Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](#[N:3])[CH3:2].[F:4][C:5]([F:17])([F:16])[C:6]1[N:11]=[CH:10][C:9]([C:12](O)([CH3:14])[CH3:13])=[CH:8][CH:7]=1.S(=O)(=O)(O)[OH:19].N>COC(C)(C)C.O>[CH3:13][C:12]([NH:3][C:1](=[O:19])[CH3:2])([C:9]1[CH:10]=[N:11][C:6]([C:5]([F:17])([F:16])[F:4])=[CH:7][CH:8]=1)[CH3:14]
Reactant: O=S(=O)(O)O
Reactant: CC#N
Reactant: CC(C)(O)c1ccc(C(F)(F)F)nc1
Agent: N
Solvent: O
Solvent: COC(C)(C)C
Product: CC(=O)NC(C)(C)c1ccc(C(F)(F)F)nc1
Temperature: 2.5 °C

Procedure:
Add acetonitrile (67.4 L; 53.0 kg) to a reaction vessel containing 2-(6-trifluoromethyl-pyridin-3-yl)-propan-2-ol (52 moles; 12.8 kg) and cool to 0-5° C. Add concentrated sulfuric acid (372 moles; 19.8 L; 36.5 kg) slowly, maintaining the internal reaction temperature between 0-15° C. Heat the solution to 25-30° C. for 24 hours, and observe the completion of the reaction by HPLC. Cool the mixture to 0° C. while stirring and add water (95.0 L; 95.0 kg). Add a solution of aqueous ammonia (57.5 kg) to adjust the solution pH to 8.0-9.0, and then add tert-butyl methyl ether (81.1 L; 60.0 kg). Separate the lower aqueous layer, concentrate the organic layer to approximately 3 volumes, and cool the contents of the reaction to −5-0° C. Filter the resultant solids and dry under vacuum until constant weight and collect (13.4 kg; 87.3%, based on HPLC) of the titled compound as a pale yellow solid in 81.8% purity. 1H NMR (DMSO-d6, 500 MHz): δ 8.68 (d, 1H, J=2 Hz), 8.30 (s, 1H), 7.92 (dd, 1H, J=2.5, 8.5 Hz), 7.79 (d, 1H, J=5.8 Hz), 1.82 (s, 3H), 1.56 (s, 6H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.C(N(CC)CC)C.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>C(O)C>[CH3:21][P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([N:34]3[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH3:22])=[O:20]
Reactant: CN1CCNCC1
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1CCN(c2nc(Nc3ccc(P(C)(C)=O)cc3)ncc2C(F)(F)F)CC1
Yield: 79 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (25 mg, 0.072 mmol) in 1.5 mL of ethanol was added 10 L of triethylamine and 1-Methyl piperazine (7.2 mg, 0.072 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (24 mg, 79% yield.) MS/ES+: m/z=414.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:18])=[N:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].[NH2:19][C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1.I([O-])(=O)(=O)=O.[Na+].CO>O>[OH:9][CH:8]1[C@H:7]([N:6]2[CH:16]=[C:2]([F:1])[C:3]([NH2:18])=[N:4][C:5]2=[O:17])[O:15][C@H:12]([CH2:13][OH:14])[CH:10]([OH:11])[N:19]1[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: Nc1nc(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1F
Reactant: Nc1ncccn1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: O
Product: Nc1nc(=O)n([C@@H]2O[C@H](CO)C(O)N(c3ncccn3)C2O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a solution of 5-fluorocytidine (2.42 g) and 2-aminopyrimidine (0.95 g) in water (50 ml) was added sodium metaperiodate (2.13 g) under cooling with an ice-water bath. The solution was stirred at ambient temperature for 8 hours. To the reaction mixture was added methanol (50 ml). The precipitate was filtered off and the filtrate was evaporated in vacuo. The residue was triturated with acetone and air-dried to give 1-[(2R, 6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-pyrimidinyl)morpholin-2-yl]-5-fluorocytosine (2.3 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:14](=[CH2:15])[C:13](=[O:16])[C@@H:12]2[C@H:10]1[C@H:11]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:33]=[C:34]([SH:39])[CH:35]=[CH:36][C:37]=1[F:38]>C(OCC)C.CCCCCC.C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][C@@:9]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:14]([CH2:15][S:39][C:34]2[CH:35]=[CH:36][C:37]([F:38])=[C:32]([F:31])[CH:33]=2)[C:13](=[O:16])[C@@H:12]2[C@H:10]1[C@H:11]2[C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(S)cc1F
Reactant: C=C1C(=O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]2[C@]1(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2C(=O)[C@H]1CSc1ccc(F)c(F)c1
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 97.5 %

Procedure:
Di-tert-butyl (1S,2R,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-methylidene-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylate (1.03 g, 2.43 mmol) in diethyl ether (100 mL) is bubbled with nitrogen gas for 10 minutes. Add 3,4-difluorobenzenethiol (0.36 g, 2.43 mmol) and triethylamine (0.01 mL, 0.05 μmol). The mixture is warmed to 40° C. and stirred for 15 minutes. The mixture is then allowed to cool to ambient temperature, transferred to a separatory funnel, diluted with hexane (40 mL), washed with of 2N aqueous KOH (1×30 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure giving di-tert-butyl (1S,2R,3S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-{[(3,4-difluorophenyl)sulfanyl]methyl}-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylate (1.35 g, 2.37 mmol): MS (m/z): 567.8 (M−H). This material is taken up in 120 mL of diethyl ether and added slowly over 2 hours to a 200 mL ether solution at −10° C. which contains R-(+)-2-methyl-CBS-oxazaborolidine (981.72 mg, 3.54 mmol) and borane-methyl sulfide complex (2M in tetrahydrofuran, 5.02 mL, 10.04 mmol). The mixture is stirred for an additional hour after final addition of di-tert-butyl (1S,2R,3S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-{[(3,4-difluorophenyl)sulfanyl]methyl}-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylate. Silica gel (30 g) is added over 30 minutes and the reaction mixture is gradually warmed to ambient temperature. The suspension is filtered, and washed with 300 mL of diethyl ether. The solvent is concentrated under reduced pressure giving a residue. The residue is purified by flash chromatography, eluting with (0 to 15% ethyl acetate/hexanes) to give the title compound (0.844 g, 1.48 mmol, 60.7% yield): MS (m/z): 569.8 (M−H).
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=1.[CH3:12][NH:13][CH3:14]>C(OCC)C>[CH3:12][N:13]([CH2:2][C:3]1[S:7][CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=1)[CH3:14]
Reactant: COC(=O)c1csc(CCl)c1
Reactant: CNC
Solvent: CCOCC
Product: COC(=O)c1csc(CN(C)C)c1

Procedure:
A solution of methyl 5-(chloromethyl)-3-thiophene-carboxylate (1.9 g) in dry diethylether (100 ml) was treated with anhydrous dimethylamine (5 ml). After 6 hours the solvent was removed in vacuo and the residue was dissolved in 5 M hydrochloric acid (20 ml). The aqueous solution was washed with diethylether, basified with 5 M sodium hydroxide (30 ml) and extracted with ether. The ethereal extracts were evaporated to give an oily residue which was distilled to yield the title compound as a colourless oil (1.6 g) b.p. 120°-130°/0.5 mm.
Reaction SMILES: N(OC(C)(C)C)=O.[C:8](#[N:11])[CH:9]=[CH2:10].[Br:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[C:14]=1N.[ClH:21]>C(#N)C>[Br:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[C:14]=1[CH2:10][CH:9]([Cl:21])[C:8]#[N:11]
Reactant: Cl
Reactant: Nc1c(Br)cccc1Br
Reactant: C=CC#N
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: N#CC(Cl)Cc1c(Br)cccc1Br
Reaction time: 1 h

Procedure:
To 62.4 g (464 mmol/1.2 eq.) of cupric chloride, 76 mL (580 mmol/1.5 eq.) of tert-butyl nitrite and 483 mL (7.34 moles/19 eq.) of acrylonitrile in 475 mL of acetonitrile, at ambient temperature, there is poured, dropwise, over 1 hour, 100 g (386 mmol) of 2,6-dibromoaniline dissolved in 380 mL of acetonitrile. Stirring is carried out for a further 1 hour at ambient temperature, and then the reaction mixture is poured into 1 liter of 20% aqueous hydrochloric acid solution. The aqueous phase is extracted with toluene and the combined toluene phases are washed with aqueous saturated sodium chloride solution. After concentration, the desired product is obtained and used as such in the following Step.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2.[CH2:18]([NH2:24])[C:19]1[O:23][CH:22]=[CH:21][CH:20]=1.C(O)C>CO>[CH:16]1[C:17]2[N:5]([CH2:4][CH:2]([OH:1])[CH2:3][NH:24][CH2:18][C:19]3[O:23][CH:22]=[CH:21][CH:20]=3)[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: c1ccc2c(c1)c1ccccc1n2CC1CO1
Reactant: NCc1ccco1
Solvent: CO
Solvent: CCO
Product: OC(CNCc1ccco1)Cn1c2ccccc2c2ccccc21
Temperature: 110 °C
Yield: 56.3 %

Procedure:
A suspension of 9-(oxiran-2-ylmethyl)-9H-carbazole (2.97 g, 13.3 mmol) in a solution of furfurylamine (5.3 mL, 60 mmol) and ethanol (11 mL) was heated to 110° C. for 15 minutes in a Biotage Initiator microwave reactor. The resulting solution was diluted with methanol and cooled in an ice bath to precipitate a white solid. The solid was recrystallized by dissolving in a minimal volume of hot methanol and slowly cooled to give the desired product as a fine crystalline white solid (2.4 g, 57%). 1H NMR (CDCl3, 300 MHz) δ 8.10-8.08 (d, 2H, J=8.1 Hz), 7.46-7.44 (m, 3H), 7.32-7.25 (m, 4H), 6.29-6.27 (dd, 1H, J=1.8, 3.3 Hz), 6.11-6.10 (d, 1H, J=3 Hz), 4.39-4.38 (d, 1H, J=2.1 Hz), 4.37 (d, 1H, J=0.9 Hz), 4.21-4.17 (m, 1H), 3.75 (s, 2H), 2.85-2.79 (dd, 1H, J=3.8, 12.3 Hz), 2.69-2.62 (dd, 1H, J=8.4, 12.3 Hz), 2.00 (br s, 2H). ESI m/z: 321.1 (M+H). HPLC analysis: (C18, 10-90% acetonitrile in water+0.1% trifluoroacetic acid over 10 min: retention time, % area at 254 nm): 6.1 min, 99.0%.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:9]=[N:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:12][CH:13]=2)[CH:5]=[CH:4][CH:3]=1.[Se](=O)=[O:21].ClC1C=CC=CC=1Cl.[OH2:31]>>[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:8]2[N:9]=[N:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:12][CH:13]=2)[N:7]=1)([OH:21])=[O:31]
Reactant: O=[Se]=O
Reactant: Cc1cccc(-c2ccc(-c3ccccn3)nn2)n1
Reactant: O
Solvent: Clc1ccccc1Cl
Product: O=C(O)c1cccc(-c2ccc(-c3ccccn3)nn2)n1
Temperature: 150 °C
Yield: 74 %

Procedure:
400 mg (2.42 mmol) of pyridazine 44, 177 mg (1.60 mmol) of selenium dioxide and 7 ml of o-dichlorobenzene are introduced into a 100 ml round-bottomed flask equipped with a condenser. The mixture is heated at 150° C. for 4 hours, and then cooled to ambient temperature. An excess of water is added to the precipitate formed, which is filtered off and washed with water. The solid obtained is dried, so as to give the acid 45 with a yield of 74%.
Reaction SMILES: F[C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.C(O)(=O)C.[CH:15]([NH2:17])=[NH:16].CCN(C(C)C)C(C)C.[NH4+].[Cl-]>CC(N(C)C)=O>[F:8][C:6]1[CH:5]=[N:4][C:3]2[C:9]([NH2:10])=[N:17][CH:15]=[N:16][C:2]=2[CH:7]=1
Reactant: N#Cc1ncc(F)cc1F
Reactant: N=CN
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncnc2cc(F)cnc12
Temperature: 100 °C
Reaction time: 16 h

Procedure:
3,5-Difluoro-pyridine-2-carbonitrile (2.54 mmol, 356 mg) is dissolved in DMA (5 mL) and then formamidine acetate is added (2.54 mmol, 264.6 mg) followed by DIEA (7.62 mmol, 983 mg). The reaction mixture is stirred for 16 h at 100° C., then poured into saturated NH4Cl aq. and extracted 3 times with CH2Cl2. The organics are dried with Na2SO4, concentrated, and purified on Biotage with 0-20% MeOH in CH2Cl2. This gives the desired product 7-Fluoro-pyrido[3,2-d]pyrimidin-4-ylamine (27 mg, LC/MS m/z=165 [M+H]+) as a white powder.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][C@@H:5]([NH:7][C:8](=[O:23])[CH2:9][NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH2:4][N:3]1C(OC(C)(C)C)=O.Cl>CO.O1CCOCC1>[CH3:1][C@@H:2]1[NH:3][CH2:4][C@H:5]([NH:7][C:8](=[O:23])[CH2:9][NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)[CH2:6]1
Reactant: C[C@H]1C[C@@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@H]1C[C@@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)CN1
Temperature: 25 °C
Reaction time: 4 h
Yield: 121.5 %

Procedure:
The intermediate of step F (0.6 g, 1.4 mmol) was dissolved in MeOH (3 mL) and a solution of 4 N HCl in dioxane (3 mL). After being stirred at room temperature for 4 hours, the solution was concentrated to give 0.56 g of the title compound. MS calculated (M+H)+330. Found 330.2.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[CH:21]([CH3:23])[CH3:22])[C:12]2=[O:31])[CH:5]=1.[OH-].[Li+]>C1COCC1.O>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C:20](=[C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]([CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:32])=[O:2])[C:12]2=[O:31])[CH:21]([CH3:23])[CH3:22])=[CH:29][CH:28]=1
Reactant: COC(=O)c1cccc(CN2C(=O)C(=C(c3ccc(Cl)cc3)C(C)C)c3ccccc32)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(=C1C(=O)N(Cc2cccc(C(=O)O)c2)c2ccccc21)c1ccc(Cl)cc1
Reaction time: 12 h
Yield: 51.5 %

Procedure:
A solution of 3-{3-[1-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester (0.40 g, 0.90 mmol) was dissolved in THF 15 ml. Then a solution of lithium hydroxide (0.38 g, 9.0 mmol) in water (3.0 ml) was added. After stirring for 12 hours, the solvent was removed under reduced pressure. The residue was dissolved in 2 ml DMF for prepared HPLC to give 3-{3-[1-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid as a yellow powder (200 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00 (d, J=6.82 Hz, 6H) 4.90-4.99 (m, 1H) 5.05 (s, 2H) 5.59 (d, J=7.83 Hz, 1H) 6.64 (t, J=7.71 Hz, 1H) 6.91 (d, J=7.83 Hz, 1H) 7.10 (t, J=7.71 Hz, 1H) 7.27 (d, J=8.34 Hz, 2H) 7.49 (t, J=7.58 Hz, 1H) 7.63 (d, J=8.34 Hz, 2H) 7.59 (d, J=7.58 Hz, 1H) 7.85 (d, J=7.58 Hz, 1H) 7.92 (s, 1H) 13.05 (s, 1H). MS calcd. for C26H22ClNO3 431.5, obsd. (ESI+) [(M+H)+] 432.0.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH2:4][NH:5][C:6]([CH2:8][C@@H:9]1[CH2:27][CH2:26][C@@:12]2([O:16][C@:15]3([CH:21]4[CH2:22][CH:23]5[CH2:25][CH:19]([CH2:20]4)[CH2:18][CH:17]3[CH2:24]5)[O:14][O:13]2)[CH2:11][CH2:10]1)=[O:7])[NH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[Si](N=[N+]=[N-])(C)C.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.O>[CH3:1][C:2]([CH3:28])([CH2:4][NH:5][C:6]([CH2:8][C@@H:9]1[CH2:27][CH2:26][C@:12]2([O:16][C:15]3([CH:21]4[CH2:20][CH:19]5[CH2:25][CH:23]([CH2:22]4)[CH2:24][CH:17]3[CH2:18]5)[O:14][O:13]2)[CH2:11][CH2:10]1)=[O:7])[NH2:3]
Reactant: CC(C)(N)CNC(=O)C[C@H]1CC[C@]2(CC1)OO[C@]1(O2)C2CC3CC(C2)CC1C3
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: C[Si](C)(C)N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(N)CNC(=O)C[C@H]1CC[C@@]2(CC1)OOC1(O2)C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of OZ277 free base (0.46 g, 1.17 mmol), triphenylphosphine (0.77 g, 2.94 mmol), and trimethylsilyl azide (0.34 g, 2.95 mmol) in THF (20 ml) at 0° C. under N2 was added dropwise diisopropyl azodicarboxylate (0.71 g, 3.51 mmol). The mixture was slowly warmed to rt and stirred for 72 h. The reaction mixture was diluted with water (50 ml) and extracted with EtOAc (2×50 ml). The combined extracts were washed with saturated aqueous NaHCO3 (2×50 ml) and brine (50 ml), dried over MgSO4, filtered, and concentrated. To a solution of the residue CHCl3 (20 ml) was added a solution of p-toluenesulfonic acid monohydrate (0.22 g) in ethanol (10 ml). After evaporation of the solvents, the crude product was purified by crystallization from MeOH/CH2Cl2 (1:4) to afford trioxolane OZ373 (0.12 g, 17%) as a colorless solid. mp 220° C. dec; 1H NMR (500 MHz, CD3OD) δ1.28-1.38 (m, 2H), 1.38 (s, 6H), 1.65-2.09 (m, 21H), 2.37 (s, 3H), 2.86 (d, J=6.8 Hz, 2H), 4.58 (s, 2H), 7.23 (d, J=7.8 Hz, 2H), 7.70 (d, J=7.8 Hz, 2H); 13C NMR (125.7 MHz, CD3OD) δ21.30, 23.79, 27.97, 28.37, 30.04, 30.87, 34.87, 35.77, 35.78, 36.04, 37.80, 37.88, 54.02, 55.39, 109.53, 112.40, 126.97, 129.81, 141.66, 157.09.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[CH:16][C:15]([C:24]([NH2:26])=O)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].N1C(Cl)=NC(Cl)=NC=1Cl.CN(C)C=O>O>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[CH:16][C:15]([C:24]#[N:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccs2)c2cc(C(N)=O)ccc2c1=O
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccs2)c2cc(C#N)ccc2c1=O
Yield: 91.4 %

Procedure:
A solution of tert-butyl[6-(aminocarbonyl)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.23 g, 0.5 mmol) and cyanuric chloride (0.28 g, 1.5 mmol) in N,N-dimethylformamide (10 mmol) was stirred at 0° C. for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[6-cyano-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.20 g, 95.2%) as crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH:13]=[C:14]([C:17]4[N:24]5[C:20]([O:21][CH:22]=[CH:23]5)=[N:19][C:18]=4[C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[CH:15]=[CH:16][C:11]3=[N:10][N:9]=2)=[C:4]([F:32])[CH:3]=1.[NH2:33][CH2:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37].CN([CH:43]=[O:44])C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:32][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[C:8]1[N:12]2[CH:13]=[C:14]([C:17]3[N:24]4[C:20]([O:21][CH:22]=[CH:23]4)=[N:19][C:18]=3[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1)[C:43]([NH:33][CH2:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])=[O:44]
Reactant: CC(C)(CN)CO
Reactant: CN(C)C=O
Reactant: Fc1ccc(-c2nc3occn3c2-c2ccc3nnc(-c4ccc(Br)cc4F)n3c2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC(C)(CO)CNC(=O)c1ccc(-c2nnc3ccc(-c4c(-c5ccc(F)cc5)nc5occn45)cn23)c(F)c1
Temperature: 100 °C
Yield: 85 %

Procedure:
A mixture of 3-(4-bromo-2-fluorophenyl)-6-[6-(4-fluorophenyl)-imidazo[2,1-b]oxazol-5-yl]-[1,2,4]triazolo[4,3-a]pyridine (0.20 g, 0.41 mmol; Example #K.1.3), 3-amino-2,2-dimethyl-propan-1-ol (0.21 g, 2.0 mmol; Lancaster), and TEA (0.175 mL, 1.21 mmol) in DMF (5 mL) was vacuum purged with carbon monoxide three times followed by the addition of dichlorobis(triphenylphosphine)palladium (II) (0.03 g, 0.04 mmol) and subsequent vacuum purging with carbon monoxide five times. The reaction was heated at about 100° C. under an atmosphere of carbon monoxide for about 2 h after which the reaction was cooled and concentrated under reduced pressure. The crude material was dissolved in DCM and purified by flash chromatography using DCM/MeOH (90:10) as eluent. After concentration of the clean fractions, the resulting oil was triturated with Et2O. The resulting solid was filtered and dried to provide the title compound as a light yellow solid (0.19 g, 85%): LC/MS (Table 1, Method a) Rt=2.11 min; MS m/z: 543.2 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH2:3][CH:4]([C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[N:29]=[CH:28]2)=[CH:23][CH:22]=1)[O:5][C:6]1[CH:20]=[CH:19][C:9]([C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[O:11])=[CH:8][CH:7]=1.[OH-].[Li+]>CO>[CH3:1][CH:2]([CH3:36])[CH2:3][CH:4]([C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[N:29]=[CH:28]2)=[CH:23][CH:22]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:11])=[CH:19][CH:20]=1
Reactant: COC(=O)CCNC(=O)c1ccc(OC(CC(C)C)c2ccc(-n3cnc(C(F)(F)F)c3)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CC(Oc1ccc(C(=O)NCCC(=O)O)cc1)c1ccc(-n2cnc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
Methyl 3-(4-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenyl)butoxy)benzamido)propanoate (70 mg, 0.14 mmol) was dissolved in methanol (2 mL) and 1M lithium hydroxide (1 mL) was added. The reaction was stirred at room temperature for 1 hour. The methanol was removed under reduced pressure and the residue was diluted with water (2 mL). Upon stirring a precipitate forms. The solution was further diluted with water (15 mL) and 1M NaOH (3 mL). The solution was extracted with ether (20 mL). The organics were washed with water (10 mL) and the aqueous layers were combined. The aqueous solution was acidified with 1M HCl to give a cloudy solution. The solution was extracted with ethyl acetate (2×15 mL). The combined organics were dried over sodium sulfate, filtered and concentrated to give (+/−)-3-(4-(3-methyl-1-(4-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenyl)butoxy)benzamido)propanoic acid (53.1 mg, 78%) as an off-white solid. 1H NMR (400 MHz, CDCl3, δ): 7.89 (s, 1H), 7.66-7.60 (m, 2H), 7.58 (s, 1H), 7.49 (d, J=8.5 Hz, 2H), 7.36 (d, J=8.5 Hz, 2H), 6.97-6.92 (m, 2H), 6.77 (t, J=6 Hz, 1H), 5.29 (dd, J=9, 4.4 Hz, 1H), 3.73-3.63 (m, 2H), 2.66-2.64 (m, 2H), 2.06-2.00 (m, 1H), 1.95-1.83 (m, 1H), 1.62 (m, 1H), 1.03 (d, J=6.6 Hz, 3H), 0.99 (d, J=6.6 Hz, 3H). MS (M+1): 490.2.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:28]1([NH:34][CH:35]([CH:39](O)[CH3:40])[C:36]([O-:38])=[O:37])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[C:28]1([NH:34][CH:35]([CH:39]([Cl:1])[CH3:40])[C:36]([OH:38])=[O:37])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(O)C(Nc1ccccc1)C(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Cl)C(Nc1ccccc1)C(=O)O
Reaction time: 8 h

Procedure:
To a solution of N-chlorosuccinimide (1.24 g) and dry THF (60 ml), stirring at RT, is slowly added triphenylphosphine (2.43 g) in 50 ml of THF. Then the m-phenoxybenzyl ester of 2-phenylamino-3-hydroxybutanoate (3.5 g) in 30 ml of THF is added slowly. The reaction mixture is stirred overnight. The reaction is then concentrated under reduced pressure. The residue (oil) is taken up in ether, washed with water, dried over magnesium sulfate and evaporated to yield the m-phenoxybenzyl ester of 2-phenylamino-3-chloro-butanoic acid, MS m/e 395 (M+).