (25 mL) were added. The aqueous phase was separated and extracted with dichloromethane (2×30 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude product was subjected to flash chromatography on SiO2 eluting with 60% diethyl ether in hexanes to give the title compound (0.309 g, 33%) as a white crystalline solid.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH2:33]1[C:36]2([CH2:40][CH2:39][NH:38][CH2:37]2)[CH2:35][N:34]1C(OC(C)(C)C)=O>>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([N:38]3[CH2:39][CH2:40][C:36]4([CH2:33][NH:34][CH2:35]4)[CH2:37]3)=[N:3][CH:4]=2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CC2(CCNC2)C1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CCC3(CNC3)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 33 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2) and tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate to afford an off-white powder. UPLC-MS (Condition 3) tR=0.79 min, m/z=475.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.04 (t, J=6.65 Hz, 2H) 3.14 (d, J=4.69 Hz, 3H) 3.46 (s, 2H) 3.76 (q, J=10.04 Hz, 4H) 6.39 (s, 1H) 7.31 (d, J=8.60 Hz, 2H) 7.78-7.92 (m, 3H) 8.08 (br. s, 1H) 8.74 (br. s, 1H) 10.27 (s, 1H) 12.90-13.01 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([C@@H:4]([C@H:6]([CH2:8]O)O)O)=O.[CH2:10]([O:17][CH2:18][CH:19]=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.P([O-])([O-])([O-])=O.OCC(=O)C>C(#N)C>[CH2:10]([O:17][CH2:18][C:19]1[CH:8]=[CH:6][CH:4]=[CH:2][CH:1]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=CCOCc1ccccc1
Reactant: CC(=O)[C@H](O)[C@@H](O)CO
Agent: CC(=O)CO
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Product: c1ccc(COCc2ccccc2)cc1
Reaction time: 48 h
Yield: 32 %

Procedure:
FIG. 41 illustrates Ketone 2111a was easily transformed to 1-deoxy-L-xylulose (1111) by hydrogenation. Benzyloxyacetaldehyde (80 mg, 0.53 mmol) in ) in ) 0.5 mL of acetonitrile, was added to 9 mL of a solution of antibody 38C2 (35 mg, 0.23 mmol) in PBS (phosphate buffer saline, 100 mM), followed by the addition of of hydroxyacetone. (0.5 mL, 6.3 mmol). After 48 hr at room temperature the reaction reached 56% conversion and the mixture was freeze dried. The remaining residue was extracted with methylene chloride. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel, ethyl acetate/hexane, 1/1) to give pure 2111a (39 mg, 0.17 mmol, 32%) in 97% ee. Benzyl ether 2111a (39 mg, 0.17 mmol) was dissolved in 1 mL of methanol and hydrogenated with a catalytic amount of palladium hydroxide on carbon. After two hr, the mixture was filtered through celite and the solvent was removed under reduced pressure to give pure 1-deoxy-L-xylulose (19 mg, 0.14 mmol, 81%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.B([O-])([O-])O[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(OCC)(=O)C.O1CCCC1>[Cl:1][C:2]1[N:11]=[C:10]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:27])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH:22]=[CH:23][CH:24]=2)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Reactant: CC(C)(C)OC(=O)Nc1cccc(OB([O-])[O-])c1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2nc(Cl)nc(-c3cccc(NC(=O)OC(C)(C)C)c3)c2cc1OC
Temperature: 60 °C
Reaction time: 6.5 h
Yield: 92.2 %

Procedure:
To a mixture of 1.00 g (3.86 mmol) of 2,4-dichloro-6,7-dimethoxyquinazoline, 1.14 g (4.63 mmol) of 3-(N-t-butoxycarbonylamino)phenyl borate, tetrahydrofuran (25 mL), and 2 M sodium carbonate aqueous solution (5 mL) were added palladium acetate (8.84 mg) and 1,1′-bis(diphenylphosphino)ferrocene (21.4 mg) in this order, and the mixture was stirred at 60° C. for 6.5 hours under a nitrogen atmosphere. The reaction solution was allowed to cool, and ethyl acetate (25 mL) and 5% w/w sodium chloride solution (20 mL) were added to extract the organic layer. The organic layer was washed twice with 5% w/w sodium chloride solution (20 mL) and then concentrated under reduced pressure. To the concentration residue were added ethyl acetate (1 mL) and 2-propanol (4 mL), and the mixture was suspended by stirring at 40° C. for 0.5 hours. The suspension was cooled, and the precipitated crystals were collected by filtration and dried to give 1.48 g of a target product (yield: 91.5%, HPLC purity: 99.02%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:33])[NH:6][C:7]([C:15]1[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]([O:31]C)=[O:30])[CH2:23][CH2:22]3)[CH:18]=[CH:17][CH:16]=1)=[N:8]2.[OH-].[Li+]>C1COCC1.O.CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:33])[NH:6][C:7]([C:15]1[N:20]=[C:19]([N:21]3[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:25][CH2:26]3)[CH:18]=[CH:17][CH:16]=1)=[N:8]2
Reactant: COC(=O)CCN1CCN(c2cccc(-c3nc4cc(OC)cc(OC)c4c(=O)[nH]3)n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(N4CCN(CCC(=O)O)CC4)n3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
To a solution of methyl 3-(4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)propanoate (0.200 g, 0.44 mmol) in THF (10 mL), water (5 mL) and methanol (3 mL) was added lithium hydroxide (0.053 g, 2.21 mmol). The reaction was stirred for 2 h at rt. After that time the reaction was concentrated under reduced pressure, diluted with water (5 mL) and acidified using 1N HCl to pH 4.5-5.0. The precipitated solids were collected by filtration, washed with water and dried under high vacuum to give 3-(4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)propanoic acid (0.160 g, 83%) as a yellow solid: mp 241° C. dec.; 1H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 7.68-7.80 (m, 2H), 7.09 (d, J=8.20 Hz, 1H), 6.78 (d, J=1.95 Hz, 1H), 6.58 (d, J=1.95 Hz, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 3.73 (br s, 4H), 2.77-2.85 (m, 2H), 2.73 (br s, 4H), 2.55 (t, J=7.22 Hz, 2H); ESI MS m/z 440 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:14]3[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]4[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]4)[C:13]=3[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:14]3[N:15]=[C:16]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:17]=[C:18]([N:19]4[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]4)[C:13]=3[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: O=S1CCN(c2nc(Cl)nc3c(Sc4ccc(Br)cc4)ncnc23)CC1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(Sc4ccc(Br)cc4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 1 from 8-(4-bromophenyl-thio)-2-chloro-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 272°-275° C.) and piperazine.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]([O:12]CCCCl)=[O:11])=[C:8]([F:19])[CH:7]=1.[OH-].[Na+]>CO>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]([OH:12])=[O:11])=[C:8]([F:19])[CH:7]=1
Reactant: O=C(OCCCCl)c1ccc(OCCCCl)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OCCCCl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
A mixture of 3-chloropropyl 4-(3-chloropropoxy)-2-fluorobenzoate i76 (2 g, 6.47 mmol, 1 eq) and 1 M sodium hydroxide (6.47 ml, 6.47 mmol, 1 eq) in methanol (25 ml) is stirred at room temperature overnight. The mixture is concentrated under vacuum, taken up in water and extracted with diethyl ether. The aqueous phase is acidified with a 1 N hydrochloric acid solution to reach pH 2, and the resulting suspension is filtered and the solid dried to give 0.68 g of 4-(3-chloropropoxy)-2-fluorobenzoic acid i78.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl.CN(C=O)C>[Cl:23][C:17]([CH:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH2:13]1)=[O:19]
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 3 h
Yield: 80.5 %

Procedure:
To a solution of 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid (4.50 g, 17.1 mmol, Preparation #5, Step A) in DCM (40 mL) at ambient temperature was added oxalyl chloride (3.00 mL, 34.2 mmol) followed by DMF (0.10 mL, 1.3 mmol). After about 3 h, the reaction was concentrated under reduced pressure to constant weight to afford benzyl 4-(chlorocarbonyl)piperidine-1-carboxylate as a yellow oil (3.88 g, 81%): 1H NMR (CDCl3) δ 7.44-7.35 (m, 5H), 5.16 (s, 2H), 4.20-4.10 (m, 2H), 3.03-2.89 (m, 3H), 2.15-2.05 (m, 2H), 1.81-1.76 (m, 2H).