Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:28]([OH:32])[CH2:29][C:30]#[CH:31]>>[F:26][C:2]([F:27])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:31]#[C:30][CH2:29][CH2:28][OH:32])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: C#CCCO
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1)C(F)(F)F
Product: OCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 14.1, Trifluoro-methanesulfonic acid 3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester and 3-butyn-1-ol were converted to yield 4-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-ol as orange semisolid, MS: 347 (M).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:4]=[C:5](CO)[CH:6]=[CH:7][CH:8]=1.C=O.[C:14](O)(=[O:16])C.C([BH3-])#N.[Na+]>C(OCC)(=O)C.O>[CH3:11][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:14][OH:16]
Reactant: CC(=O)O
Reactant: CN(C)c1cccc(CO)c1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)c1ccccc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 250 mL round-bottomed flask, (3-(dimethylamino)phenyl)methanol (1 g) and paraformaldehyde (2.5 g) were added to acetic acid (150 mL) to give a suspension. Sodium cyanoborohydride (2.6 g) was added slowly. The mixture was stirred at room temperature overnight. After concentration of the solvent, water and ethyl acetate (1:1, 100 mL) were added. After separation, the aqueous layer was extracted by ethyl acetate (2×20 mL). The combined organic layers were washed with water (3×50 mL), saturated aqueous NaHCO3 (2×30 mL), and dried over Na2SO4. After filtration and concentration, the residue was taken up into CH2Cl2 and the product was purified by flash chromatography (Varian, Superflash SF40-80 g column), eluting with 0-20% methanol/dichloromethane, to provide the title compound.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:51])[C@@H:15]([O:49][CH3:50])[C@@H:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][C:27]2[N:28]=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:30][C:31]=2[CH3:32])=[CH:20][C:19]=1[O:39][Si:40]([CH3:48])([CH3:47])[C:41]([CH3:46])([CH3:45])[CH:42]([CH3:44])[CH3:43])O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:51])[C@@H:15]([O:49][CH3:50])[CH2:16][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][C:27]2[N:28]=[C:29]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[O:30][C:31]=2[CH3:32])=[CH:20][C:19]=1[O:39][Si:40]([CH3:47])([CH3:48])[C:41]([CH3:45])([CH3:46])[CH:42]([CH3:43])[CH3:44])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1O[Si](C)(C)C(C)(C)C(C)C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CO[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1O[Si](C)(C)C(C)(C)C(C)C)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 3 h

Procedure:
The above prepared (S)-4-benzyl-3-((2S,3R)-3-{2-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-3-hydroxy-2-methoxy-propionyl)-oxazolidin-2-one (2.8 g, 3.91 mmol) was dissolved in 10 ml of trifluoroacetic acid, treated at 0° C. with 10 ml of triethylsilane and then kept for 3 hours at ambient temperature. The reaction mixture was then poured onto crashed ice/AcOEt/NaOH (1M), the organic layer was washed with water and brine, dried over magnesium sulfate and evaporated to dryness. Flash chromatography (SiO2, heptane/AcOEt) delivered 1.6 g (58%) of the title compound (purity ˜80%) as a yellow foam.
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[C:17]([C:19]2[N:23]=C(C3C=C(C)N=C(NCC)N=3)O[N:20]=2)[CH:16]=[C:15]([CH3:34])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])[CH3:2].[CH2:35]([NH:39][C:40]1[N:45]=[C:44]([C:46]([OH:48])=O)[CH:43]=[C:42]([CH3:49])[N:41]=1)[CH:36]([CH3:38])[CH3:37]>>[CH2:1]([C:3]1[CH:18]=[C:17]([C:19]2[N:23]=[C:46]([C:44]3[CH:43]=[C:42]([CH3:49])[N:41]=[C:40]([NH:39][CH2:35][CH:36]([CH3:37])[CH3:38])[N:45]=3)[O:48][N:20]=2)[CH:16]=[C:15]([CH3:34])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])[CH3:2]
Reactant: Cc1cc(C(=O)O)nc(NCC(C)C)n1
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(CC)c3)no2)n1
Product: CCc1cc(-c2noc(-c3cc(C)nc(NCC(C)C)n3)n2)cc(C)c1OC[C@@H](O)CNC(=O)CO

Procedure:
N—((S)-3-{2-Ethyl-4-[5-(2-isobutylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide is prepared in analogy to N—((S)-3-{2-ethyl-4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide using 2-isobutylamino-6-methyl-pyrimidine-4-carboxylic acid; LC-MS: tR=0.96 min; [M+H]+=499.25. 1H NMR (D6-DMSO): δ 0.92 (d, J=6.5 Hz, 6H), 1.22 (t, J=7.5 Hz, 3H), 1.91 (m, 1H), 2.35 (s, 3H), 2.41 (s, 3H), 2.73 (q, J=7.5 Hz, 2H), 3.15-3.28 (m, 3H), 3.43 (m, 1H), 3.70-3.80 (m, 2H), 3.84 (d, J=4.8 Hz, 2H), 3.96 (m, 1H), 5.30 (d, J=5.0 Hz, 1H), 5.55 (m, 1H), 7.29 (s, 1H), 7.69 (m, 2H), 7.78 (s, 2H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:32]=[C:33]([O:35]CC2C=CC=CC=2)[CH:34]=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][CH:17]=[C:16]([O:23][CH2:24][CH:25]([OH:31])[CH2:26][NH:27][CH:28]([CH3:30])[CH3:29])[CH:15]=2)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:32]=[C:33]([OH:35])[CH:34]=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][CH:17]=[C:16]([O:23][CH2:24][CH:25]([OH:31])[CH2:26][NH:27][CH:28]([CH3:29])[CH3:30])[CH:15]=2
Reactant: CC(C)NCC(O)COc1ccc2c(=O)cc(-c3cc(OCc4ccccc4)cc(OCc4ccccc4)c3)oc2c1
Agent: [Pd]
Solvent: CO
Product: CC(C)NCC(O)COc1ccc2c(=O)cc(-c3cc(O)cc(O)c3)oc2c1

Procedure:
3′,5′-Dibenzyloxy-7-(2-hydroxy-3-iso-propylamino-propoxy)-flavone, 35 (1.2 g, 2.12 mmol) was debenzylated in dry methanol (40 mL) with 10% Pd/C (30 mg) under hydrogen atmosphere as described for 48 to provide 49. Yield 800 mg (98%); mp 185° C. (decomposes); MS (FAB) 386 (M++1); IR (KBr) 3244, 1623; 1H NMR (200 MHz, DMSO-d6) δ 9.85 (s, 2H), 7.72 (d, J=8.8 Hz, 1H), 7.06 (d, J=1.7 Hz, 1H), 6.87 (dd, J=8.8 Hz, 1.9 Hz, 1H), 6.66 (d, J=1.7 Hz, 2H), 6.45 (s, 1H), 6.29 (s, 1H), 4.00-3.97 (m, 3H), 3.13-3.03 (m, 1H), 2.94-2.75 (m, 2H), 1.24 (d, J=5.7 Hz, 6H); 13C NMR δ 176.7, 163.3, 163.1, 159.3, 157.7, 133.2, 126.6, 117.6, 115.4, 106.9, 106.3, 104.6, 101.9, 70.9, 65.3, 50.3, 46.9, 19.0, 18.6. Analysis Calcd for C21H23NO6: C, 65.44; H, 6.02; N, 3.63. Found: C, 66.26; H, 6.18; N, 3.44.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH:9]([NH:13]C(OC(C)(C)C)=O)[CH2:8]2)=[CH:4][CH:3]=1>Cl.CCOCC>[ClH:1].[ClH:1].[NH2:13][CH:9]1[CH2:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:22][CH:21]=2)[CH2:8]1
Reactant: CC(C)(C)OC(=O)NC1CCCN(Cc2ccc(Cl)cc2)C1
Agent: Cl
Solvent: CCOCC
Product: NC1CCCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 1-(4-chlorobenzyl)-3-{(tert-butoxycarbonyl)amino}piperidine (2.55 g, 7.85 mmol) in CH2OH (25 mL) was treated with 1 N HCl-Et2O (50 mL). The reaction mixture was stirred at 25° C. for 15 h. The solvent was removed under reduced pressure to afford 3-amino-l-(4-chlorobenzyl)piperidine dihydrochloride as an amorphous solid (2.49 g, quant).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[N:13]=[C:14]([NH:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH3:34][S:35](OCl)(=[O:37])=[O:36].C(Cl)Cl>CS(C)=O.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[N:13]=[C:14]([NH:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([NH:24][S:35]([CH3:34])(=[O:37])=[O:36])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Reactant: CS(=O)(=O)OCl
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a 0° C. solution of trans-N1-(3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)cyclohexane-1,4-diamine (50 mg, 0.146 mmol) and DIPEA (0.08 mL, 0.44 mmol) in DMSO (0.6 mL) was added dropwise MeSO3Cl (20 mg, 0.176 mmol). The resulting mixture was stirred at room temperature for 6 h. TLC (CH2Cl2:MeOH=10:1) showed most of starting material was converted. The mixture was partitioned between water (50 mL) and EtOAc (50 mL) and separated. The aqueous layer was extracted with EtOAc (50 mL×3). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to give EX. 8-80 (10.8 mg, 18%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]#[N:30])[N:24]=1>>[C:29]([C:25]1[N:26]=[C:27]([NH:1][C:2]2[S:3][C:4]([C:10]3[C:11]([F:21])=[CH:12][C:13]([C:17]([OH:20])([CH3:18])[CH3:19])=[CH:14][C:15]=3[F:16])=[CH:5][C:6]=2[C:7]([NH2:9])=[O:8])[CH:28]=[CH:23][N:24]=1)#[N:30]
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: N#Cc1nccc(Cl)n1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccnc(C#N)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (113 mg, 0.36 mmol) and 4-chloropyrimidine-2-carbonitrile (51 mg, 0.36 mmol) as starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1OC
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C(=O)O
Yield: 0.1 %

Procedure:
The title compound was prepared according to the procedure described in step-3 of Intermediate-9 by using of methyl 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (1.0 g, 2.65 mol) and sodium hydroxide (0.210 g, 5.30 mmol) to afford 0.600 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.84 (s, 3H), 7.59 (t, J=7.8 Hz, 2H), 7.67-7.75 (m, 3H), 7.81 (d, J=8.4 Hz, 1H), 12.58 (br, 1H), 12.80 (s, 1H); MS (m/z): 362.21 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([OH:43])[CH:25]=[CH:26][C:27]=1[CH:28]([CH3:42])[C:29]([C:35]1[CH:40]=[CH:39][N:38]=[C:37]([Cl:41])[CH:36]=1)([OH:34])[C:30]([F:33])([F:32])[F:31]>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][C:8]([O:43][C:24]2[CH:25]=[CH:26][C:27]([CH:28]([CH3:42])[C:29]([C:35]3[CH:40]=[CH:39][N:38]=[C:37]([Cl:41])[CH:36]=3)([OH:34])[C:30]([F:31])([F:32])[F:33])=[C:22]([Cl:21])[CH:23]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)cc1
Reaction time: 8 h

Procedure:
Copper(II)acetate (30 mg), (4-methoxycarbonylphenyl)boronic acid (CAS Reg. No. 99768-12-4, 30 mg), and triethylamine (22 mg) were added to a solution of 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (Example 19 step 5, 20 mg) in DCM (2 ml). The mixture was stirred with molecular sieves under air atmosphere overnight and then concentrated to an oil. The residue was purified by prep. HPLC (C18-column, solvent gradient 30-98% CH3CN in 0.1% HCOOH[aq]) to give the title compound (15 mg) as a white solid. MS (m/e)=500.1 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([CH3:13])=[CH:6][C:4]=1N.N([O-])=O.[Na+].[BrH:18]>O>[Br:18][C:4]1[CH:6]=[C:7]([CH3:13])[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:3]=1[O:2][CH3:1]
Reactant: COc1cc([N+](=O)[O-])c(C)cc1N
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc([N+](=O)[O-])c(C)cc1Br
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
a mixture of 2-methoxy-5-methyl-4-nitroaniline (20 g, 110 mmol) in 140 mL of water was heated under reflux and 48% hydrobromic acid (56 mL) was added dropwise and the mixture was heated for 20 minutes. The resulting suspension was cooled to 0° C. and treated with 40 mL of aqueous sodium nitrite (7.6 g, 110 mmol) dropwise keeping the temperature at 0° C. The suspension was added carefully dropwise to a 0° C. solution of cuprous bromide (18.1 g, 126 mmol) in 96 mL of water and 38 mL of 48% HBr. The mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hour and finally on a steam bath for 20 minutes to complete the reaction. The solid precipitate was suction filtered and dissolved in methylene chloride, washed with 400 mL of 10% sodium hydroxide, 5% sodium bisulfite, and water. The organic layer was dried, filtered, and evaporated in vacuo to give 24.9 g of dark brown solid. This was recrystallized from hexane to give 13.4 g of bromo compound.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[C:14]([O:18][C:19]([N:21]1[CH2:27][C@H:26]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:25][C@H:22]1[CH:23]=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15].O>O1CCCC1>[C:14]([O:18][C:19]([N:21]1[CH2:27][C@H:26]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:25][C@H:22]1[CH:23]([OH:24])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Reactant: Br[Mg]c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
2.0M Phenylmagnesium bromide-tetrahydrofuran solution (22.8 ml, 45.6 mmol) was added dropwise to a solution of (2S,4R)-N-t-butoxycarbonyl-4-(t-butyldimethylsiloxy)prolinal (10 g, 30.4 mmol) in tetrahydrofuran (200 ml) at -78° C. in a nitrogen stream over 15 minutes. This reaction solution was gradually warmed and stirred at room temperature for 3 hours. After addition of water, the reaction solution was concentrated in vacuo. The resulting residue was poured into a liquid mixture of ethyl acetate with water. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting oily residue was subjected to silica gel column chromatography (Wakogel™ C-300, heptane-ethyl acetate=4:1) to give (2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxy-2-(α-hydroxybenzyl)pyrrolidine (12.0 g, yield: 96.8%) as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[S:10](=[O:12])(=[O:11])[N:9]([CH2:13][C:14]2[S:18][C:17]([C:19](O)=[O:20])=[CH:16][CH:15]=2)[CH2:8][C:7]1=[O:22].O=S(Cl)Cl.[CH3:33][NH:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:33][N:34]([CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:19]([C:17]1[S:18][C:14]([CH2:13][N:9]2[CH2:8][C:7](=[O:22])[N:6]([CH2:5][C:4]3[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:3]=3[O:2][CH3:1])[S:10]2(=[O:12])=[O:11])=[CH:15][CH:16]=1)=[O:20]
Reactant: COc1ccc(CN2C(=O)CN(Cc3ccc(C(=O)O)s3)S2(=O)=O)c(OC)c1
Reactant: CNCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: COc1ccc(CN2C(=O)CN(Cc3ccc(C(=O)N(C)CCc4ccccc4)s3)S2(=O)=O)c(OC)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of the title D compound, 5-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-thiophene-2-carboxylic acid (220 mg, 0.52 mmol) in toluene (10 mL) is treated with SOCl2 (3 mL) and the mixture is heated at 80° C. for 1 h. The volatiles are evaporated and the residue is dissolved in toluene. The solvent is evaporated again and the residue is dissolved in CH2Cl2(10 mL). A mixture of N-methylphenethylamine (35 mg, 0.25 mmol) and triethylamine (39 mg, 38.7 mmol) in CH2Cl2 (1 mL) is added and the mixture is stirred for 16 h. The solvent is evaporated and the residue is chromatographed over silica gel using 0-100% EtOAc in hexane as the eluent to afford 5-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-thiophene-2-carboxylic acid methyl-phenethyl-amide as a clear oil: [M+1]+=544.
Reaction SMILES: [O:1]=[C:2]1[O:6][CH:5]([C:7]([O:9]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:8])[CH:4]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:3]1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[C:26]([O:25][C:23]([CH:4]1[CH2:3][C:2](=[O:1])[O:6][CH:5]1[C:7]([OH:9])=[O:8])=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C1CC(=O)OC1C(=O)OC(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1CC(=O)OC1C(=O)O
Yield: 76.8 %

Procedure:
148 mg of 3-tert-butyl 2-diphenylmethyl (2RS,3RS)-5-oxotetrahydrofuran-2,3-dicarboxylate in 4 ml of ethyl acetate was catalytically reduced with 15 mg of a 10% palladium-carbon catalyst at room temperature at atmospheric pressure of hydrogen for 15 hours. The catalyst was filtered off, and the solvent was evaporated in vacuo. The residue was washed with benzene to give 66 mg of the title compound as a white crystalline powder.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([OH:33])=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O[C@H:35]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:12])[NH:13][C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][C@H:39]4[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38]4)=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a suspension of 1-(5-tert-butylisoxazol-3-yl)-3-[3-(7-hydroxy-6-methoxyquinazolin-4-yloxy)phenyl]urea from Example 95B (0.45 g, 1 mmol), (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (0.225 g, 1.2 mmol), and Ph3P (0.393 g, 1.5 mmol) in THF (10 mL) was added di t-butyl azodicarboxylate (0.345 g, 1.5 mmol). After it was stirred at room temperature overnight, it was quenched with saturated NaHCO3 solution and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure. It was purified by silica gel chromatography with 70-90% EtOAc/hexane as eluants to afford (S)-tert-butyl 3-(4-{3-[3-(5-tert-Butylisoxazol-3-yl)ureido]phenoxy}-6-methoxyquinazolin-7-yloxy)pyrrolidine-1-carboxylate as solid (0.609 g, 98%). 1H NMR (300 MHz, CDCl3) δ 9.4 (s, 1H), 8.8 (s, 1H), 8.61 (s, 1H), 7.67 (m, 1H), 7.50 (m, 2H), 7.34 (t, 1H), 7.31 (m, 1H), 6.96 (d, 1H), 6.13 (s, 1H), 5.12 (m, 1H), 4.06 (s, 3H), 3.61-3.80 (m, 4H), 2.34 (m, 2H), 1.47 (s, 9H), 1.31 (s, 9H); LC-MS (ESI) m/z 619 (M+H)+.
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH2:28]([C:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]([N:45]2[CH2:50][CH2:49][N:48]([C:51]3[CH:56]=[N:55][C:54]([C:57](=O)[CH3:58])=[CH:53][N:52]=3)[CH2:47][CH2:46]2)=[N:37][N:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[CH2:28]([C:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]([N:45]2[CH2:50][CH2:49][N:48]([C:51]3[CH:56]=[N:55][C:54]([C:57]([CH3:58])=[CH2:2])=[CH:53][N:52]=3)[CH2:47][CH2:46]2)=[N:37][N:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)cn1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)cn1
Temperature: 5 °C
Yield: 78.9 %

Procedure:
Methyltriphenylphosphonium iodide (115 mg, 0.28 mmol) is dissolved in THF (750 μL) and chilled to 5° C. While stirring add potassium t-butoxide (310 μL, 1M in THF, 0.31 mmol) to the solution. After 30 minutes add the mixture to a solution of 1-[4-(4-Benzyl-phthalazin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-5′-yl]-ethanone (100 mg, 0.24 mmol) and THF (750 μL). Stir 30 minutes. Analysis shows 60-70% completion. A second portion of methyl triphenyl phosphonium iodide (115 mg, 0.28 mmol) is dissolved in THF (750 μl) and chilled to 5° C. While stirring add potassium t-butoxide (310 μL, 1M in THF, 0.31 mmol) to the solution. Again add this mixture to the current reaction. Reaction quickly proceeds to completion. Quench by adding saturated ammonium chloride. Concentrate in vacuo to remove THF and partition between water and EtOAc. Extract with EtOAc, and wash combined organics with brine. Concentrate EtOAc in vacuo. The residue is purified by flash chromatography on silica gel (EtOAc/Heptane) to afford the title compound (80 mg, 78%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]([CH3:14])[C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:15])[CH:6]=1)=[O:4].[N+](=[CH2:18])=[N-].O.[OH-].[Li+]>CO.O>[CH3:15][C:7]1[CH:6]=[C:5]([CH:13]=[C:12]([CH3:14])[C:8]=1[C:9]([O:11][CH3:18])=[O:10])[C:3]([OH:2])=[O:4]
Reactant: COC(=O)c1cc(C)c(C(=O)O)c(C)c1
Reactant: C=[N+]=[N-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1c(C)cc(C(=O)O)cc1C
Reaction time: 8 h

Procedure:
A solution of 4-(methoxycarbonyl)-2,6-dimethylbenzoic acid (2.08 g: 10 mmol) in methanol (25 mL) is treated with ethereal diazomethane until the yellow color persists and the solution is left at room temperature overnight. The solution is concentrated in vacuo to remove the remaining diethyl ether, then tetrahydrofuran (25 mL) is added. The solution is stirred in an ice-water bath as a solution of lithium hydroxide monohydrate (0.462 g, 11 mmol) in water (25 mL) is added. After the cooling bath is removed, the reaction is allowed to proceed at room temperature overnight. The volatiles are removed under reduced pressure on a rotary evaporator (bath temperature <30° C.), then the concentrate is diluted with brine and extracted with dichloromethane to remove residual 2,6-dimethylterephthalic acid dimethyl ester. The aqueous phase is acidified to pH 2 using 3N hydrochloric acid (4 mL), then is extracted with dichloromethane (2×25 mL). The combined organic extracts are washed with brine, then are dried (MgSO4), filtered and evaporated in vacuo to yield 3,5-dimethyl-4-(methoxycarbonyl)benzoic acid.