Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH:7]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH:8]([OH:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[C:21](Cl)([Cl:23])=[O:22].N1C=CC=CC=1>C1COCC1>[Cl:23][C:21]([O:13][CH:8]([C:9]([CH3:11])([CH3:12])[CH3:10])[CH:7]([O:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:20][CH:19]=1)[N:14]1[CH2:18][N:17]=[CH:16][NH:15]1)=[O:22]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)C(O)C(Oc1ccc(Cl)cc1)n1cncn1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)C(OC(=O)Cl)C(Oc1ccc(Cl)cc1)N1CN=CN1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a solution of 29.6 g (0.1 mole) of 1-(4-chlorophenoxy)-3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)-2-butanol in 250 ml of THF was added 20 ml of liquid phosgene, followed by 9 ml of pyridine. The mixture was stirred at ambient temperature for about 21 hours. White solid (water-soluble) was filtered off and the THF filtrate concentrated in vacuum to a residual oil, the intermediate chloroformate. Further purification of the chloroformate was accomplished by dissolving it in about 300 ml of 1-chlorobutane, washing the butyl chloride solution with 0.5 N HCl (twice), water and saturated brine, drying (MgSO4), filtration, and evaporation of the filtrate in vacuum to leave, as a residual oil, 1-(4-chlorophenoxy)-3,3-dimethyl-1-(1H-1,2,4-triazol-2-yl)-2-butyl chloroformate.
Reaction SMILES: [C:1]1([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:25]=[CH:24][CH:23]=[CH:22][C:16]=2[O:17][CH2:18][CH:19]2[CH2:21][O:20]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:26][NH:27][CH3:28]>O1CCCC1>[CH3:26][N:27]([CH3:28])[CH2:21][CH:19]([OH:20])[CH2:18][O:17][C:16]1[CH:22]=[CH:23][CH:24]=[CH:25][C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CNC
Reactant: c1ccc(OCC2CO2)c(CCCCc2cccc3ccccc23)c1
Solvent: C1CCOC1
Product: CN(C)CC(O)COc1ccccc1CCCCc1cccc2ccccc12
Yield: 77 %

Procedure:
Following a procedure similar to that described in Example 1(b), 300 mg of 2-{2-[4-(1-naphthyl)butyl]phenoxymethyl}oxirane [prepared as described in step (a) above] dissolved in 6 ml of tetrahydrofuran were treated with 1.2 ml of 50% by volume aqueous dimethylamine. The crude product was purified as described in Example 1(b), to give 265 mg (yield 77%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:11](=[CH2:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:5][C:4]=1[O:17][CH3:18])[CH3:2].[CH3:19][NH:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH2:26]([O:25][C:23]([CH2:22][CH2:21][N:20]([CH3:19])[CH2:16][CH:11]([C:6]1[CH:7]=[C:8]([O:9][CH3:10])[C:3]([CH2:1][CH3:2])=[C:4]([O:17][CH3:18])[CH:5]=1)[C:12]([O:14][CH3:15])=[O:13])=[O:24])[CH3:27]
Reactant: C=C(C(=O)OC)c1cc(OC)c(CC)c(OC)c1
Reactant: CCOC(=O)CCNC
Product: CCOC(=O)CCN(C)CC(C(=O)OC)c1cc(OC)c(CC)c(OC)c1
Yield: 59.5 %

Procedure:
A solution of 78.4 g (313 mmol) of methyl 2-(4-ethyl-3,5-dimethoxy-phenyl)-acrylate and 47.7 g (364 mmol) of ethyl 3-methylamino-propionate was stirred at room temperature for 48 hours. Chromatography of the reaction mixture (silica gel, ethyl acetate/hexane 1:1) and crystallization from hexane gave 71.1 g (59%) of methyl 3-[(2-ethoxycarbonyl-ethyl)-methyl-amino]-2-(4-ethyl-3,5-dimethoxy-phenyl)-propionate as colorless crystals of m.p. 74-75°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=O)[CH:3]=1.Cl.[NH2:20][OH:21].[OH-].[Na+]>CO.O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:20][OH:21])[CH:3]=1
Reactant: NO
Reactant: COc1ccc(C(=O)Cc2cc(Br)ccn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C(Cc2cc(Br)ccn2)=NO)cc1
Reaction time: 0.25 h
Yield: 84.3 %

Procedure:
To a solution of Example 19A (13.41 g, 43.8 mmol) in methanol (231 mL) was added hydroxylamine hydrochloride (15.22 g, 219 mmol) to give a thick slurry. The mixture was treated with a solution of sodium hydroxide (8.76 g, 219 mmol) in water (58 mL), heated at reflux for two hours, cooled and concentrated to a paste. The paste was treated with 100-150 mL of water and stirred for 15 minutes to give a solid that was collected by filtration, washed with water and dried to constant mass to give the title compound as a powder (11.86 g, 84%). MS (ESI+) m/z 321/323 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH2:14][C@H:15]([OH:26])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([NH:23][CH:24]=[O:25])[CH:17]=2)=[CH:7][CH:6]=1.[Cl:33]Cl.O>C(O)(C)C>[ClH:33].[OH:1][C@H:2]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH2:14][C@H:15]([OH:26])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([NH:23][CH:24]=[O:25])[CH:17]=2)=[CH:7][CH:6]=1.[OH:1][C@H:2]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH2:14][C@H:15]([OH:26])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([NH:23][CH:24]=[O:25])[CH:17]=2)=[CH:7][CH:6]=1
Reactant: ClCl
Agent: O=CNc1cc([C@@H](O)CNCCc2ccc(NC[C@H](O)c3ccccc3)cc2)ccc1O
Solvent: CC(C)O
Solvent: O
Product: Cl
Temperature: 57.5 °C

Procedure:
A 250 mL three-necked flask was charged with a hydrochloride salt of compound 1 having 1.52 equivalents of chlorine per mole of compound 1 (6.1 g, 12 mmol) and 1:1 isopropanol:water (98 mL). The mixture was heated to 50-65 ° C. to dissolve the solid and the solution was stirred at 50-60 ° C. Isopropanol (98 mL) was slowly added over 30 min at 50-60 ° C. and the solution was cooled to room temperature over 3 h. Isopropanol (98 mL) was slowly added over 30 min and the solution was stirred at room temperature for 7h. The crystals were isolated by filtration, washed with isopropanol (30 mL) and dried under vacuum for 16 h to yield the monohydrochloride salt of compound 1 (3.8 g, 8.0 mmol, 67% yield, 99.7% purity by HPLC)
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=[C:16]([NH:29][NH2:30])[CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:31]([C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH:37]=O)([OH:33])=[O:32]>C(O)C>[C:31]([C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH:37]=[N:30][NH:29][C:16]1[CH:15]=[C:14]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:19]2[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:22]=[C:18]2[N:17]=1)([OH:33])=[O:32]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: O=C(O)c1cccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccccc4)cc3n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
There was dissolved, in ethanol (2 mL), trifluoroacetic acid salt of (7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (20.3 mg, 0.0377 mM), then 3-carboxy-benzaldehyde (5.7 mg, 0.038 mM) was added to the solution and the mixture was stirred at room temperature for one hour. This reaction liquid was filtered and the resulting solid was washed with methanol to thus give the title compound (14.0 mg, yield: 84%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1.[C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)#[N:21]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[O:11]=[C:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:26]3[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=3)[C:20]#[N:21])[CH:10]=2)[CH2:6][C:7]21[CH2:12][C:13]1[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:19]2
Reactant: O=C1c2cc(Br)ccc2CC12Cc1ccccc1C2
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2ccc3c(c2)C(=O)C2(Cc4ccccc4C2)C3)c1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 10.1 %

Procedure:
6-Bromo-1′,3′-dihydro-2,2′-spirobi[inden]-1(3H)-one (314 mg, 1 mmol), 3-cyanophenylboronic acid (294 g, 2 mmol) in [1,4]-dioxane (12 mL), Cs2CO3 (2 N, 3.2 mL), then Pd(PPh3)2Cl2 (5 mg, 0.01 mmol) was added under Ar2, the mixture was stirred at 100° C. for 5 minutes under microwave. The reaction mixture was concentrated in vacuo to give the residue, which was purified by TLC to give 3-(1-oxo-1,1′,3,3′-tetrahydro-2,2′-spirobi[indene]-6-yl)benzonitrile (34 mg, 10%). 1H-NMR (CDCl3): 3.00 (d, 2H), 3.33 (s, 2H), 3.62 (d, 2H), 7.31 (m, 3H), 7.67 (m, 2H), 7.78 (m, 1H), 7.96 (m, 2H), 8.02 (m, 1H), 8.11 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[OH:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>O>[N:10]1[CH:9]=[CH:8][N:6]2[C:5]=1[CH:4]=[CH:3][C:2]([O:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16])=[N:7]2
Reactant: COC(=O)c1cccc(O)c1
Reactant: Clc1ccc2nccn2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1cccc(Oc2ccc3nccn3n2)c1
Temperature: 120 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
A mixture of 6-chloroimidazo[1,2-b]pyridazine (1536 mg, 10.0 mmol), methyl 3-hydroxybenzoate (1978 mg, 13.0 mmol), potassium carbonate (4146 mg, 30.0 mmol) and N-methylpyrrolidone (10 mL) was stirred at 120° C. for 18 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate=90/10→20/80). The objective fraction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=60/40→0/100) and precipitated from diisopropyl ether to give the title compound (1722 mg, 6.4 mmol, yield 64%) as a white solid.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][N:15]([CH3:19])[C:16](=[O:18])[CH3:17].[CH:20]1([C:23]2[C:32]([CH:33]=[O:34])=[C:31]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)[CH2:22][CH2:21]1>C1COCC1>[CH3:13][O:14][N:15]([CH3:19])[C:16](=[O:18])[CH2:17][CH:33]([C:32]1[C:23]([CH:20]2[CH2:21][CH2:22]2)=[N:24][C:25]2[C:30]([C:31]=1[C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)[OH:34]
Reactant: CON(C)C(C)=O
Reactant: O=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CON(C)C(=O)CC(O)c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
Butyllithium (1.64M hexane solution, 7.54 ml, 12.4 mmol) was added to a THF (40 ml) solution of diisopropylamine (1.25 g, 12.4 mmol) at -78° C. and the mixture was stirred for 15 minutes. Thereto was added a THF (20 ml) solution of N-methoxy-N-methylacetamide (1.27 g, 12.3 mmol) at -78° C., and the resulting mixture was stirred at -78° C. for 15 minutes. To this mixture was added a THF (40 ml) solution of 2-cyclopropyl-4-(4-fluorophenyl)-3-formylquinoline (3.00 g, 10.3 mmol). The reaction mixture was stirred at -78° C. to room temperature over a period of 3 hours before quenching with water and extraction with diethyl ether. The ethereal organic layer was washed with saturated sodium chloride aq solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (hexane:ethyl acetate=2:1) to give N-methoxy-N-methyl-3-{2-cyclopropyl- 4-(4-fluorophenyl)quinoline-3-yl}-3-hydroxypropanamide (3.70 g, 91% yield). Rf =0.30 (hexane:ethyl acetate=2:1) IR (CHCl3): 3450, 3000, 1640, 1515, 1490, 1420, 1230, 1070, 780 cm-1.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH:14]=[C:13]([C:27]([F:30])([F:29])[F:28])[N:12]=2)[CH:10]=1)CCC.[C:39]([NH:43][S:44]([C:47]1[S:51][C:50](Cl)=[N:49][C:48]=1[CH3:53])(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40].CCCCCCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:39]([NH:43][S:44]([C:47]1[S:51][C:50]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[C:15]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:22]=4)[CH:14]=[C:13]([C:27]([F:30])([F:29])[F:28])[N:12]=3)[CH:10]=2)=[N:49][C:48]=1[CH3:53])(=[O:45])=[O:46])([CH3:42])([CH3:41])[CH3:40]
Reactant: Cc1nc(Cl)sc1S(=O)(=O)NC(C)(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(-c3ccc(C(F)(F)F)cc3)cc(C(F)(F)F)n2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: Cc1nc(-c2cn(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)sc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Yield: 25.1 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-pyridine (Example G.12) (0.570 g, 0.88 mmol), 2-chloro-4-methyl-thiazole-5-sulfonic acid tert-butylamide (Example H.5) (0.266 g, 0.99 mmol), tetrakis(triphenylphosphine)palladium (0.061 g, 0.046 mmol) in toluene (6 mL) was heated under reflux conditions for 16 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), added heptane, filtered the precipitate off, washed with toluene/heptane, dried in HV to give the title compound as a white solid (130 mg, 25%). MS (ISP) 590.4 [(M+H)+]; mp 260° C.
Reaction SMILES: [Br:1][C@H:2]1[C@H:7]([OH:8])[C:6]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:5]=2[O:4][C:3]1([CH3:16])[CH3:15].C(Cl)CCl.[N+:21]([C:24]1[CH:25]=[C:26]([CH:36]=[C:37]([N+:39]([O-:41])=[O:40])[CH:38]=1)[C:27]([S:29][CH2:30][C@H:31]([CH3:35])[C:32](Cl)=[O:33])=[O:28])([O-:23])=[O:22]>N1C=CC=CC=1>[Br:1][C@H:2]1[C@H:7]([O:8][C:32](=[O:33])[C@H:31]([CH3:35])[CH2:30][S:29][C:27](=[O:28])[C:26]2[CH:36]=[C:37]([N+:39]([O-:41])=[O:40])[CH:38]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=2)[C:6]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:5]=2[O:4][C:3]1([CH3:16])[CH3:15]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](O)[C@@H]1Br
Reactant: C[C@@H](CSC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: C[C@H](CSC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)C(=O)O[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.1 %

Procedure:
To a mixture of 14.5 g of (±)-trans-3-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-4-hydroxy-2H-1-benzopyran, 60 ml of ethylene chloride and 1.6 ml of pyridine was added 5.5 g of (S)-(-)-3-(3,5-dinitrobenzoylthio)-2-methylpropionyl chloride under ice-cooling and was stirred for 1.5 hours under room temperature. The reaction mixture was washed with diluted hydrochloric acid once and 10% aqueous sodium chloride solution twice. The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure to give 8.9 g of (±)-trans-3-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-4-[(S)-(-)-3-(3,5-dinitrobenzoylthio)-2-methylpropionyloxy]-2H-1-benzopyran as light yellow semicrystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:35])[NH:20][CH2:21][CH2:22][C:23]3[C:24]([O:33][CH3:34])=[N:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:36]([OH:38])=[O:37].C[O-].[Na+:41].CO>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:35])[NH:20][CH2:21][CH2:22][C:23]3[C:24]([O:33][CH3:34])=[N:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:36]([O-:38])=[O:37].[Na+:41]
Reactant: COc1nc(C(F)(F)F)ccc1CCNC(=O)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1nc(C(F)(F)F)ccc1CCNC(=O)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Reaction time: 0.25 h
Yield: 101 %

Procedure:
6-Chloro-7-(4-(2-(2-methoxy-6-(trifluoromethyl)pyridin-3-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylic acid (255 mg, 0.463 mmol) in 2:1 THF-MeOH (2 ml) was treated with 0.5 N sodium methoxide in methanol (926 μl, 0.463 mmol) at ambient temperature. After 15 minutes, the reaction was concentrated in vacuo. The material was suspended in ethyl acetate and concentrated to a solid. The solid was suspended in ethyl acetate, hexanes were added, and the mixture was concentrated in vacuo to a solid. The material was suspended in dichloromethane, hexanes were added, and the suspension concentrated to provide the desired compound (268 mg, 0.468 mmol, 101% yield) as a solid. MS (apci) m/z=551.0 (M-Na+2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[CH3:10][CH2:11][C:12](=O)[CH2:13][CH3:14].C(O)(C(F)(F)F)=O>C(OC(C)=O)(C)C>[Cl:9][C:5]1[CH:6]=[C:7]([NH:8][CH:12]([CH2:13][CH3:14])[CH2:11][CH3:10])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1cc(Cl)cnc1N
Reactant: CCC(=O)CC
Solvent: CC(=O)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)Nc1cc(Cl)cnc1N
Reaction time: 0.17 h
Yield: 25 %

Procedure:
To a solution of 2,3-diamino-5-chloropyridine (7.0 g, 48.6 mmol, 1.0 equiv) and 3-pentanone (6.16 mL, 58.3 mmol, 1.2 equiv) in iPrOAc (100 mL) was added TFA (7.2 mL, 97.2 mmol, 2.0 equiv) by syringe. After stirring for 10 min, NaHB(OAc)3 (20 g, 97.2 mmol, 2.0 equiv) was added as a solid in several portions over ˜5 min. The reaction was allowed to stir overnight. The reaction mixture was then washed with satd. aq. NaHCO3 and brine, and the resulting organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel MPLC (10%-40% EtOAc/Hexanes) provided 5-chloro-N3-(pentan-3-yl)pyridine-2,3-diamine as a beige solid (2.6 g, 25%). m/z=214.1 [M+H]+
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:4][N:3]=1.[C:16]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>C1COCC1>[CH3:16][O:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([NH:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[S:4][N:3]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: N#Cc1c(O)nsc1Nc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: COc1nsc(Nc2ccccc2)c1C#N
Temperature: 25 °C
Yield: 41.9 %

Procedure:
To a solution of 3-hydroxy-5-phenylamino-isothiazol-4-carbonitrile (2.82 g, 13 mmol), triphenylphosphine (4.04 g, 15.6 mmol), methanol (0.53 ml) in THF (25 ml) was added diethyl azadicarboxylate (DEAD, 2.46 ml, 15.6 mmol) at 0° C. The mixture was stirred at ambient temperature and evaporated to give a residue. The crude product was purified on silica gel (hexane/EtOAc, 1:1) to give a yellow powder (1.26 g, 42%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:28])[N:6]2[C@H:21]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]1.[O:29]1[CH:34]=[CH:33][CH2:32][CH2:31][CH2:30]1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl.C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:28])[N:6]2[C@H:21]1[CH2:22][CH2:23][C@H:24]([O:27][CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][O:29]2)[CH2:25][CH2:26]1
Reactant: C1=COCCC1
Reactant: O=c1[nH]c2c(Cl)nc(-n3cnc4ccc(F)cc43)nc2n1[C@H]1CC[C@H](O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=c1[nH]c2c(Cl)nc(-n3cnc4ccc(F)cc43)nc2n1[C@H]1CC[C@H](OC2CCCCO2)CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A solution of 6-chloro-2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-9-(trans-4-hydroxycyclohexyl)-7H-purin-8(9H)-one (0.8 mmol) and dihydropyran (15 equiv.) in anhydrous chloroform/THF (30 mL/15 mL) containing p-TsOH (0.1 equiv.) was stirred at 50° C. for 1 day (LCMS indicative of complete reaction). The reaction mixture was concentrated in vacuo and the residue purified by column chromatography on neutral alumina to give the desired product. MS (EI) m/z 487.3 (MH)+.
Reaction SMILES: O=O.[C:3]([O:7][C:8](=[O:17])[C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11](Cl)[CH:10]=1)([CH3:6])([CH3:5])[CH3:4].[CH2:18]([NH2:22])[CH2:19][CH:20]=[CH2:21]>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:3]([O:7][C:8](=[O:17])[C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH:22][CH2:18][CH2:19][CH:20]=[CH2:21])[CH:10]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: C=CCCN
Reactant: Cc1cc(C(=O)OC(C)(C)C)cc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCCNc1cc(C(=O)OC(C)(C)C)cc(C)n1
Temperature: 60 °C

Procedure:
Under rigorous exclusion of oxygen a mixture of 200 mg (0.88 mmol) 2-chloro-6-methyl-isonicotinic acid tert-butyl ester, 10 mg palladium(II)acetate (0.044 mmol), 27 mg (0.44 mol) BINAP (R(+)-2,2-bis(diphenylphosphino)-1,1-binaphtalene) and 62 mg (0.88 mmol) but-3-enylamine in 10 ml toluene is heated at 60° C. for 4 h. The mixture is diluted with EtOAc, washed with 10% aqueous NaHCO3 and water, dried with sodium sulfate and evaporated. Chromatography of the product on silica gel (hexane/EtOAc 9:1) yields the title compound.
Reaction SMILES: C([O-])(=O)C.[Na+].[Cl:6][C:7]1[CH:12]=[C:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]=[CH:9][C:8]=1[C:18](=[O:29])[C:19](=[CH:25]OCC)[C:20]([CH:22]1[CH2:24][CH2:23]1)=[O:21].Cl.[NH2:31]O.O>C(O)C>[Cl:6][C:7]1[CH:12]=[C:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:10]=[CH:9][C:8]=1[C:18]([C:19]1[CH:25]=[N:31][O:21][C:20]=1[CH:22]1[CH2:24][CH2:23]1)=[O:29]
Reactant: NO
Reactant: CCOC=C(C(=O)c1ccc(OS(C)(=O)=O)cc1Cl)C(=O)C1CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)Oc1ccc(C(=O)c2cnoc2C2CC2)c(Cl)c1
Reaction time: 0.75 h
Yield: 89.6 %

Procedure:
Sodium acetate (1.52 g) was added to a stirred mixture of 1-[2-chloro-4-(methylsulphonyloxy)phenyl]-3-cyclopropyl-2-ethoxymethylenepropan-1,3-dione (5.6 g) and hydroxylamine hydrochloride (1.3 g) in ethanol. The mixture was stirred for 0.75 hours. Water was added and the mixture was extracted with dichloromethane. The organic layer was washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography eluted with a mixture of ethyl acetate and dichloromethane to give 4-[2-chloro-4-(methylsulphonyloxy)benzoyl]-5-cyclopropylisoxazole (compound 1, 4.60 g) as a brown oil, NMR (CDCl3) 1.25-1.35(m,2H), 1,4-1.5 (m,2H), 2.6-2.7(m, 1H), 3.2(s, 1H), 7.3(d, 1H), 7.4(s, 1H), 7.45 (d, 1H), 8.15 (s, 1H).