Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([NH:20][CH2:21][C:22]([OH:24])=O)[S:18][CH:19]=2)=[CH:11][CH:10]=1.[NH:25]1[CH2:28][CH2:27][CH2:26]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:25]1([C:22](=[O:24])[CH2:21][NH:20][C:17]2[S:18][CH:19]=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([F:8])=[CH:14][CH:13]=3)[N:16]=2)[CH2:28][CH2:27][CH2:26]1
Reactant: O=C(O)CNc1nc(-c2ccc(F)cc2)cs1
Reactant: C1CNC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1nc(-c2ccc(F)cc2)cs1)N1CCC1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.27 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylamino]-acetic acid trifluoroacetic acid salt and 31.2 mg (0.54 mmol) of azetidine. Yield: 27 mg.
Reaction SMILES: C([NH:11][CH2:12][CH2:13][CH2:14][C@H:15]([C:32]([NH:34][C@@H:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)[CH3:36])=[O:33])[NH:16][C:17](=[O:31])[CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(OCC1C=CC=CC=1)=O.Cl>CO.[Pd]>[C:19]1([CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]([NH:16][C@@H:15]([C:32]([NH:34][C@@H:35]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[CH3:36])=[O:33])[CH2:14][CH2:13][CH2:12][NH2:11])=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc([C@@H](C)NC(=O)[C@@H](CCCNC(=O)OCc2ccccc2)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc([C@@H](C)NC(=O)[C@@H](CCCN)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Reaction time: 3 h
Yield: 95.2 %

Procedure:
A solution of (R)-N5 -(Cbz)-N2 -(Diphenylacetyl)-(R)-N-[1-(4-methoxy-phenyl)ethyl]ornithine amide (5.7 g; 9.6 mmol; from step (d) above) and HCl (2 N; 6 mL) in MeOH (200 mL) was flushed with nitrogen prior to the addition of 10% Pd/C (w/w; 530 mg). The heterogeneous solution was briefly flushed with hydrogen and then stirred under 1 atmosphere of hydrogen for 3 hours. When the deprotection was complete, as determined by TLC analysis, the solution was filtered through a pad of Celite to remove the catalyst. The filtrate was then evaporated at reduced pressure to give the crude product. The residue from evaporation of the filtrate was dissolved in water (300 mL) and washed with diethyl ether (2×50 mL). The aqueous layer was adjusted to pH 12 with concentrated NH4OH, then extracted with EtOAc (3×200 mL). The combined organic extracts were washed with brine (200 mL), then dried (Na2SO4) and filtered. The filtrate was evaporated at reduced pressure to give 4.2 g (95%) of the sub-title compound (free base) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[C:27]1([NH:33][CH2:34][CH2:35][NH2:36])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:36][CH2:35][CH2:34][NH:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: NCCNc1ccccc1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C(NCCNc1ccccc1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
62 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to N′-phenylethane-1,2-diamine via Procedure G. The crude product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(2-(phenylamino)ethyl)terephthalamide. MS (Q1) 505.1 (M)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH:7]2[CH2:16][CH2:15][C:14]3[N:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:8]2=O)[N:3]=[CH:2]1.NN.[OH-].[K+]>C(O)COCCO.O.C([O-])(O)=O.[Na+]>[NH:1]1[CH:5]=[C:4]([CH2:6][CH:7]2[CH2:16][CH2:15][C:14]3[N:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH2:8]2)[N:3]=[CH:2]1
Reactant: O=C1c2cccnc2CCC1Cc1c[nH]cn1
Agent: NN
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: OCCOCCO
Product: c1cnc2c(c1)CC(Cc1c[nH]cn1)CC2
Temperature: 170 °C

Procedure:
Use of 7,8-dihydro-6H-quinolin-5-one (Intermediate TWENTYTWO-1) (obtained as described in Molina, et. al. Tetrahedron 1995, 51, 1265, incorporated herein by reference) in Method E produced 6-(1H-imidazol-4-ylmethyl)-7,8-dihydro-6H-quinolin-5-one (Intermediate TWENTYTWO-2). To a solution of 6-(1H-imidazol-4-ylmethyl)-7,8-dihydro-6H-quinolin-5-one (Intermediate TWENTYTWO-2) (1.31 g, 227 mmol) in diethylene glycol (10 mL) was added hydrazine (6.3 mL, 200 mmol) followed by KOH (4.85 g, 56.2 mmol). The mixture was heated to 170° C. for 5 h. The mixture was diluted with water (200 mL) and sat. NaHCO3. The aqueous solution was extracted with CHCl3 (3×50 mL). The combined organic portions were washed with water and brine. The organic layer was dried over MgSO4, filtered and evaporated to give 6-(1H-imidazol-4-ylmethyl)-5,6,7,8-tetrahydro-quinoline as a foamy solid, 1.15 g (92%). By the applicable process steps described in Method A, the imidazole compound was used to produce 4-(5,6,7,8-tetrahydro-quinolin-6-ylmethyl)-1,3-dihydro-imidazole-2-thione (Compound 162).
Reaction SMILES: C(OC(=O)[CH2:5][N:6]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:7]([C:9]1([NH:12][C:13](OCC2C=CC=CC=2)=[O:14])[CH2:11][CH2:10]1)=[O:8])C.[H][H]>[C].[Pd].C(O)C>[CH2:23]([N:6]1[C:7](=[O:8])[C:9]2([CH2:11][CH2:10]2)[NH:12][C:13](=[O:14])[CH2:5]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: [H][H]
Reactant: CCOC(=O)CN(Cc1ccccc1)C(=O)C1(NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: O=C1CN(Cc2ccccc2)C(=O)C2(CC2)N1
Yield: 100.4 %

Procedure:
5% Palladium carbon (3.6 g) was added to an ethanol (700 ml) solution of the compound (35.5 g, 86.5 mmol) obtained in Step 1 above and contact reduction was performed for 2 hours in a hydrogen atmosphere. The catalyst was filtrated through celite, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give the title compound (20 g, 100%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([N+]([O-])=O)[CH:3]=1.F[C:16]1C=C(C=CC=1F)C(O)=O>>[CH3:16][C:6]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]([F:11])[CH:9]=1)=[O:8]
Reactant: O=C(O)c1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: O=C(O)c1ccc(F)c(F)c1
Product: CC(=O)c1ccc(F)c(F)c1

Procedure:
Briefly, the benzoyl ester derivatives of formula II are prepared by reacting 5-fluoro-4-halo-2-nitrobenzoic acid with a chlorinating agent, such as thionyl chloride or trichlorophosphorous, followed by reacting the acid chloride so formed with a dialkylmalonate. The 4,5-difluoro-2-nitrobenzoic acid starting material can be prepared by nitration in mixed acid of 3,4-difluorobenzoic acid, which is obtained by oxidation 3,4-difluoroacetophenone. The 4- chloro-5-fluoro-2-nitrobenzoic acid starting material can be obtained by the following process:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[N:2]1.CO[CH:21]1[CH2:25][CH:24]([CH:26]=O)[CH:23](OC)[O:22]1.O>C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[CH:21]=[CH:25][C:24]([CH:23]=[O:22])=[CH:26]2)=[N:2]1
Reactant: Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Reactant: COC1CC(C=O)C(OC)O1
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1ccn(-c2ccccc2/C=C/c2n[nH]c3ccccc23)c1
Yield: 21.6 %

Procedure:
Compound 2 (0.30 g, 1.3 mmol) was dissolved in acetic acid (5.0 mL) and 2,5-dimethoxy-4-tetrahydrofurancarbaldehyde (0.36 mL, 2.6 mmol) was added, followed by heating under reflux for 3 days. The reaction mixture was added with water and filtered through Celite, extracted with ethyl acetate and the organic layer was concentrated. The mixture was purified by silica gel column chromatography (hexane/ethyl acetate=4/1 to ethyl acetate) to obtain Compound 167 (88 mg, 22%).
Reaction SMILES: C([N:9]1[C:13](=[O:14])[C:12]([CH:16]([CH3:18])[CH3:17])([CH3:15])[N:11]=[C:10]1[C:19]1[N:28]=[CH:27][C:26](C(Br)Br)=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22])(=O)C1C=CC=CC=1.C(NCCN)C.C(N(CC)CC)C.[O:45]1CCC[CH2:46]1>>[CH:46]([C:26]1[CH:27]=[N:28][C:19]([C:10]2[NH:9][C:13](=[O:14])[C:12]([CH:16]([CH3:17])[CH3:18])([CH3:15])[N:11]=2)=[C:20]([CH:25]=1)[C:21]([O:23][CH3:24])=[O:22])=[O:45]
Reactant: COC(=O)c1cc(C(Br)Br)cnc1C1=NC(C)(C(C)C)C(=O)N1C(=O)c1ccccc1
Reactant: C1CCOC1
Agent: CCNCCN
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C=O)cnc1C1=NC(C)(C(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 1.38 g of 2-(1-benzoyl-4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-5-(dibromomethyl)nicotinic acid, methyl ester, in 35 mL tetrahydrofuran is cooled to -78° and treated with a mixture of 0.3 mL of N-ethylethylenediamine, 10 mL tetrahydrofuran, and 0.8 mL of triethylamine. After warming to room temperature, the reaction solution is treated with 0.3 mL of N-ethylethylenediamine, stirred for 2 hours, heated at reflux for 24 hours, and concentrated in vacuo. The residue is partitioned between methylene chloride and water; the aqueous phase is further extracted with methylene chloride, and the combined organic phases are dried and concentrated in vacuo. Chromatography of the residue on silica gel using hexane-ethyl acetate mixtures affords the desired product, mp 113°-117°.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([NH:7][C:8]2[S:9][C:10]3[N:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[N:13]=2)=[CH:5][CH:4]=1)#[N:2].[H-].[Li+].[CH3:23]I>>[C:1]([C:3]1[CH:20]=[CH:19][C:6]([N:7]=[C:8]2[N:13]([CH3:23])[C:12](=[O:14])[C:11]3[CH:15]=[CH:16][CH:17]=[N:18][C:10]=3[S:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CI
Reactant: N#Cc1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Agent: [H-]
Agent: [Li+]
Product: Cn1c(=Nc2ccc(C#N)cc2)sc2ncccc2c1=O
Yield: 80.7 %

Procedure:
The reaction procedure of Example 11 was followed except that 900 mg (3.21 mmol) of 2-(4-cyanoanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 42 mg of lithium hydride and 547 mg of methyl iodide were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform) to obtain 762 mg of 2-[(4-cyanophenyl)imino]-2,3-dihydro-3-methyl-4H-pyrido[3,2-e]-1,3-thiazin-4-one (81%, recrystallized from a mixture of ether and hexane).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH:9]=[O:10])=[CH:5][CH:4]=1.[CH2:13]([Mg]Br)[CH3:14].C([O-])(O)=O.[Na+]>C1COCC1>[F:12][C:2]([F:11])([F:1])[C:3]1[N:8]=[CH:7][C:6]([CH:9]([OH:10])[CH2:13][CH3:14])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Reactant: CC[Mg]Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(O)c1ccc(C(F)(F)F)nc1
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
Dissolve 6-trifluoromethyl-pyridine-3-carboxaldehyde (3.526 g, 20.136 mmol) in THF (50 mL). Add ethylmagnesium bromide (3.0 M in Et2O, 7.38 mL, 22.1 mmol) quickly. Stir 30 minutes. Pour the reaction mixture into a saturated NaHCO3 aqueous solution (100 mL). Extract with EtOAc (3×50 mL). Wash the combined organic extracts with a saturated NaCl aqueous solution (75 mL). Dry the organic extracts over Na2SO4; filter; collect the filtrate; and concentrate the filtrate under reduced pressure. Purify the residue by flash chromatography (Analogix® 40 g @ 40 mL/min) eluting with a gradient of EtOAc/hexanes (5% to 50%) over 30 minutes to give the title compound (2.01 g, 49% yield) as a yellow oil. 1H NMR (400.43 MHz, d6-DMSO) δ 8.66 (d, J=1.6 Hz, 1H), 7.95 (dd, J=1.9, 8.1 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 5.47 (d, J=4.5 Hz, 1H), 4.60 (q, J=5.8 Hz, 1H), 1.65-1.59 (m, 2H), 0.79 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][CH2:11][N:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][C:16]([C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:18]=3)[C:13]2=[O:26])=[CH:5][CH:4]=1.[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1>>[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][N:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:10][CH2:11][N:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][C:16]([C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:18]=3)[C:13]2=[O:26])=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc2ccn(CCNc3ccc(OC)cc3)c(=O)c2c1
Reactant: O=Cc1ccc(Cl)cc1
Product: COC(=O)c1ccc2ccn(CCN(Cc3ccc(Cl)cc3)c3ccc(OC)cc3)c(=O)c2c1

Procedure:
The title compound was prepared from methyl 2-{2-[(4-methoxyphenyl)amino]ethyl}-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (60 mg, 0.17 mmol) and 4-chlorobenzaldehyde (34 mg, 0.24 mmol) following the procedure outlined in Example 54, step 3 (50 mg, 62%). LC-MS: (FA) ES+ 477.
Reaction SMILES: C([O:8][C@H:9]([CH3:59])[C:10]([NH:12][C@H:13]1[CH2:17][C@@H:16]([N:18]2[CH:26]=[N:25][C:24]3[C:19]2=[N:20][C:21]([N:42]2[CH2:46][CH2:45][C@@H:44]([NH:47][C:48]([NH:50][C:51]4[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=4)=[O:49])[CH2:43]2)=[N:22][C:23]=3[NH:27][CH2:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:15]([OH:57])[C@@H:14]1[OH:58])=[O:11])C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[C:30]1([CH:29]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:28][NH:27][C:23]2[N:22]=[C:21]([N:42]3[CH2:46][CH2:45][C@@H:44]([NH:47][C:48]([NH:50][C:51]4[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=4)=[O:49])[CH2:43]3)[N:20]=[C:19]3[C:24]=2[N:25]=[CH:26][N:18]3[C@@H:16]2[CH2:17][C@H:13]([NH:12][C:10](=[O:11])[C@H:9]([OH:8])[CH3:59])[C@@H:14]([OH:58])[C@H:15]2[OH:57])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: C[C@@H](O)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a stirred solution of (R)-2-Benzyloxy-N-((1S,2R,3S,4R)-4-{6-(2,2-diphenyl-ethylamino)-2-[(R)-3-(3-pyridin-3-yl-ureido)-pyrrolidin-1-yl]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide in ethanol is added 10 equivalents of ammonium formate and 20 mol % of 10% palladium on carbon. The mixture is stirred at 80° C. for five hours, allowed to cool and filtered through Celite™. Removal of the solvent under reduced pressure affords the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH:4]=[O:5].[Si:8](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C=CN=C1.O>CN(C)C=O>[Si:8]([O:5][CH2:4][C:3]([CH3:7])([CH3:6])[CH:2]=[O:1])([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C=O)CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 18 h
Yield: 56.1 %

Procedure:
3-Hydroxy-2,2-dimethylpropanal (5.1 g, 50 mmol) and tert-butyl-diphenylsilyl chloride (15.10 g, 55 mmol) were dissolved in dimethylformamide (50 ml). Imidazole (3.74 g, 55 mmol) was added in one portion. After stirring for 18 hours the mixture was hydrolyzed with water and extracted several times with ether. The combined organic layers were dried with MgSO4. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography (hexane/ethyl acetate 15:1) to give the title compound (9.55 g, 56%) as a colorless oil.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[NH:15]1CCOCC1>ClCCl>[NH2:15][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3]
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Reactant: C1COCCN1
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Yield: 99.2 %

Procedure:
5-Chlorosulfonyl-2-indolinone (2.3 g) and 2.2 g morpholine in 50 mL of dichloromethane was stirred for 3 hours at room temperature. The precipitate was collected by vacuum filtration, washed with ethyl acetate and hexane and dried to give 2.09 g (74%) of the title compound as a white solid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([CH3:11])([CH3:10])[CH:7]([CH3:9])[CH3:8])C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[CH3:10][C:6]([CH3:11])([CH:7]([CH3:9])[CH3:8])[CH2:5][CH2:4][OH:3]
Reactant: CCOC(=O)CC(C)(C)C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)C(C)(C)CCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
Step B To a solution of 3,3,4-trimethyl-pentanoic acid ethyl ester (7 g, 41 mmol) in anhydrous ethyl ether (100 mL) at 0° C. was added a ethyl ether solution (1 M) of LiAlH4 (67 mL, 67 mmol) under nitrogen. The reaction mixture was stirred at 0° C. for 1 h, then poured into a ice-water. The mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HCl solution, brine, dried over MgSO4, and concentrated to give 3,3,4-trimethyl-pentan-1-ol as a colorless oil (5.4 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([OH:12])[C:5]=1[CH3:13].[Br:15]Br>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[C:5]([CH3:13])=[C:6]([OH:12])[CH:7]=[C:8]([O:10][CH3:11])[C:9]=1[Br:15]
Reactant: BrBr
Reactant: COC(=O)c1cc(OC)cc(O)c1C
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(C)c(O)cc(OC)c1Br
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 23.5 g of 3-hydroxy-5-methoxy-2-methylbenzoic acid methyl ester in 1.3 l of chloroform was added over 1 h at -50° to -60° C. a solution of 19.2 g of bromine in 0.2 l of chloroform. Stirring was continued for 2.5 h at -40° C. and for 2 h at 0° C. The reaction mixture was evaporated in vacuo at 0° C.; the residue was dissolved in a mixture of toluene/ethanol (1:1, v/v) and the solvent was again evaporated in vacuo. This procedure was repeated twice with toluene/ethanol (1:1, v/v), and finally once with toluene. The residue was chromatographed on silica gel using ethyl acetate as eluent and the pure product was crystallized from ethyl acetate to yield 28 g of 2-bromo-3-methoxy-5-hydroxy-6-methylbenzoic acid methyl ester as white crystals, m.p. 105°-110° C.
Reaction SMILES: Cl.[N:2]1[CH:3]=[CH:4][N:5]2[CH2:10][CH:9]([C:11](OCC)=[O:12])[CH2:8][CH2:7][C:6]=12.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>ClCCl.O>[N:2]1[CH:3]=[CH:4][N:5]2[CH2:10][CH:9]([CH2:11][OH:12])[CH2:8][CH2:7][C:6]=12
Reactant: CCOC(=O)C1CCc2nccn2C1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: OCC1CCc2nccn2C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 69.5 %

Procedure:
Suspend ethyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-6-carboxylate hydrochloride (5.74 g; 1.0 equiv; 24.88 mmoles) in dichloromethane (100 mL), and tetrahydrofuran (40 mL) and cool to 0° C. Add lithium aluminum hydride (1.77 g; 1.8 equiv; 44.79 mmoles) portionwise over 10 minutes. After an additional 5 minutes, allow the reaction mixture to warm to ambient temperature. After 15 minutes, cool the reaction mixture to 0° C. and slowly add water (1.77 mL), 15% sodium hydroxide solution (1.77 mL), and water (5.31 mL) sequentially with vigorous stirring. Continue to stir at ambient temperature for 15 minutes. Add magnesium sulfate then filter the reaction mixture, rinsing the filter cake with 200 mL dichloromethane. Concentrate the filtrate to give 5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-ylmethanol (2.63 g; 69%). MS (m/z): 153(M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)=[O:7].C(Cl)CCl.OC1C2N=NNC=2C=CC=1.CCN(C(C)C)C(C)C.[CH3:47][N:48]1[CH2:53][CH2:52][C:51]2[N:54]=[C:55]([NH2:57])[S:56][C:50]=2[CH2:49]1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:12]([C:13](=[O:15])[NH:57][C:55]2[S:56][C:50]3[CH2:49][N:48]([CH3:47])[CH2:53][CH2:52][C:51]=3[N:54]=2)[CH:11]=1)=[O:7]
Reactant: CN1CCc2nc(N)sc2C1
Reactant: COc1ccc(C(=O)NCc2cccc(C(=O)O)c2)cc1OC
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3nc4c(s3)CN(C)CC4)c2)cc1OC
Reaction time: 1 h

Procedure:
Dissolved 3-[(3,4-dimethoxy-benzoylamino)-methyl]-benzoic acid (100 mg, 0.317 mmol), EDC (105 mg, 0.55 mmol) and hydroxybenzotriazole (84.2 mg, 0.55 mmol) in 1 mL of DMF. The mixture was stirred for 1 h. To this was added DIPEA (0.12 mL, 0.64 mmol) and 5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylamine (107 mg, 0.63 mmol). The mixture was placed in a 60° C. bath with an Ar stream blowing over it. The mixture stirred 14 h resulting in a concentrated residue. LC-MS analysis indicated the desired product. Dissolved in 5 mL of DMF/H2O and purified via prep HPLC (5%-95% CH3CN/H2O) to give 121.9 mg of 3,4-dimethoxy-N-[3-(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylcarbamoyl)-benzyl]-benzamide. MS, electrospray 467.4 (M+H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].[N+](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N-].CO>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][O:8][CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH3:16]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: OCC1CCCCO1
Agent: [Rh]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)COCC1CCCCO1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82.1 %

Procedure:
To a solution of tetrahydropyran-2-methanol (1.13 mL, 10.0 mmol) in dichloromethane (20 mL) is added rhodium (II) acetate dimer (11 mg) followed by ethyl diazoacetate (1.05 mL, 10.0 mmol). The reaction mixture is stirred at rt for 20 min. To the reaction mixture is added MeOH (0.5 mL), and the solvents rotary evaporated. The residue is purified by chromatography on silica gel; elution with EtOAc:heptane (30:70) gives 1.66 g of the product 458. 1H NMR (CDCl3) δ 4.3-4.1 (m, 4 H), 4.0 (m, 1 H), 3.6-3.4 (m, 4 H), 1.85 (m, 1 H), 1.6-1.3 (m, 5 H), 1.25 (t, 3 H); MS: m/z 203 (M++1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH2:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][C:11]#[CH:12]>>[Cl:1][C:2]1[N:7]=[C:6]([C:12]#[C:11][CH2:10][CH2:9][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C#CCCc1ccccc1
Product: Clc1nccc(C#CCCc2ccccc2)n1
Yield: 68.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2,4-dichloropyrimidine (250 mg, 1.68 mmol) and 1-(but-3-ynyl)benzene (218 mg, 1.68 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 280 mg (1.15 mmol, 69%) of 2-chloro-4-(4-phenylbut-1-ynyl)pyrimidine as a brown oil.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:8]=2)[C@@H:4]([C:21]([OH:23])=O)[O:3]1.S(Cl)([Cl:26])=O>ClCCl>[O:1]=[C:2]1[NH:6][C@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:8]=2)[C@@H:4]([C:21]([Cl:26])=[O:23])[O:3]1
Reactant: O=C1N[C@H](c2cccc(C#Cc3ccccc3)c2)[C@@H](C(=O)O)O1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C1N[C@H](c2cccc(C#Cc3ccccc3)c2)[C@@H](C(=O)Cl)O1
Yield: 94.9 %

Procedure:
To a solution of (4R,5S)-2-oxo-4-(3-(phenylethynyl)phenyl)oxazolidine-5-carboxylic acid (120 mg, 0.390 mmol) in dichloromethane (5 mL) was added thionyl chloride (0.285 mL, 3.90 mmol) and the solution was heated to reflux for 3 h. The reaction mixture was concentrated in vacuo providing (4R,5S)-2-oxo-4-(3-(phenylethynyl)phenyl)oxazolidine-5-carbonyl chloride (127 mg, 0.370 mmol, 95% yield) as a light brown wax.