Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21](/[CH:25]=[CH:26]/[C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][C:31]([Cl:37])=[CH:32][CH:33]=3)[N:28]=2)[CH:20]=1)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15].[OH-].[Na+]>O1CCOCC1>[Cl:37][C:31]1[CH:30]=[C:29]2[C:34]([CH:35]=[CH:36][C:27](/[CH:26]=[CH:25]/[C:21]3[CH:20]=[C:19]([C:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[CH2:11][CH2:10][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[C:3]([OH:38])=[O:2])[CH:24]=[CH:23][CH:22]=3)=[N:28]2)=[CH:33][CH:32]=1
Reactant: CCOC(CCc1ccccc1C(=O)OC)(OCC)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOC(CCc1ccccc1C(=O)O)(OCC)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Temperature: 80 °C

Procedure:
To a stirred solution of Ketal-ester 42 (0.65 g, 1.29 mmol) in 1,4-dioxane (10.0 ml) was added a solution of Sodium hydroxide (0.6 g, 15 mmol). The reaction mixture was heated at 80° C. for 18 hours. The resulting mixture was concentrated to remove dioxane, diluted with water (25 ml) and acidify with acetic acid, followed by usual workup with dichloromethane and FC to give (Ib.96) (0.35 g, 55%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[N:11]([CH3:15])[N:12]=[CH:13][CH:14]=2)[S:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO>[CH3:15][N:11]1[C:10]([C:8]2[S:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:9]=2)=[CH:14][CH:13]=[N:12]1
Reactant: COC(=O)c1csc(-c2ccnn2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1nccc1-c1cc(C(=O)O)cs1
Reaction time: 2 h
Yield: 55 %

Procedure:
5-(2-Methyl-2H-pyrazol-3-yl)-thiophene-3-carboxylic acid methyl ester (0.163 g, 073 mmol) was suspended in methanol (1 mL) then sodium hydroxide (1 M, 0.95 mL) was added and the mixture stirred for 2 hours. The solution was evaporated, the residue was taken up in HCl (1 N, 1.5 mL) and the resultant precipitate was collected by filtration and dried in vacuo to afford the title compound as a white solid (0.084 g). LCMS m/z 209.15 [M+H]+ R.T.=2.76 min (Analytical Method 6).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:4]1(=[O:6])[N:12]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]12
Reactant: NCCCC(=O)O
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(O)CCCN1C(=O)c2ccccc2C1=O

Procedure:
To a mixture of phthalic anhydride (14.8 g, 100 mmole) and 4-aminobutyric acid (10.3 g, 100 mmole) in 150 mL of dry toluene was added triethylamine (1.3 mL, 9.3 mmole). The reaction mixture was heated to reflux in a flask equipped with a Dean Stark trap and condensor. After refluxing for 2.5 hours, the reaction solution was cooled in an ice bath which resulted in the formation of a white precipitate. The solid was isolated by filtration and washed with 5% HCl (3×80 mL) followed by cold water (2×70 mL). 4-Phthalimidobutyric acid was obtained as a white powder (16.8 g, 72%). m.p.: 118-118.6° C.
Reaction SMILES: [ClH:1].[C:2]1([N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C@@H:10]3[CH2:17][N:18]([CH2:21][CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])[CH2:19][CH2:20][C@@H:9]23)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>>[ClH:1].[C:2]1([N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C@@H:10]3[CH2:17][N:18]([CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH2:19][CH2:20][C@@H:9]23)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCN1CC[C@@H]2[C@@H](C1)c1ccccc1N2c1ccccc1
Agent: Cl
Product: O=C(O)CCCN1CC[C@@H]2[C@@H](C1)c1ccccc1N2c1ccccc1

Procedure:
10.6 grams (0.264 moles) of (±)-trans-1,3,4,4a,5,9b-hexahydro-5-phenyl-2H-pyrido[4,3-b]indole-2-butyric acid, ethyl ester, hydrochloride (the compound of Example 4) was suspended in 80 ml. of 6N hydrochloric acid and was refluxed for 20 minutes. Immediately upon cooling, a precipitate was obtained which was filtered and washed with a small quantity of water giving the title compound, m.p. 238.5°-240° C. (dec.).
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]([CH3:14])=[C:8]([CH2:10][C:11](O)=[O:12])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:1]([C:5]1[O:6][C:7]([CH3:14])=[C:8]([CH2:10][CH2:11][OH:12])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1oc(C(C)(C)C)nc1CC(=O)O
Solvent: C1CCOC1
Product: Cc1oc(C(C)(C)C)nc1CCO

Procedure:
13.77 g of the above prepared (2-tert-butyl-5-methyl-oxazol-4-yl)-acetic acid (69.8 mmol) was dissolved in 460 ml of abs. THF and treated at 0° C. with 174.5 ml of 1M BH3,THF (2.5 eq.). The reaction mixture was then kept over night at ambient temperature. Careful quenching with ice, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents left a crude product which was refluxed for 60 Min. in MeOH to liberate quantitatively the free alcohol. Removing of the solvent and flash chromatography (SiO2, AcOEt) delivered finally 9.23 g of the title compound as colorless oil.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)=O.Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]C.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCBr
Reactant: O=CN1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCN1CCNCC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
A 20 g (0.18 mole) quantity of N-formylpiperazine, 37.2 ml (0.18 mole) of 1-bromodecane and 25 g (0.18 mole) of potassium carbonate were suspended in 20 ml of N,N-dimethylformamide and the suspension was stirred at 80° C. for 3 hours. The suspension was further extracted with 300 ml of benzene, and the organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 80 ml of methanol, and 20 ml of concentrated hydrochloric acid was added thereto and the mixture was refluxed for 3 hours. The solvent was evaporated under reduced pressure and the precipitated crystals were washed with acetone, giving 35.6 g (yield: 66%) of N-decylpiperazine as the hydrochloride.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([C:30](=[O:32])[NH2:31])([NH:16][C:17](=O)[C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=2[F:28])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CS(C)=O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]2([N:16]=[C:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=3[F:28])[NH:31][C:30]2=[O:32])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc(C(F)(F)F)cc2F)(C(N)=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)N=C(c1ccc(C(F)(F)F)cc1F)NC2=O
Temperature: 25 °C
Reaction time: 27 h
Yield: 56.8 %

Procedure:
A 6 N aqueous NaOH solution (54.8 μL, 323 μmol) was added to a solution of 4-carbamoyl-4-(2-fluoro-4-trifluoromethyl-benzoylamino)-piperidine-1-carboxylic acid tert-butyl ester (100 mg, 231 μmol) in DMSO (0.3 mL), and the mixture was stirred at room temperature for 27 hours. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution and then diluted with EtOAc, and the organic layer was sequentially washed with H2O and saturated brine. The organic layer was dried over MgSO4 and then concentrated under reduced pressure. The resulting residue was purified by column chromatography (CH2Cl2/MeOH=95:5) to give 2-(2-fluoro-4-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-carboxylic acid tert-butyl ester as a white solid (54.5 mg, 57%).
Reaction SMILES: NCC1C=C(NC(=O)N(CCC2C=CC(C(NC3C=C4C(=CC=3)C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=NC=C4)C(O)=O)=CC=2)C)C=CC=1S(CC)(=O)=O.[C:57]([O:61][C:62]([N:64]([C:106]([O:108][C:109]([CH3:112])([CH3:111])[CH3:110])=[O:107])[C:65]1[C:74]2[C:69](=[CH:70][C:71]([NH:75][CH:76]([C:80]3[CH:85]=[CH:84][C:83]([CH2:86][CH2:87][O:88][C:89](=[O:104])[NH:90][C:91]4[CH:96]=[CH:95][C:94]([S:97]([CH2:100][CH3:101])(=[O:99])=[O:98])=[C:93]([C:102]#[N:103])[CH:92]=4)=[C:82]([CH3:105])[CH:81]=3)[C:77]([OH:79])=[O:78])=[CH:72][CH:73]=2)[CH:68]=[CH:67][N:66]=1)=[O:63])([CH3:60])([CH3:59])[CH3:58]>>[NH2:103][CH2:102][C:93]1[CH:92]=[C:91]([NH:90][C:89]([O:88][CH2:87][CH2:86][C:83]2[CH:84]=[CH:85][C:80]([CH:76]([NH:75][C:71]3[CH:70]=[C:69]4[C:74](=[CH:73][CH:72]=3)[C:65]([N:64]([C:106]([O:108][C:109]([CH3:112])([CH3:111])[CH3:110])=[O:107])[C:62]([O:61][C:57]([CH3:60])([CH3:58])[CH3:59])=[O:63])=[N:66][CH:67]=[CH:68]4)[C:77]([OH:79])=[O:78])=[CH:81][C:82]=2[CH3:105])=[O:104])[CH:96]=[CH:95][C:94]=1[S:97]([CH2:100][CH3:101])(=[O:99])=[O:98]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)OCCc2ccc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2C)cc1C#N
Agent: CCS(=O)(=O)c1ccc(NC(=O)N(C)CCc2ccc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2)cc1CN
Product: CCS(=O)(=O)c1ccc(NC(=O)OCCc2ccc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2C)cc1CN
Reaction time: 15 h
Yield: 95 %

Procedure:
Using a procedure analogous to that used to prepare 25E, 31C (419 mg) was hydrogenated for 15 h to give 31D (400 mg, 95%) as a yellow glass. MS (ESI) m/z 792.43 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:14][S:13](=[O:15])[CH2:12][C:11](=[O:16])[N:10]2[CH2:17][C:18]([O:20]CC2C=CC=CC=2)=[O:19])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[Na+].[Cl-]>CO.C(=O)(O)[O-].[Na+].CCOCC>[F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:14][S:13](=[O:15])[CH2:12][C:11](=[O:16])[N:10]2[CH2:17][C:18]([OH:20])=[O:19])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(CN1C(=O)CS(=O)C[C@H]1c1cc(F)cc(F)c1)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCOCC
Solvent: CO
Product: O=C(O)CN1C(=O)CS(=O)C[C@H]1c1cc(F)cc(F)c1

Procedure:
A solution of benzyl [(3R)-3-(3,5-difluorophenyl)-1-oxido-5-oxothiomorpholin-4-yl]acetate (93.6 mg, 0.238 mmol, major isomer, from Step B) in MeOH (5 mL) was purged with nitrogen. The septum sealing the reaction vessel was briefly removed to allow introduction of Pd/C (˜18 mg, 10% Pd/C). The vessel was then purged with hydrogen from a balloon, before a fresh balloon of hydrogen was attached. After LCMS analysis indicated that the reaction had stalled at 60% conversion, the hydrogen atmosphere was replaced with nitrogen. The mixture was then filtered through a pad of celite, washing with MeOH as needed. The filtrate was concentrated in vacuo to provide a residue which was diluted with aqueous sodium bicarbonate (2%) and ether. The aqueous layer was extracted with ether (4 times) to remove un-reacted starting material. The aqueous layer was then made acidic by the addition of 3M HCl, and was then saturated with NaCl. This acidic aqueous layer was then extracted three times with DCM and three times with EtOAc. Both organics were dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound. MS: m/z=304 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[Li+].[OH-]>O1CCOCC1.O>[CH3:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(C)nc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2cc(C(=O)O)ccc2nc1-c1ccccc1
Reaction time: 1 h
Yield: 35.5 %

Procedure:
A solution of methyl 3-methyl-2-phenylquinoxaline-6-carboxylate (90 mg, 0.32 mmol, 1.00 equiv) and LiOH (20.7 mg, 0.90 mmol, 5.00 equiv) in 1,4-dioxane/H2O (9/3 mL) was placed in a 50-mL round-bottom flask and allowed to react, with stirring, for 1 hr while the temperature was maintained at reflux in an oil bath. The resulting mixture was concentrated under vacuum, and the pH adjusted to 4 with HCl (1M). The solids were collected by filtration and dried in an oven under reduced pressure, yielding 30 mg (33%) of 3-methyl-2-phenylquinoxaline-6-carboxylic acid as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[CH2:10][CH2:11][CH2:12][CH:3]([C:4]=23)[C:2]1=[O:13].[H-].[Na+].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20]Br>CN(C)C=O>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][C:3]12[CH2:12][CH2:11][CH2:10][C:5]3[C:4]1=[C:9]([CH:8]=[CH:7][CH:6]=3)[NH:1][C:2]2=[O:13]
Reactant: BrCCCCBr
Reactant: O=C1Nc2cccc3c2C1CCC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2cccc3c2C1(CCCCBr)CCC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.1 %

Procedure:
2a, 3,4,5-Tetrahydrobenz [cd]indole-2(1H) -one (3.0 g, 17 mmol) was dissolved in anhydrous N,N-dimethylformamide (120 ml). Thereto was added an oily sodium hydride (760 mg, 19 mmol), and the resulting solution was stirred at a room temperature for 1 hour. The reaction solution was mixed with 1,4-dibromobutane (6.3 ml, 52 mmol) and again stirred for 17 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was mixed with ethyl acetate, water and hydrochloric acid (1 N). The reaction product was extracted with ethyl acetate, washed with saturated brine and dried with anhydrous sodium sulfate. Then the compound obtained by the evaporation of the solvent under a reduced pressure was separated and purified by a silica gel column chromatography to obtain 1.8 g of the title compound (5.8 mmol, 33% in yield).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6](=O)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:10][CH:9]=1)C.[NH2:24][C:25]([NH2:27])=[S:26].CC(C)([O-])C.[K+].Cl>C(O)CCC.O>[C:18]([O:17][C:15](=[O:16])[NH:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:6]2[CH:5]=[C:4]([OH:3])[N:27]=[C:25]([SH:26])[N:24]=2)=[CH:9][CH:10]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: NC(N)=S
Reactant: CCOC(=O)CC(=O)Cc1ccc(NC(=O)OC(C)(C)C)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCCCO
Product: CC(C)(C)OC(=O)Nc1ccc(Cc2cc(O)nc(S)n2)cc1
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
A mixture of 4-(4-tert-butoxycarbonylamino-phenyl)-3-oxo-butyric acid ethyl ester (10.5 g, 32.7 mmol), thiourea (2.5 g, 32.7 mmol) and potassium tert-butoxide (8.3 g, 71.9 mmol, 2.2 equiv) in butan-1-ol (30 mL) is heated to 50° C. (oil bath temperature) for 23 h, under an argon atmosphere. The resulting yellow suspension is diluted with butan-1-ol (30 mL), neutralized by addition on 1N HCl (65 mL), diluted with H2O (20 mL) and extracted with CHCl3 (2×100 mL). The organic phase is dried (Na2SO4), filtered (washing the filter cake with copious amount of CHCl3) and concentrated in vacuo. After silica gel (300 g) column chromatography purification (CHCl3/MeOH, 90/10), the product is treated with CH2Cl2 (200 mL). The resulting suspension is allowed to stir at rt for 20 min, then diluted with hexane (200 mL) and filtered through a glass sintered funnel. The white residue is washed with a mixture (120 mL) of CH2Cl2/hexane (11, v/v) and dried in vacuo to afford the title compound: ES-MS: 334.0 [M+H]+; single peak at tR=7.04 min (System 2); Rf=0.34 (CHCl3/MeOH, 90/10).
Reaction SMILES: [CH2:1]([N:8]([CH3:30])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:26])([CH2:23][C:24]#[N:25])[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:11][C:10]=1[N+:27]([O-:29])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn]([N:44]=[N+:45]=[N-:46])(CCCC)CCCC)CCC>>[CH2:1]([N:8]([CH3:30])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:26])([CH2:23][C:24]2[NH:46][N:45]=[N:44][N:25]=2)[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:11][C:10]=1[N+:27]([O-:29])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)c1ccc(C(C)(CC#N)C(=O)N2CCCC2)cc1[N+](=O)[O-]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Product: CN(Cc1ccccc1)c1ccc(C(C)(Cc2nnn[nH]2)C(=O)N2CCCC2)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to Example 4g from 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-cyano-1-pyrrolidino-propan-1-one and tributyl tin azide.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[OH:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:25]#[N:26].O>C(#N)C>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=[C:2]([O:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:25]#[N:26])[CH:7]=1
Reactant: N#Cc1ccc(OCc2ccccc2)c(O)c1
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(OCc2ccccc2)c(Oc2cc(Cl)nc(-c3ccccc3)n2)c1
Reaction time: 24 h
Yield: 96.7 %

Procedure:
To 4,6-dichloro-2-phenylpyrimidine (1.5 g, 6.7 mmol) in acetonitrile (20 mL) was added Cs2CO3 (2.4 g, 7.4 mmol) and 3-hydroxy4-(benzyloxy)benzonitrile (1.5 g, 6.5 mmol). After stirring for 24 hours, water was added to the reaction mixture and the resulting solid was collected by suction filtration to give 2.6 g of 3-[(6-chloro-2-phenylpyrimidin-4-yl)oxy]-4-(benzyloxy)benzonitrile.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[CH:20]=[N:19][CH:18]=[C:17](/[CH:21]=[CH:22]/[C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[N:16]=3)=[N:12][C:11]=2[CH3:30])=[O:9])=[CH:4][CH:3]=1>C(OCC)(=O)C.C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[CH:20]=[N:19][CH:18]=[C:17]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[N:16]=3)=[N:12][C:11]=2[CH3:30])=[O:9])=[CH:31][CH:32]=1
Reactant: Cc1nc(-c2cncc(/C=C/c3ccc(F)cc3)n2)sc1C(=O)NCc1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cncc(CCc3ccc(F)cc3)n2)sc1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 76 %

Procedure:
Part B. To a solution of 2-{6-[(E)-2-(4-fluoro-phenyl)-vinyl]-pyrazin-2-yl}-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide (150 mg, 0.33 mmol, 1.0 equiv) in ethyl acetate/ethanol (1:1) was added Pd/C (70 mg, 10%). The flask was first purged with nitrogen, then with hydrogen in a Parr apparatus. The reaction mixture was stirred at ambient temperature for 12 hr at 50 psi. Upon completion by LCMS, the reaction mixture was diluted with ethyl acetate, filtered through Celite and concentrated in vacuo. The crude product was purified by preparative HPLC (acetonitrile/water, 0.1% trifluoroacetic acid) to afford 2-{6-[2-(4-fluoro-phenyl)-ethyl]-pyrazin-2-yl}-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide (113 mg, 75%). 1H NMR (400 MHz, CD2Cl2) δ 9.15 (s, 1H), 8.36 (s, 1H), 7.33-7.37 (m, 2H), 7.13-7.16 (m, 2H), 7.03-7.08 (m, 2H), 6.92-6.96 (m, 2H), 6.20 (bs, 1H), 4.56 (d, J=4.0 Hz, 2H), 3.08-3.14 (m, 4H), 2.72 (s, 3H); HRMS (M+H)+=451.15.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([NH2:9])[C:3]=1[NH2:10].[C:11]([O-])(O)=O.[Na+]>C(O)=O.O>[CH3:1][C:2]1[C:3]2[N:10]=[CH:11][NH:9][C:4]=2[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)c(N)c(N)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: Cc1cc(C)c2nc[nH]c2c1

Procedure:
Intermediate 179.1 (275 mg) in 3 mL formic acid was irradiated in a microwave reactor at 150° C. for 5 min. The mixture was diluted with water, neutralized with sat. NaHCO3, then extracted with EtOAc (3×). The organic phase was washed with water and brine, dried (Na2SO4) and concentrated to afford 245 mg of Intermediate 179.2 as an orange solid.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[O:3][C:4]1[CH:32]=[CH:31][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][NH:16][CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[O:11])=[CH:6][CH:5]=1.Cl[C:36]1[S:37][C:38]2[CH:43]=[N:42][NH:41][C:40](=[O:44])[C:39]=2[N:45]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[F:34][C:2]([F:1])([F:33])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:36]3[S:37][C:38]4[CH:43]=[N:42][NH:41][C:40](=[O:44])[C:39]=4[N:45]=3)[CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[O:11])=[CH:31][CH:32]=1
Reactant: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CNCCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: O=c1[nH]ncc2sc(Cl)nc12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3c(=O)[nH]ncc3s2)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
To a mixture of the compound (87 mg) obtained in Example 983, Step 2 and the compound (32 mg) obtained in Step 5 in isopropanol (0.9 ml) was added N,N-diisopropylethylamine (30 μl) at room temperature. After stirring overnight at room temperature, and the mixture was stirred with heating under reflux for 5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by thin layer silica gel chromatography (methanol:chloroform=5:95) to give the title compound (84 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([CH2:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:16][CH3:17])[N:5]=[C:4]([CH3:18])[C:3]=1[CH2:19]Cl.[CH3:21][C:22]1([CH3:28])[O:27][CH2:26][CH2:25][NH:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CC#N.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([CH2:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:16][CH3:17])[N:5]=[C:4]([CH3:18])[C:3]=1[CH2:19][N:24]1[CH2:25][CH2:26][O:27][C:22]([CH3:28])([CH3:21])[CH2:23]1
Reactant: CCc1cccc(CC)c1-c1cc(Cl)c(CCl)c(C)n1
Reactant: CC1(C)CNCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCc1cccc(CC)c1-c1cc(Cl)c(CN2CCOC(C)(C)C2)c(C)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-chloro-3-chloromethyl-6-(2,6-diethyl-phenyl)-2-methyl-pyridine (310 mg, 1.0 mmol), 2,2-dimethyl-morpholine (150 mg, 1.3 mmol) and K2CO3 (417 mg, 3 mmol) in CH3CN (10 mL) is stirred at room temperature for 16 hours. EtOAc (20 mL) and water (20 ml) are added to the mixture. The organic layer is separated, washed once with brine, dried (Na2SO4) and concentrated to give the title compound.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.N1C(C)=CC=CC=1C.[F:24][C:25]([F:52])([F:51])[C:26]1[CH:27]=[C:28]([C@H:36]2[O:40][C:39](=[O:41])[N:38]([CH2:42][C:43]3[C:48](O)=[N:47][CH:46]=[CH:45][N:44]=3)[C@H:37]2[CH3:50])[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1>C(Cl)Cl>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][C:48]1[C:43]([CH2:42][N:38]2[C@@H:37]([CH3:50])[C@@H:36]([C:28]3[CH:29]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:31]=[C:26]([C:25]([F:52])([F:24])[F:51])[CH:27]=3)[O:40][C:39]2=[O:41])=[N:44][CH:45]=[CH:46][N:47]=1)(=[O:8])=[O:9]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nccnc1O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nccnc1OS(=O)(=O)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cold (−78° C.) mixture of trifluoromethanesulfonic anhydride (0.284 mL, 1.681 mmol), 2,6-lutidine (0.261 mL, 2.241 mmol) and CH2Cl2 (1 mL) was added (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-hydroxypyrazin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (472 mg, 1.120 mmol) in CH2Cl2 (1 mL). The resulting mixture was stirred at −78° C. for 30 min then the cold bath was switched to an ice bath. Reaction mixture was stirred cold (0° C.) for additional 2 h. Crude mixture was worked up with water/CH2Cl2/Na2SO4/filtration/concentration to afford an orange oil. This was purified by preparative TLC (silica gel) developed with a EtOAc (30% v/v)/hexanes mixture to give a yellow oil as the titled compound. LCMS calc.=553.04; found=554.02 (M+H)+.