Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:26])[C:10]1[C:15]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[CH:14][N:13]=[CH:12][C:11]=1[F:25].C[Si](C)(C)N[Si](C)(C)C.[O:36]1CC[CH2:38][CH2:37]1>>[C:37]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:26])[C:10]1[C:15]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[CH:14][N:13]=[CH:12][C:11]=1[F:25])(=[O:36])[CH3:38]
Reactant: C1CCOC1
Reactant: Nc1ccccc1NC(=O)c1c(F)cncc1Nc1ccc(I)cc1F
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: CC(=O)Nc1ccccc1NC(=O)c1c(F)cncc1Nc1ccc(I)cc1F
Reaction time: 18 h

Procedure:
69 mg of N-(2-aminophenyl)-3-fluoro-5-[(2-fluoro-4-iodophenyl)amino]isonicotinamide (0.148 mmol, 1 eq.) were dissolved in 1 mL of terahydrofurane under a nitrogen athmoshere, then 0.592 ml of a hexamethyl disilazane solution (1M in THF, 4 eq.) were added and stirring was continued at room temperature for 18 h. The reaction mixture was partitioned between 20 ml of ethyl acetate and 15 ml of aqueouse HCL solution (1M). The aqueouse layer was reextracted twice with 20 ml of ethyl acetate each. The combined organic layers were washed with 20 ml of brine, dried over a silicone filter and concentrated in vacuo. The residue was purified by flash chromatography to yield 14 mg (0.03 mmol, 19%) of the analytically pure target compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:15]2[C:10]3=[C:11]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[N:9]3[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=3)[CH:12]=[CH:13][CH:14]=2.C1C(=O)N([Br:30])C(=O)C1.O>C(Cl)Cl.C(#N)C>[Br:30][C:13]1[CH:14]=[C:15]2[C:10]3=[C:11]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[N:9]3[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:2]2([CH3:22])[CH3:1])[CH:12]=1
Reactant: CC1(C)c2ccccc2-n2c3ccccc3c3cccc1c32
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CC1(C)c2ccccc2-n2c3ccccc3c3cc(Br)cc1c32
Reaction time: 4 h

Procedure:
6.3 g (22.2 mmol) of 8,8-dimethylindolo[3,2,1-de]acridine are initially introduced in 150 ml of CH2Cl2. A solution of 8 g (45.1 mmol) of NBS in 100 ml of acetonitrile is subsequently added dropwise at −15° C. with exclusion of light, and the mixture is allowed to come to room temperature and is stirred at this temperature for a further 4 h. 150 ml of water are subsequently added to the mixture, which is then extracted with CH2Cl2. The organic phase is dried over MgSO4, and the solvents are removed in vacuo. The product is washed by stirring with hot hexane and filtered off with suction. Yield: 4.5 g (12 mmol), 57% of theory, purity according to 1H-NMR about 97%.
Reaction SMILES: [Cl:1][CH2:2][C:3]([OH:5])=[O:4].[F:6][C:7]1[C:8]([CH2:40]O)=[C:9]([F:39])[C:10]2[O:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([NH:22]C(=O)C(C)(C)C)=[C:18]([F:29])[CH:17]=3)=[CH:13][C:12](=[O:30])[C:11]=2[C:31]=1[NH:32]C(=O)C(C)(C)C>S(=O)(=O)(O)O>[NH2:32][C:31]1[C:11]2[C:12](=[O:30])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([F:29])[CH:17]=3)[O:15][C:10]=2[C:9]([F:39])=[C:8]([CH2:40][O:4][C:3](=[O:5])[CH2:2][Cl:1])[C:7]=1[F:6]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(CO)c(F)c3o2)cc1F
Reactant: O=C(O)CCl
Agent: O=S(=O)(O)O
Product: Nc1ccc(-c2cc(=O)c3c(N)c(F)c(COC(=O)CCl)c(F)c3o2)cc1F
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 96.9 %

Procedure:
100 g (1.06 mol) of chloroacetic acid and 30 mL of sulfuric acid were added to 10.8 g (20.0 mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-hydroxymethyl-5-pivaloylamino-4H-1-benzopyran-4-one obtained in EXAMPLE 118 (4), and the mixture was stirred at 100° C. for 20 minutes. The reaction solution was poured into 1 L of ice-water and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was triturated with diisopropyl ether, to give 8.00 g of Compound 159 (yield: 97%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:11])[NH:6]2.[CH2:12]([O:19][C:20](=[O:23])[CH2:21]Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:12]([O:19][C:20](=[O:23])[CH2:21][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:11])[NH:6]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: Cc1cc2c(O)cccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc2c(OCC(=O)OCc3ccccc3)cccc2[nH]1

Procedure:
A mixture of 4-hydroxy-2-methylindole (3.0 g, 0.02 mole), bromo-acetic acid benzyl ester (4.6 g, 0.02 mole), potassium carbonate (2.8 g, 0.02 mole) in acetone was refluxed for 48 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (10:1 Hex:EtOAc) to afford intermediate (2). Yield: 3.5 g, 58%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.Br[C:10]1[C:11](=[O:18])[N:12]([CH3:17])[CH:13]=[C:14]([Br:16])[CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:16][C:14]1[CH:15]=[C:10]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)[C:11](=[O:18])[N:12]([CH3:17])[CH:13]=1
Reactant: Nc1ccc(F)cn1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2ccc(F)cn2)c1=O
Temperature: 25 °C
Yield: 60.4 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1,4-dioxane (50 mL), 5-fluoropyridin-2-amine (0.67 g, 6 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1.34 g, 5 mmol) and cesium carbonate (4.89 g, 15 mmol). After bubbling nitrogen through the resulting solution for 30 minutes, XantPhos (576 mg, 1 mmol) and tris(dibenzylideneacetone)dipalladium(0) (460 mg, 0.5 mmol) were added, and the reaction mixture was heated at reflux for 15 h. After this time the reaction was cooled to room temperature, partitioned between ethyl acetate (100 mL) and water (100 mL) and filtered. The aqueous layer was separated and extracted with ethyl acetate (50 mL×2). The organic layers were combined and washed with brine (50 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was washed with acetonitrile (30 mL) and filtered to afford 148a (900 mg, 61%). MS: [M+H]+ 298.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([OH:10])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C.O>C(Cl)Cl>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:10][C:6]2[CH:7]=[C:8]([CH3:9])[C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N+:11]([O-:13])=[O:12])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc([N+](=O)[O-])c(O)cc1C
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc([N+](=O)[O-])c(OS(=O)(=O)c2ccc(C)cc2)cc1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
To a solution of 4-methoxy-5-methyl-2-nitro phenol (8.0 g) in methylene chloride (80 mL) was added p-toluenesulfonyl chloride (9.15 g) at room temperature under nitrogen atmosphere. The mixture was cooled to 0° C. To this mixture triethylamine (4.86 g) was added and stirred for 2 h. Then the reaction mixture was poured into water (150 mL) and extracted with methylene chloride (150 mL). The organic layer was washed with water (100 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using hexane/ethyl acetate (9:1) to give the title compound (12.0 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]1[CH2:23][CH2:22][CH2:21][CH:20]=[CH:19][CH2:18][CH2:17][C@@H:16]([CH3:24])[CH2:15][C@@H:14]([C@@H:25]2[CH2:29][C@@H:28]([CH3:30])[C:27](=[O:31])[O:26]2)[NH:13][C:12](=[O:32])[C@H:11]([CH3:33])[NH:10][C:9]1=[O:34])([CH3:4])([CH3:3])[CH3:2]>C(N)CCC>[C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]1[CH2:23][CH2:22][CH2:21][CH:20]=[CH:19][CH2:18][CH2:17][C@@H:16]([CH3:24])[CH2:15][C@@H:14]([C@@H:25]([OH:26])[CH2:29][C@H:28]([C:27](=[O:31])[NH:7][CH2:8][CH2:23][CH2:22][CH3:21])[CH3:30])[NH:13][C:12](=[O:32])[C@H:11]([CH3:33])[NH:10][C:9]1=[O:34])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CCC=CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@H]([C@@H]2C[C@@H](C)C(=O)O2)C1
Solvent: CCCCN
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H]1C[C@H](C)CCC=CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1

Procedure:
A solution of 183 mg (0.37 mmol) [(3S,6S,14R,16S)-3,14-dimethyl-16-((2S,4R)-4-methyl-5-oxo-tetrahydro-furan-2-yl)-2,5-dioxo-1,4diaza-cyclohexadec-10-en-6-yl]-carbamic acid tert-butyl ester in 1.5 ml butylamine is heated to 65° C. under nitrogen for two hours. The reaction mixture is evaporated, the residue taken up in toluene and evaporated to dryness to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[N+:14]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)([O-:16])=[O:15].C([O-])([O-])=O.[Na+].[Na+].ClCCl>C1(C)C=CC=CC=1.CCOC(C)=O.O.O1CCOCC1>[CH3:13][O:12][C:4]1[CH:3]=[C:2]([C:20]2[CH:21]=[CH:22][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Br)cc1OC
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1OC
Temperature: 25 °C
Yield: 60.2 %

Procedure:
To a solution of methyl 4-bromo-2-methoxybenzoate (0.95 g, 3.9 mmol) and 4-nitrophenylboronic acid (1.29 g, 7.75 mmol) in toluene (10 mL) was added Na2CO3 (1.85 g, 17.4 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium(II) chloride complex with dichloromethane (0.06 g, 0.08 mmol), 1,4-dioxane (5 mL), and water (5 mL). The mixture was heated at reflux for 3 h and then allowed to cool to rt. The mixture was diluted with EtOAc and water, and the organic layer was isolated, dried over MgSO4, and concentrated in vacuo. The material was purified by column chromatography (25% EtOAc in hexanes), yielding 0.675 g (61%) of the title compound. LC/MS m/z 287.9 (MH+); retention time 3.14 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:5]=[N:6][C:7]=1[O:8][C@@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1.[F:18][CH:19]([F:22])[CH2:20]I.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:14]([NH2:17])(=[O:15])=[O:16])[CH:5]=[N:6][C:7]=1[O:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH2:20][CH:19]([F:22])[F:18])[CH2:10]1
Reactant: NS(=O)(=O)c1cnc(O[C@@H]2CCNC2)c(Cl)c1
Reactant: FC(F)CI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cnc(O[C@@H]2CCN(CC(F)F)C2)c(Cl)c1
Temperature: 25 °C

Procedure:
A mixture of EXAMPLE 261B (353 mg), 1,1-difluoro-2-iodoethane (268 mg), sodium carbonate (283 mg) in N,N-dimethylformamide (10 mL) was heated at 80° C. overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated. The residue was loaded onto silica gel column and eluted using a gradient of 0.5 to 3% methanol in dichloromethane to provide the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.Cl.[Cl:28][C:29]1[N:34]=[CH:33][C:32]([C:35]2[NH:39][C:38]([C@@H:40]3[CH2:44][CH2:43][CH2:42][NH:41]3)=[N:37][CH:36]=2)=[CH:31][N:30]=1.[N:45]1[CH:50]=[CH:49][CH:48]=[C:47]([CH2:51][C:52](O)=[O:53])[CH:46]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:28][C:29]1[N:34]=[CH:33][C:32]([C:35]2[NH:39][C:38]([C@@H:40]3[CH2:44][CH2:43][CH2:42][N:41]3[C:52](=[O:53])[CH2:51][C:47]3[CH:46]=[N:45][CH:50]=[CH:49][CH:48]=3)=[N:37][CH:36]=2)=[CH:31][N:30]=1
Reactant: Clc1ncc(-c2cnc([C@@H]3CCCN3)[nH]2)cn1
Reactant: O=C(O)Cc1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1cccnc1)N1CCC[C@H]1c1ncc(-c2cnc(Cl)nc2)[nH]1
Yield: 24.8 %

Procedure:
HATU (0.60 g, 1.57 mmol) was added in one portion to a stirred solution of intermediate (S)-2-chloro-5-(2-(pyrrolidin-2-yl)-1H-imidazol-5-yl)pyrimidine trihydrochloride (0.46 g, 1.43 mmol, theoretical amount), 2-(pyridin-3-yl)acetic acid (0.25 g, 1.43 mmol) and DIEA (1.0 mL, 5.72 mmol) in anhydrous DMF (10 mL) at ambient temperature. The mixture was stirred at room temperature for 2 h before the DMF was removed in vacuo. The residue was taken up in CH2Cl2 and subjected to Biotage™ flash chromatography on silica gel (40M column, preequilibration with 0% B for 600 mL followed by step gradient elution with 0% B to 0% B for 150 mL followed by 0% B to 15% B for 1500 mL followed by 15% B to 25% B for 999 mL where B=MeOH and A=CH2Cl2). There was isolated the title compound (0.131 g, 25%, 2 steps) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:5]2[OH:22].[CH2:23](O)[CH2:24][CH2:25][CH3:26].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]1[CH2:15][CH2:16]1)[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:5]2[O:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCO
Reactant: CCOC(=O)c1c(O)c2cc(Br)ccc2c(=O)n1CC1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCCOc1c(C(=O)OCC)n(CC2CC2)c(=O)c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
To a solution of ethyl 6-bromo-2-cyclopropylmethyl-4-hydroxy-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (7.32 g, 20 mmol), 1-butanol (2.7 mL, 30 mmol) and tributylphosphine (10.0 mL, 40 mmol) in tetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (10.09 g, 40 mmol) and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was purified, by silica gel column chromatography to give ethyl 6-bromo-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (7.24 g, 85.8%) as an oil.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=1)=[O:8].I[C:19]1[C:27]2[C:22](=[N:23][CH:24]=[N:25][C:26]=2[NH2:28])[N:21]([CH:29]([CH3:31])[CH3:30])[N:20]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:28][C:26]1[N:25]=[CH:24][N:23]=[C:22]2[N:21]([CH:29]([CH3:31])[CH3:30])[N:20]=[C:19]([C:11]3[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=3)[C:7]([NH:6][C:2]3[S:1][CH2:5][CH2:4][N:3]=3)=[O:8])[C:27]=12
Reactant: O=C(NC1=NCCS1)c1cccc(B(O)O)c1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2cccc(C(=O)NC3=NCCS3)c2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 66.7 %

Procedure:
A solution of [3-((4,5-dihydrothiazol-2-yl)carbamoyl)phenyl]boronic acid (19 mg, 0.08 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (20 mg, 0.07 mmol) in DME (12 mL). Pd(PPh3)4 (16 mg, 0.014 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA30 (17.8 mg, 67% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:8][C:4]=1[C:5]([OH:7])=O.CC(C)=O.ClC(OCC(C)C)=O.[CH:30]1([CH2:36][N:37]2[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>O.C(N(CC)CC)C>[CH:30]1([CH2:36][N:37]2[CH2:41][CH2:40][CH:39]([NH:42][C:5](=[O:7])[C:4]3[CH:8]=[C:9]([S:14](=[O:17])(=[O:16])[NH2:15])[CH:10]=[C:11]([O:12][CH3:13])[C:3]=3[O:2][CH3:1])[CH2:38]2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: COc1cc(S(N)(=O)=O)cc(C(=O)O)c1OC
Reactant: NC1CCN(CC2CCCCC2)C1
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(S(N)(=O)=O)cc(C(=O)NC2CCN(CC3CCCCC3)C2)c1OC
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 53.2 %

Procedure:
7.85 g of 2,3-dimethoxy-5-sulphamoyl benzoic acid, 50 ml of acetone, 10 ml of water and 3 g of triethylamine are placed in a 250 ml flask fitted with an agitator, a thermometer and a dropping funnel. The mixture is cooled to 0° and 4.2 g of isobutyl chloroformate is poured in drop by drop. The mixture is agitated for 45 minutes at 0° C., after which 6 g of 1-cyclohexylmethyl-3-amino-pyrrolidine is dripped in. It is agitated for 2 hours at room temperature, then 80 ml of water is added and the acetone evaporated under vacuum. The product crystallises. It is filtered, washed with water then re-dissolved in 150 ml of water and 20 ml of hydrochloric acid. The solution is filtered with charcoal and the filtrate made alkaline with ammonia. An oil is precipitated and crystallises slowly. The crystals are drained, washed with water and dried in an oven at 50° C. 6.8 g (53%) of product is obtained, with a melting point of 167° C.
Reaction SMILES: [S:1]([CH:4]([CH2:8][CH2:9][Cl:10])[C:5](=O)[CH3:6])[C:2]#[N:3].P(=O)(O)(O)[OH:12]>O>[OH:12][C:2]1[S:1][C:4]([CH2:8][CH2:9][Cl:10])=[C:5]([CH3:6])[N:3]=1
Reactant: O=P(O)(O)O
Reactant: CC(=O)C(CCCl)SC#N
Solvent: O
Product: Cc1nc(O)sc1CCCl
Temperature: 20 °C
Yield: 95 %

Procedure:
355,3 g (2 moles) of distilled 3-thiocyanato-5-chloro-2-pentanone are added into 360 cm3 of 85% phosphoric acid under stirring. The temperature of the reaction mixture is increased to 95° C. in water bath within about 1 hour and then it is stirred for half and hour between 95° to 100° C. The brown solution is cooled to 20° C. and poured into 660 cm3 of water. The precipitated beige crystals are removed by suction after a stirring for half an hour, washed neutral with water and dried in vacuo at a temperature of 60° C. 337 g (95%) of pale beige 2-hydroxy-4-methyl-5-(2-chloroethyl)thiazole are obtained, m.p.: 151°-152° C. After recrystallization from benzene the melting point is 157°-158° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12].[Cl:17][C:18]1[CH:19]=[C:20]([NH:24][CH2:25][C:26](O)=[O:27])[CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C.ClCC(OCC)=O.Cl>O1CCCC1>[Cl:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:25][C:26](=[O:27])[N:14]([S:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)(=[O:13])=[O:12])[C:15]2=[O:16])[CH:21]=[CH:22][CH:23]=1
Reactant: O=C=NS(=O)(=O)c1ccc2ccccc2c1
Reactant: O=C(O)CNc1cccc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(=O)CCl
Solvent: C1CCOC1
Product: O=C1CN(c2cccc(Cl)c2)C(=O)N1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 23.2 %

Procedure:
In accordance with the synthesis process (B), 1.0 g (81%, 3.49 mmol) of 2-naphthalenesulfonyl isocyanate was added to a solution of 647 mg (3.49 mmol) of N-3-chlorophenylaminoacetic acid in 50 ml of tetrahydrofuran at room temperature, and the resultant mixture was stirred for 16 hours. After completion of the reaction, the liquid reaction mixture was cooled to 0° C. and added with 881 mg (8.72 mmol) of triethylamine and 417 mg (3.84 mmol) of ethyl chloroacetate, followed by stirring at 0° C. for 1 hour. After completion of the reaction, the liquid reaction mixture was added with 20 ml of 1N hydrochloric acid and 30 ml of saturated saline and subjected to extraction with ethyl acetate. After washing the resultant extract with water, it was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The thus-obtained crude product was purified by column chromatography on silica gel (hexane/ethyl acetate=3:1) and subjected to crystallization from hexane/ethyl acetate, thereby obtaining 324 mg (0.81 mmol) of the title compound as white crystals (yield: 23.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:30][C:31]([NH:33][C@H:34]2[CH2:38][CH2:37][CH2:36][C@H:35]2[OH:39])=O)([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.CCN(S(F)(F)F)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:30][C:31]2[O:39][C@H:35]3[CH2:36][CH2:37][CH2:38][C@@H:34]3[N:33]=2)([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1
Reactant: O=C(N[C@H]1CCC[C@H]1O)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1
Agent: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: Fc1cc(OC(F)(F)C(F)F)cc([C@](Cc2ccccc2)(NC2=N[C@H]3CCC[C@@H]3O2)c2ccc(Cl)cn2)c1
Reaction time: 0.08 h
Yield: 90.6 %

Procedure:
To a solution of 1-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-((1S,2R)-2-hydroxycyclopentyl)urea (9 mg, 0.016 mmol) in CH2Cl2 (1 mL) was added DAST (3 mg, 0.02 mmol). The reaction mixture was stirred for 5 min and concentrated under vacuum. The residue was purified by preparative HPLC Shimadzu-Phenomenex Luna 5μ column, 21.2×100 mm eluting with 10-90% CH3CN (90% in H2O, 0.1% TFA) gradient over 15 min with flow rate 20 mL/min and UV detection at 220 nm to give (3aS,6aS)-N-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]oxazol-2-amine as a white solid (8 mg, 91%). LCMS RT=3.27 min [M+H] 551.94 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm) NMR: 500 MHz 1H (CDCl3) 10.57 ppm, 1H, m; 8.54 ppm, 1H, m,; 7.67 ppm, 1H, m; 7.16 ppm, 5H, m; 7.05 ppm, 1H, m; 6.94 ppm, 1H, m; 6.67 ppm, 2H, m; 5.95 ppm, 1H, t; 5.19 ppm, 1H, t; 4.54 ppm, 1H, t; 3.87 ppm, 2H, m; 2.12 ppm, 1H, m; 1.91 ppm, 1H, m; 1.83 ppm, 1H, m; 1.68 ppm, 2H, m; 1.50 ppm, 1H, m.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]([CH3:21])([N+:18]([O-])=O)[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][CH3:17])[CH:13]=2)[NH:8][CH:7]=1>CO>[CH3:1][O:2][C:3](=[O:22])[C:4]([NH2:18])([CH3:21])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][CH3:17])[CH:13]=2)[NH:8][CH:7]=1
Reactant: CCOc1ccc2[nH]cc(CC(C)(C(=O)OC)[N+](=O)[O-])c2c1
Solvent: CO
Product: CCOc1ccc2[nH]cc(CC(C)(N)C(=O)OC)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
To a stirred solution of (+/−)-3-(5-ethoxy-1H-indol-3-yl)-2-methyl-2-nitro-propionic acid methyl ester (5.3 g, 17.3 mmol) in dry methanol (50 ml) Raney nickel is added and the mixture is stirred at room temperature under H2 at atmospheric pressure overnight. The reaction mixture is filtered through a pad of Celite and the solid is washed with methanol. The filtrate is concentrated and the residue is purified by column chromatography (dichloromethane-methanol, 95:5) to give (+/−)-2-amino-3-(5-ethoxy-1H-indol-3-yl)-2-methyl-propionic acid methyl ester (4.2 g, 90%) as a white crystals. M.p. 165-166° C. (from ethyl acetate-hexane).