Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].Cl.[O:10]1CCC[CH2:11]1>[Cl-].[Na+].O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](=[O:7])[CH2:11][OH:10]
Reactant: C1CCOC1
Reactant: O=C(Cl)CCCCBr
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(CO)CCCCBr
Temperature: 10 °C

Procedure:
To 191.4 g of tris-trimethylsilyloxyethylene (Example 267) containing 15 drops of stannic tetrachloride under argon with stirring at 10° C. is added 87 g of 5-bromopentanoyl chloride (Example 274) dropwise. After one-half of the acid chloride added, the mixture is stirred until an exotherm ensues. The remaining acid chloride is added dropwise maintaining the reaction exotherm at 65° C. The mixture is then stirred for 2.5 hours. The mixture is slowly poured into a stirred mixture of 100 ml of 0.6 N hydrochloric acid and 200 ml of tetrahydrofuran. The mixture is stirred for 30 minutes and poured into brine. Th mixture is extracted with ether. The ether solution is washed with saturated sodium bicarbonate and dried over magnesium sulfate. The solvent is removed. The residue is mixed with petrolium ether and cooled in dry-ice-acetone to induce crystallization. The petrolium ether is decanted and the solid is dried at reduced pressure to give 64.72 g of the title compound.
Reaction SMILES: [OH:1][CH:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].F[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]>C1COCC1>[F:19][C:17]1[CH:16]=[CH:15][C:14]([N+:20]([O-:22])=[O:21])=[C:13]([CH:18]=1)[O:1][CH:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CCOC(=O)CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 3-Hydroxybutyrate (6.5 ml) was dissolved in THF (350.0 ml) at 0° C. and NaH (4.8 g) was added. The reaction was stirred at room temperature for 30 min. Then 5.5 g 2,4-difluoronitrobenzene was added and the mixture was heated at reflux overnight. The reaction was concentrated in vacuo and the residue was dissolved in water and dichloromethane. The organic layer was separated, dried and concentrated in vacuo. The residue was purified by chromatography (silica/dichloromethane) to yield the title compound.
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:13][CH2:14][C@H:15]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]1>C(O)C>[CH3:12][C:2]1[CH:3]=[CH:4][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[F:13][CH2:14][C@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CF)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: FC[C@H]1CCNC1

Procedure:
Prepare using the method of Intermediate 49 with p-toluenesulfonic acid monohydrate (0.14 g, 0.74 mmol), tert-butyl (3S)-3-(fluoromethyl)pyrrolidine-1-carboxylate (See Intermediate 54) (0.15 g, 0.74 mmol) and ethanol (2 mL) to give the title compound as a white solid (0.20 g): MS (m/e): 104 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)CCC>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([O:11][CH2:7][CH2:2][CH2:3][CH3:4])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)c(F)c1
Solvent: CCCCO
Product: CCCCOC(=O)Cc1ccc(-c2ccccc2)c(F)c1

Procedure:
n-butyl 2-(2-fluorobiphenyl-4-yl)acetate (22) was synthesized from 2-(2-fluorobiphenyl-4-yl)acetic acid and n-butanol according to a similar procedure to the step 1 of Example 15. The 1H NMR spectrum of this substance is shown below.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=1.P(OCC)(OCC)OCC.[I-].[K+].[CH2:24]([N:31]1[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CC(C)([O-])C.[K+]>O.CN(C)C=O.C(#N)C>[CH2:24]([N:31]1[CH2:36][CH2:35][C:34](=[CH:2][C:3]2[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=2)[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NC(=O)c1ccc(CCl)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: CCOP(OCC)OCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: NC(=O)c1ccc(C=C2CCN(Cc3ccccc3)CC2)cc1
Yield: 85.9 %

Procedure:
The compound (25.0 g, 0.147 mol) obtained in Example 1, triethyl phosphite (29.4 g, 0.177 mol), potassium iodide (22.0 g, 0.133 mol) and acetonitrile (125 mL) were charged and stirred under reflux for 3 hrs. The reaction mixture was allowed to return to room temperature, and concentrated under reduced pressure. To the residue were added N,N-dimethylformamide (100 mL) and 1-benzyl-4-piperidone (30.6 g, 0.162 mol), and the mixture was stirred under ice-cooling. Potassium t-butoxide (23.1 g, 0.206 mol) was added in 3 portions at 15 min. intervals. The reaction mixture was stirred at room temperature for 45 min. Water (400 mL) was dropwise added under ice-cooling, and the mixture was stirred for 30 min. Crystals were collected by filtration, washed with cold water (180 mL) and dried in vacuo at 40° C. to give the title compound (38.7 g, yield 85.2%) as pale-yellow powdery crystals.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:39]([O:41][CH:42]([O:45][CH2:46][CH3:47])[C:43]#[CH:44])[CH3:40].CCCCCC.C(OCC)(=O)C>C1(C)C=CC=CC=1.C(N(CC)CC)C>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:2]([C:44]#[C:43][CH:42]([O:45][CH2:46][CH3:47])[O:41][CH2:39][CH3:40])=[CH:7][N:6]=1
Reactant: CC(C)(C)OC(=O)NCCNc1nc(Cl)ncc1Br
Reactant: C#CC(OCC)OCC
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(C#Cc1cnc(Cl)nc1NCCNC(=O)OC(C)(C)C)OCC

Procedure:
To tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate 5 g (14.23 mmole) in toluene (42 mL) and triethylamine (8.33 mL) under nitrogen was added triphenyl arsine (4.39 g), 3,3-diethoxyprop-1-yne (3.24 mL) and Pddba (1.27 g). The contents were heated at 70 degrees for 24 hrs. After filtration through celite, the crude reaction was columned using hexane/ethyl acetate (0-20%) to afford the desired product. 3.9 g. Column chromatography of the resulting residue using hexane/ethyl acetate (0-30%) afforded tert-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]ethyl]carbamate. LCMS (ESI) 399 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:42])[C:7]=1[C:8](=[O:41])[CH2:9][N:10]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[CH:34]=1)[C:11]([C:13]1[CH:14]=[N:15][N:16]([C@H:21]2[CH2:26][CH2:25][C@H:24]([C:27]([O:29]CC)=[O:28])[CH2:23][CH2:22]2)[C:17]=1[CH:18]([F:20])[F:19])=[O:12].Cl.O>O1CCOCC1>[Cl:42][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[C:8](=[O:41])[CH2:9][N:10]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[CH:34]=1)[C:11]([C:13]1[CH:14]=[N:15][N:16]([C@H:21]2[CH2:26][CH2:25][C@H:24]([C:27]([OH:29])=[O:28])[CH2:23][CH2:22]2)[C:17]=1[CH:18]([F:19])[F:20])=[O:12]
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(CC(=O)c3c(Cl)cncc3Cl)Cc3cc(F)cc(F)c3)c2C(F)F)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(CN(Cc1cc(F)cc(F)c1)C(=O)c1cnn([C@H]2CC[C@H](C(=O)O)CC2)c1C(F)F)c1c(Cl)cncc1Cl
Temperature: 80 °C

Procedure:
To a solution of compound 20-3 (106 mg, 0.17 mmol) in dioxane (6 mL) was added 6 M HCl (6 mL) and heated at 80° C. for 16 h. The reaction mixture was cooled to room temperature, added H2O and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (2×10 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18 silica gel, 75% CH3CN/water as eluent) to provide the compound of example 20 (36 mg, 62%) as a white solid. 1H NMR (DMSO-d6) rotamers present δ 8.76 and 8.69 (2H, 2×s); 7.77 and 7.67 (1H, 2×s); 7.45-7.00 (4H, m); 4.91-4.70 (4H, m); 4.36-4.29 (1H, m); 2.31-2.24 (1H, m); 2.06-2.02 (2H, m); 1.94-1.89 (4H, m); 1.56-1.45 (2H, m); LCMS (ESI): 599 (M+H)+.
Reaction SMILES: [N+](C1C=CC(COC([NH:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([C@@H:20]3[CH2:24][C@H:23]([S:25][C:26]4[C@H:27]([CH3:50])[C@@H:28]5[C@@H:45]([C@H:46]([OH:48])[CH3:47])[C:44](=[O:49])[N:29]5[C:30]=4[C:31]([O:33]CC4C=CC([N+]([O-])=O)=CC=4)=[O:32])[CH2:22][N:21]3[CH3:51])=[O:19])[CH2:14]2)=O)=CC=1)([O-])=O.[ClH:54]>O1CCCC1.O>[ClH:54].[NH2:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:18]([C@@H:20]2[CH2:24][C@H:23]([S:25][C:26]3[C@H:27]([CH3:50])[C@@H:28]4[C@@H:45]([C@H:46]([OH:48])[CH3:47])[C:44](=[O:49])[N:29]4[C:30]=3[C:31]([OH:33])=[O:32])[CH2:22][N:21]2[CH3:51])=[O:19])[CH2:14]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](NC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](N)C4)N(C)C3)[C@H](C)[C@H]12

Procedure:
1.0 g of 4-nitrobenzyl (1R, 5S ,6S)-2-{(2S, 4S)-2-[(3S)-3-(4-nitrobenzyloxycarbonyl)aminopyrrolidin-1-ylcarbonyl]-1-methylpyrrolidin-4ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] was dissolved in 30 ml of a 2:1 by volume mixture of tetrahydrofuran and water, after which 1.04 ml of 1N aqueous hydrochloric acid was added, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 1.5 g of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 18(b), to give 175 mg of the title compound as a powder.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:10]=2)=[C:5]([C:22]([NH2:24])=[O:23])[CH:4]=1)#[CH:2].[CH3:25][Si:26]([CH2:29][N:30]=[N+:31]=[N-:32])([CH3:28])[CH3:27].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CN(C=O)C.O>[N:16]1([CH2:15][C:11]2[N:10]=[C:9]([NH:8][C:6]3[S:7][C:3]([C:1]4[N:32]=[N:31][N:30]([CH2:29][Si:26]([CH3:28])([CH3:27])[CH3:25])[CH:2]=4)=[CH:4][C:5]=3[C:22]([NH2:24])=[O:23])[CH:14]=[CH:13][CH:12]=2)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: C#Cc1cc(C(N)=O)c(Nc2cccc(CN3CCOCC3)n2)s1
Reactant: C[Si](C)(C)CN=[N+]=[N-]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)Cn1cc(-c2cc(C(N)=O)c(Nc3cccc(CN4CCOCC4)n3)s2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Ethynyl-2-{[6-(morpholin-4-ylmethyl)pyridin-2-yl]amino}thiophene-3-carboxamide (Example 599, Step 4) (75 mg, 0.22 mmol) and trimethylsilylmethyl azide (0.65 ml, 0.44 mmol) were combined in DMF (1.0 mL). CuSO4.5H2O (5.5 mg, 0.022 mmol) in water (0.2 mL) and sodium ascorbate (17 mg, 0.088 mmol) in water (0.2 ml) were added, and the reaction mixture was stirred at room temperature overnight. The reaction was evaporated to dryness, combined with MeOH and silica gel, and evaporated. Flash chromatography (dry load, 0-10% MeOH/EtOAc) afforded the title compound a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=O)=[CH:15][CH:14]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]C#N)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:21][N:19]=[C:16]3[CH:15]=[CH:14][C:13]([C:12]4[N:8]([C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)[N:9]=[CH:10][CH:11]=4)=[CH:18][C:17]=23)=[CH:25][CH:24]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccc(F)cc2)cc1
Reactant: N#CCc1ccc(Cl)cc1
Product: Fc1ccc(-n2nccc2-c2ccc3noc(-c4ccc(Cl)cc4)c3c2)cc1

Procedure:
The title compound, yellow solid (81 mg, 59%), MS (ISP) m/z=390.2 [(M+H)+], mp 188° C., was prepared in accordance with the general method of example 1 from 1-(4-fluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate C) (100 mg, 353 μmol) and commercially available 2-(4-chloro-phenyl)-acetonitrile.
Reaction SMILES: Cl[C:2]1[C:3]([OH:12])=[N:4][O:5][C:6]=1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22]O)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22][O:12][C:3]1[CH:2]=[C:6]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[O:5][N:4]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Oc1noc(-c2cccs2)c1Cl
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2cccs2)on1
Yield: 74.1 %

Procedure:
4-Chloro-3-hydroxy-5-(2-thienyl)isoxazole (0.50 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.40 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 1(a) to obtain the title compound (0.57 g, 66%) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[O:18]=[C:19]1[C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][CH2:22][CH2:21][N:20]1[CH2:37][C:38](O)=[O:39].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[O:39]=[C:38]([N:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:6]2[CH:14]=[CH:15][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:4][CH:5]=2)[CH2:9][CH2:10]1)[CH2:37][N:20]1[CH2:21][CH2:22][CH2:23][C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]1=[O:18]
Reactant: FC(F)(F)c1ccc(CN2CCNCC2)cc1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(Cc2ccc(C(F)(F)F)cc2)CC1
Reaction time: 8 h

Procedure:
A solution of 1-(4-(trifluoromethyl)benzyl)piperazine (0.046 g, 0.188 mmol), 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E, 0.053 g, 0.171 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.049 g, 0.257 mmol) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring overnight, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 0.4% to 4.5% methanol/dichloromethane over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.56-7.60 (m, 2H), 7.42-7.46 (m, 2H), 7.27-7.33 (m, 8H), 7.18-7.25 (m, 2H), 4.23 (s, 2H), 3.66 (t, J=4.7 Hz, 2H), 3.55 (s, 2H), 3.50 (t, J=6.5 Hz, 2H), 3.44-3.49 (m, 2H), 2.62-2.66 (m, 2H), 2.35-2.50 (m, 4H), 1.79-1.88 (m, 2H); MS (ESI+) m/z 536 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH:10]([C:13]1[NH:17][N:16]=[C:15]([NH2:18])[CH:14]=1)([CH3:12])[CH3:11].C(N(C(C)C)CC)(C)C>C(O)CCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:18][C:15]2[CH:14]=[C:13]([CH:10]([CH3:12])[CH3:11])[NH:17][N:16]=2)[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: CC(C)c1cc(N)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)c1cc(Nc2cc(Cl)nc(Cl)n2)n[nH]1
Temperature: 80 °C
Yield: 86.2 %

Procedure:
A mixture of 2,4,6-trichloropyrimidine (1.8 g, 9.8 mmol), 5-isopropyl-1H-pyrazol-3-ylamine (1.25 g, 10.0 mmol), diisopropylethylamine (3 mL, 18 mmol) and 1-butanol (10 mL) was heated to 80° C. for 2 h, at which point LC/MS indicated that the reaction was complete. The solvents were removed on a rotary evaporator and the paste was treated with ethyl acetate. The organic solution was washed with water and brine and dried over magnesium sulfate. The residue was concentrated on a rotary evaporator, and the pale yellow solid that remained was purified via flash chromatography to yield the desired product (2.3 g, 70%) as an off white solid.
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2[S:15][C:16]3[C:21]([N:22]=2)=[CH:20][CH:19]=[C:18]([C:23]2([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:25][CH2:24]2)[N:17]=3)=[CH:9][C:8]=1[CH3:32].Cl.[OH-].[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.CCOC(C)=O.O>[CH3:13][C:12]1[CH:11]=[C:10]([C:14]2[S:15][C:16]3[C:21]([N:22]=2)=[CH:20][CH:19]=[C:18]([C:23]2([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:25][CH2:24]2)[N:17]=3)[CH:9]=[C:8]([CH3:32])[C:7]=1[CH:2]=[O:1]
Reactant: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc(C)c1C1OCCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc(C)c1C=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(4-(1,3-dioxan-2-yl)-3,5-dimethylphenyl)-5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine (96.0 mg, 0.217 mmol) and hydrochloric acid (5.0M, aq; 1.5 mL, 7.50 mmol) in THF (3.0 mL) was heated at 60° C. in a sealed flask under argon. After 2 h, the reaction was allowed to cool to 25° C. The resulting mixture was diluted with EtOAc (50 mL) and water (20 mL), neutralized with 5.0N NaOH (1.5 mL), and saturated aqueous sodium bicarbonate (10 mL) was added. The organic layer was then separated, sequentially washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to provide 2,6-dimethyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)-benzaldehyde as a yellow-orange solid. MS (ESI) m/z: Calculated: 384.1; Observed: 385.1 (M++1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][C:22]([F:25])([F:24])[F:23])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH2:10][CH2:9]1.[NH2:27][CH2:28][CH2:29][CH2:30][OH:31]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][C:22]([F:25])([F:24])[F:23])[C:14]=3[N:13]=[C:12]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])[C:11]=2[CH2:10][CH2:9]1
Reactant: NCCCO
Reactant: Cc1ccccc1N1CCc2c(Cl)nc3c(OC(F)(F)F)cccc3c21
Product: Cc1ccccc1N1CCc2c(NCCCO)nc3c(OC(F)(F)F)cccc3c21

Procedure:
1-(2-Methylphenyl)-4-chloro-6-trifluoromethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(380 mg, 1.0 mmol) was dissolved in 3-amino-1-propanol(5 ml), then reacted at the same condition of Step 5 in the Example 1 to obtain 313 mg of desired compound as solid in 75% of yield.
Reaction SMILES: C([N:11]1[CH2:18][C:17]([OH:26])([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])(OCC1C=CC=CC=1)=O.C(SCC(N1CC=C[C@@]1(CC1OC=CC=1)C(O)=O)=O)(=O)C>>[OH:26][C:17]1([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:18][NH:11][C@H:12]([C:13]([OH:15])=[O:14])[CH2:16]1
Reactant: O=C(O)[C@@H]1CC(O)(Cc2ccncc2)CN1C(=O)OCc1ccccc1
Agent: CC(=O)SCC(=O)N1CC=C[C@@]1(Cc1ccco1)C(=O)O
Product: O=C(O)[C@@H]1CC(O)(Cc2ccncc2)CN1

Procedure:
The N-carbobenzyloxy-4-hydroxy-4-[(4-pyridyl)-methyl]-L -proline from part (a) is hydrogenated according to the procedure of Example 1 (b) to yield 4-hydroxy-4-[(4-pyridyl)methyl]-L-proline. This amino acid is reacted with D-3-acetylthio-2-methylpropionyl chloride according to the procedure of Example 1 (c) to yield [1(S)]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4-hydroxy-4-[(4-pyridyl)methyl]-L-proline.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:11]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:9][N:8]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].[OH-].[Li+]>C1COCC1.O>[C:16]([O:15][C:13]([NH:12][CH:11]1[CH2:10][CH2:9][N:8]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[CH2:7][CH:6]1[C:4]([OH:5])=[O:3])=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)C1CN(c2ccc(OC)c(OC)c2)CCC1NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N2CCC(NC(=O)OC(C)(C)C)C(C(=O)O)C2)cc1OC
Temperature: 25 °C
Reaction time: 22 h
Yield: 24 %

Procedure:
To a solution of rac-4-tert-butoxycarbonylamino-1-(3,4-dimethoxy-phenyl)-piperidine-3-carboxylic acid ethyl ester (170 mg) in 2 ml THF, were added 1 ml NaOH 1M and lithium hydroxide (100 mg). The suspension was stirred 22 h at RT., diluted with water and extracted twice with tert-butylmethylether. The aqueous layer was acidified to pH 4, saturated with NaCl and then the product was extracted with 3 portions of AcOEt. The organic layers were dried over MgSO4, filtered, evaporated and chromatographed (silica gel, AcOEt) to provide the title compound (38 mg, 55%).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([NH2:14])=O)[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[S:15][C:16]([CH2:18][CH2:19][CH3:20])=[CH:17][C:3]1=2.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]#[N:14])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[S:15][C:16]([CH2:18][CH2:19][CH3:20])=[CH:17][C:3]1=2
Reactant: CCCc1cc2c(=O)n3cc(C(N)=O)ccc3nc2s1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCCc1cc2c(=O)n3cc(C#N)ccc3nc2s1
Yield: 95.5 %

Procedure:
From 2.0 g (0.007 mol) of 4-oxo-2-propyl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide (Example 23), 30 ml of phosphorus oxychloride and 30 ml of chloroform, following the procedure of Example 27, there is obtained 1.8 g of 4-oxo-2-propyl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile; mp 217°-218° C. after recrystallization from glacial acetic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.O.[NH2:26][NH2:27]>C(O)C>[NH:26]([C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1)[NH2:27]
Reactant: NN
Reactant: N#Cc1ccccc1-c1ccc(COCc2ccc(Cl)nc2)cc1
Solvent: CCO
Solvent: O
Product: N#Cc1ccccc1-c1ccc(COCc2ccc(NN)nc2)cc1
Yield: 56 %

Procedure:
4′-{[(6-Chloropyridin-3-yl)methoxy]methyl}biphenyl-2-carbonitrile (1.7 g) and hydrazine monohydrate (3 mL) were suspended in ethanol (8 mL), and the suspension was reacted at 150° C. for 2 hours using a microwave reaction apparatus (Biotage Ltd.). The reaction solution was concentrated under reduced pressure, and the obtained residue was then purified by NH-silica gel column chromatography (Moritex Corporation, elution solvent: ethyl acetate) to obtain the title compound (0.90 g) as a yellow oil (yield: 56%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.S(Cl)(Cl)=O.[CH3:19]O>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([O:14][CH3:19])=[O:13])=[CH:7][CH:6]=[CH:5]2
Reactant: O=C(O)c1cccc2cc(O)ccc12
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc2cc(O)ccc12
Temperature: 22.5 °C

Procedure:
To a cooled solution of 6-hydroxy-1-napthoic acid (TCI America) (50 g, 0.27 mmol) in methanol (500 mL), thionyl chloride (29 mL, 0.40 mmol) was added slowly. The temperature was maintained at 15 to 30° C. The reaction mixture was allowed to warm to RT and stirred O/N. The solvent was concentrated in-vacuo and the residue azeotroped with benzene. The title compound was obtained as a pink solid.