Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([C:9]([N:13]=[C:14]=[O:15])([CH3:12])[CH2:10]I)[CH:3]=1.C([OH:20])(C)(C)C>CN(C)C=O.F[B-](F)(F)F.[Ag+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([C:9]2([CH3:12])[CH2:10][O:20][C:14](=[O:15])[NH:13]2)[CH:3]=1
Reactant: CC(C)(C)O
Reactant: CC(CI)(N=C=O)c1cc(Br)ccc1F
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC1(c2cc(Br)ccc2F)COC(=O)N1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A solution of the crude (RS)-4-bromo-1-fluoro-2-(2-iodo-1-isocyanato-1-methyl-ethyl)-benzene (10.01 g, 26 mmol) in N,N-dimethyl-formamide (90 ml) was treated at room temperature with silver tetrafluoroborate (5.58 g, 29 mmol) and tert-butanol (3.86 g, 52 mmol). The yellow suspension was stirred at 80° C. overnight. For the workup, the reaction mixture was evaporated at reduced pressure, the residue triturated in ethyl acetate then filtered. The solution was concentrated at reduced pressure and the crude product purified by chromatography on silica gel using a gradient of dichloromethane/methanol=100/0 to 40/60 as the eluent. The (RS)-4-(5-bromo-2-fluoro-phenyl)-4-methyl-oxazolidin-2-one was obtained as a white solid (4.33 g, 61% of theory). MS (ISP): m/z=274.2 [M+H]+, 276.2 [M+2+H]+.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][O:7][CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][CH2:8][CH2:9][O:10][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCOCc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOCc1ccc(F)cc1
Temperature: -5 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
A solution of 2-(4-fluorobenzyloxy)-ethanol (5.11 g, 30.0 mmol, from step (i) above) in methylene chloride (60 mL) was cooled to −10° C. Triethylamine (5.0 mL, 36 mmol) was added followed by methanesulfonyl chloride (3.78 g, 33.0 mmol) and the reaction mixture was stirred at −5° C. for 2 h. The reaction mixture was diluted with methylene chloride (200 mL) and the organic phase was washed with water (2×75 mL) and brine (75 mL), dried over MgSO4, and concentrated in vacuo to give 7.16 g (96%) of the title compound as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[N:15]=[C:16]([I:18])[NH:17][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:21][Si:22]([CH2:25][CH2:26][O:27][CH2:28]Cl)([CH3:24])[CH3:23]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[N:15]=[C:16]([I:18])[N:17]([CH2:28][O:27][CH2:26][CH2:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(C)(C)OC(=O)N1CCc2nc(I)[nH]c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2nc(I)n(COCC[Si](C)(C)C)c2CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.3 %

Procedure:
To a solution of 2-iodo-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepine-6-carboxylic acid tert-butyl ester (Preparation 28, 2.2 g, 6.06 mmol) in THF (35 mL) was added NaH (60% in paraffin oil, 254 mg, 6.36 mmol) and the resulting solution was stirred at room temperature for 1.5 hours. The reaction mixture was cooled to 0° C. and SEM-Cl (1.13 mL, 6.36 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 18 hours and then cooled to 0° C. and quenched carefully with water (100 mL). The resulting solution was extracted with EtOAc (2×100 mL) and the combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (Biotage SNAP 100 g) eluting with 40% EtOAc in DCM to give the title compound (2.34 g) in a 78% yield.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[OH:27][CH:28]1[CH:32]([CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:31]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:30][CH:29]1[N:50]1[CH:55]=[C:54](I)[C:53](=[O:57])[NH:52][C:51]1=[O:58].[C:59]([O:63][CH3:64])(=[O:62])[CH:60]=[CH2:61]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:27][CH:28]1[CH:32]([CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:31]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:30][CH:29]1[N:50]1[CH:55]=[C:54]([CH:61]=[CH:60][C:59]([O:63][CH3:64])=[O:62])[C:53](=[O:57])[NH:52][C:51]1=[O:58]
Reactant: O=c1[nH]c(=O)n(C2CC(OCc3ccccc3)C(COCc3ccccc3)C2O)cc1I
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)C=Cc1cn(C2CC(OCc3ccccc3)C(COCc3ccccc3)C2O)c(=O)[nH]c1=O
Reaction time: 0.25 h
Yield: 35.8 %

Procedure:
A mixture of palladium(II) acetate (0.195 g, 0.871 mmol), triphenylphosphine (0.456 g, 1.74 mmol) and triethylamine (2.56 ml, 0.0183 mol) in dioxane (200 ml, purified on basic alumina and degassed in vacuo) was heated for 10 minutes at 90° under nitrogen. A solution of [1S-(1α,2β,3α,4β)]-1-[2-hydroxy-4-(phenylmethoxy)-3-[(phenylmethoxy)-methyl]cyclopentyl-5-iodo-2,4(1H,3H)-pyrimidine-dione (6.70 g, 0.0122 mol, dried by concentration in vacuo from dry toluene) and methyl acrylate (3.23 ml, 0.0366 mol) in degassed dioxane (20 ml) was added, and the reaction was heated at 90° for 4.5 hours. Celite (5 g) was added, and after stirring at 90° for 15 minutes, the hot slurry was filtered through Celite and washed with chloroform (80 ml). The filtrate and the wash were combined and concentrated in vacuo to a residue, which was dissolved in chloroform (400 ml). The chloroform was washed with water (100 ml), dried (sodium sulfate) and concentrated in vacuo to a residue. Chromatography of the residue on a column of Merck silica gel (800 ml, packed in dichloromethane) by eluting with a gradient of chloroform to 5% ethanol in chloroform gave 2.21 g of desired product as a residue.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([NH:7][C:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:23]4[N:24]=[CH:25][N:26]([C@@H:27]5[O:31][C@H:30]([CH2:32][OH:33])[C@@H:29]([OH:34])[C@H:28]5[OH:35])[C:22]=4[N:21]=[CH:20][N:19]=3)=[CH:13][CH:12]=2)=[O:9])[CH:4]=[C:3]([CH2:36][C:37]([NH:39][CH2:40][CH2:41][NH2:42])=[O:38])[CH:2]=1.C(N(CC)CC)C.C(Cl)(Cl)=S.[Cl-:54].[Na+].CN(C)C=[O:59]>O>[CH:1]1[CH:6]=[C:5]([NH:7][C:8]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18]3[C:23]4[N:24]=[CH:25][N:26]([C@@H:27]5[O:31][C@H:30]([CH2:32][OH:33])[C@@H:29]([OH:34])[C@H:28]5[OH:35])[C:22]=4[N:21]=[CH:20][N:19]=3)=[CH:15][CH:16]=2)=[O:9])[CH:4]=[C:3]([CH2:36][C:37]([NH:39][CH2:40][CH2:41][NH2:42])=[O:38])[CH:2]=1.[CH2:36]1[C:37](=[O:38])[N:39]([Cl:54])[C:40](=[O:59])[CH2:41]1
Reactant: [Cl-]
Reactant: CN(C)C=O
Agent: NCCNC(=O)Cc1cccc(NC(=O)Cc2ccc(Nc3ncnc4c3ncn4[C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)cc2)c1
Agent: S=C(Cl)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1CCC(=O)N1Cl

Procedure:
ADAC, 25 mg, 43 micromol, and 6 microliters triethylamine were dissolved in 1 ml dimethylformamide with warming. After cooling in an ice bath, 3.9 microl, 51 micromol of distilled thiophosgene was added with stirring. Water and saturated sodium chloride were added to obtain a white precipitate-, which was dried in vacuo over sodium hydroxide. The yield was 13 mg, or 48%, of product. IR peaks appeared at 3460, 2120, 1640, 1600, 1515, 1480, 1420, 1100, 1060, and 1030 cm-1. Thin layer chromatography and the Cf plasma desorption spectrum was consistent with the assigned structure and showed no evidence of residual ADAC.
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[Al+3].[CH3:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[C:9](Cl)=[O:10]>ClC1C=CC=CC=1>[CH3:5][C:6]1[CH:7]=[C:8]([C:9](=[O:10])[C:6]2[CH:7]=[CH:8][C:12]([Cl:1])=[CH:13][CH:14]=2)[CH:12]=[C:13]([CH3:15])[CH:14]=1
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: [Cl-]
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: Cc1cc(C)cc(C(=O)c2ccc(Cl)cc2)c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 172.3 %

Procedure:
100 ml chlorobenzene and 14.7 g aluminium trichloride are added in a 250 ml three-neck flask, and then 16.8 g 3,5-dimethyl benzoyl chloride is dropped into the solution at room temperature. Maintaining the temperature at 70° C., react with stirring for 16 h. The reaction solution is acidolyzed and washed with water, and then is distilled to remove chlorobenzene, obtaining 21 g residue, the yield is 86%. The residue is recrystallized with ethanol to obtain a purified white crystal, and the melting point is 72-73° C. 1H-NMR data (solvent CDCl3): δ2.371 ppm, s, 6H; δ7.230 ppm, s, 1H; δ7.363 ppm, s, 2H; δ7.438, 7.466 ppm, d, 2H; δ7.729, 7.757 ppm, d, 2H.
Reaction SMILES: [NH:1]([C:30]([O:32][CH2:33][CH:34]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]2[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[C@H:2]([C:27](O)=[O:28])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:26])[NH:8][S:9]([C:12]1[C:24]([CH3:25])=[C:23]2[C:17]([O:18][C:19]([CH2:22]2)([CH3:21])[CH3:20])=[C:15]([CH3:16])[C:13]=1[CH3:14])(=[O:11])=[O:10].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:80]([O:84][C:85]([N:87]1[CH2:92][CH2:91][NH:90][CH2:89][CH2:88]1)=[O:86])([CH3:83])([CH3:82])[CH3:81]>CN(C=O)C>[C:80]([O:84][C:85]([N:87]1[CH2:92][CH2:91][N:90]([C:27](=[O:28])[C@@H:2]([NH:1][C:30]([O:32][CH2:33][CH:34]2[C:46]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[C:40]3[C:35]2=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:31])[CH2:3][CH2:4][CH2:5][NH:6]/[C:7](/[NH2:26])=[N:8]/[S:9]([C:12]2[C:13]([CH3:14])=[C:15]([CH3:16])[C:17]3[O:18][C:19]([CH3:21])([CH3:20])[CH2:22][C:23]=3[C:24]=2[CH3:25])(=[O:10])=[O:11])[CH2:89][CH2:88]1)=[O:86])([CH3:83])([CH3:81])[CH3:82]
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c(C)c2c1OC(C)(C)C2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C)c(S(=O)(=O)/N=C(\N)NCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of Fmoc-Arg(Pbf)-OH 1 (25.0 g, 38.5 mmol) in DMF (200 mL) at room temperature was added DIEA (13.41 mL, 77.1 mmol). After stirring at room temperature for 10 min, the reaction mixture was cooled to ˜5° C. To the reaction mixture was added HATU (16.11 g, 42.4 mmol) in portions and stirred for 20 min and a solution of tert-butyl-1-piperazine carboxylate (7.18 g, 38.5 mmol) in DMF (50 mL) was added dropwise. The reaction mixture was stirred at ˜5° C. for 5 min. The mixture reaction was then allowed to warm to room temperature and stirred for 2 h. Solvent was removed in vacuo and the residue was dissolved in EtOAc (500 mL), washed with water (2×750 mL), 1% H2SO4 (300 mL) and brine (750 mL). The organic layer was separated, dried over Na2SO4 and solvent removed in vacuo to a total volume of 100 mL. Compound A was taken to the next step as EtOAc solution (100 mL). LC-MS [M+H] 817.5 (C43H56N6O8S+H, calc: 817.4).
Reaction SMILES: O[N:2]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.O.N.[Cl:25][C:26]1[S:27][CH:28]=[C:29]([C:31]([OH:33])=O)[N:30]=1>O.ClCCl>[Cl:25][C:26]1[S:27][CH:28]=[C:29]([C:31]([NH2:2])=[O:33])[N:30]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1csc(Cl)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1csc(Cl)n1
Temperature: 25 °C
Reaction time: 46 h
Yield: 95.5 %

Procedure:
1-hydroxybenzotriazole (0.56 g, 3.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC) (0.7 g, 3.7 mmol) and ammonia water (28%, 0.5 ml)) were added to a dichloromethane solution (10 ml) of 2-chlorothiazole-4-carboxylic acid (0.5 g, 3.06 mmol) and the mixture was stirred at room temperature for 46 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate. The extraction solution with ethyl acetate was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:5→ethyl acetate). The purified product was concentrated to dryness under reduced pressure to obtain 2-chlorothiazole-4-carboxamide (475 mg) as white powder.
Reaction SMILES: O=[C:2]1[CH:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][CH2:4][NH:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1C=CC=CC=1>[S:23]=[C:2]1[CH:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][CH2:4][NH:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)C1CCNC1=O
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)C1CCNC1=S
Reaction time: 1 h
Yield: 111.6 %

Procedure:
1.7 g of tert-butyl 2-oxopyrrolidine-3-carboxylate and 1.8 g of Lawesson's reagent were added to 20 ml of benzene and stirred at 50° to 60° C. for 1 hour. After filtering the insoluble matters the solvent was distilled off and the obtained residue was purified by silica gel chromatography to thereby give 1.0 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[CH2:9]([NH2:13])[CH:10]([CH3:12])[CH3:11]>>[CH2:1]([O:3][C:4]([NH:6][C:7]([NH:13][CH2:9][CH:10]([CH3:12])[CH3:11])=[S:8])=[O:5])[CH3:2]
Reactant: CCOC(=O)N=C=S
Reactant: CC(C)CN
Product: CCOC(=O)NC(=S)NCC(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 5.3 grams of ethoxycarbonyl isothiocyanate (Preparation 1) in 100 ml of petroleum ether (b.p. 35°-60° C.) was cooled with stirring in an ice-water bath. To the above solution was added dropwise in 20 minutes a solution of 3.9 grams of isobutylamine in 50 ml of petroleum ether. The reaction flask was cooled in the ice-water bath during the addition. After the addition was complete the reaction flask was removed from the ice-water bath and let stand at an ambient temperature overnight. The solution was concentrated by stripping off most of the solvent. The concentrated solution was cooled in a ice-water bath. The crystals were collected by filtering and washing with hexanes. The product weighed 7.5 grams and melted at 50°-52° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[CH:10][C:5]2=[CH:4][N:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:9]=[CH:10][C:5]2=[CH:4][N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ncc2cn[nH]c2n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Clc1ncc2cnn(-c3ccccc3)c2n1
Temperature: 80 °C
Yield: 92 %

Procedure:
A suspension of 6-chloro-1H-pyrazolo[3,4-d]pyrimidine (100 mg, 0.65 mmol), benzene boronic acid (1.5 eq), copper acetate (2 eq) and pyridine (2 eq) in dichloromethane (2 mL) was heated in the microwave at 80° C. for 15 min. After cooling to rt, the mixture was filtered and the resulting filtrate concentrated to give 6-chloro-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine as a green oil (138 mg, 92%) which was used without further purification in the next step.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=1.Br[C:23]1[C:24]([NH2:29])=[N:25][CH:26]=[CH:27][CH:28]=1.O>C1COCC1.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:7]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10]([C:23]2[C:24]([NH2:29])=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:9][CH:8]=1
Reactant: Nc1ncccc1Br
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
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: C1CCOC1
Solvent: O
Product: Nc1ncccc1-c1ccc(-c2ccccc2)cc1
Yield: 65.5 %

Procedure:
A mixture of 2M aqueous sodium carbonate solution (6.64 mL), tetrakis(triphenylphosphine)palladium(0) (0.512 g), biphenyl-4-ylboronic acid (2.28 g) and 3-bromopyridin-2-amine (1.532 g) in dehydrated THF (30 mL) was heated under reflux overnight. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a solid. The obtained solid was crystallized from toluene, diisopropyl ether and acetonitrile to give the title compound (1.428 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:10]([CH3:11])=[C:9]([O:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[N:8]=[CH:7][N:6]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:28]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:10]([CH3:11])=[C:9]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:34][CH2:33][C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)[CH2:15][CH2:14]2)[N:8]=[CH:7][N:6]=1
Reactant: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCCc2cccnc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCN(CCc2cccnc2)CC1
Temperature: 150 °C
Yield: 12.8 %

Procedure:
A mixture of 4-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-(piperidin-4-yloxy)-pyrimidine (100 mg, 0.24 mmol), toluene-4-sulfonic acid 2-pyridin-3-yl-ethyl ester (133 mg, 0.48 mmol), and triethylamine (167 μL, 1.2 mmol) in DMF (2 mL) was heated under microwave irradiation for 60 min at 150° C. The crude mixture was concentrated in vacuo and purified by HPLC to provide Compound C18 as an oil (15 mg, 13%). 1H NMR (CDCl3, 400 MHz) δ 2.15 (s, 3H), 2.18-2.38 (m, 4H), 3.04 (s, 3H), 3.07-3.22 (m, 2H), 3.29-3.43 (m, 4H), 3.44-3.65 (m, 2H), 5.43-5.51 (m, 1H), 7.36 (t, 1H), 7.67-7.79 (m, 3H), 8.11 (s, 1H), 8.35 (d, 1H), 8.58 (d, 1H), 8.91 (s, 1H). Exact mass calculated for C24H27FN4O4S 486.56, found 487.4 (MH+).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([N-]C(C)C)(C)C.[Li+]>C1COCC1.C(O)(=O)C>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][N:3]=[C:2]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:14])[CH3:13]
Reactant: Nc1ccccc1
Reactant: CCn1c(=O)ccc2cnc(F)cc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCn1c(=O)ccc2cnc(Nc3ccccc3)cc21
Reaction time: 8 h
Yield: 24 %

Procedure:
A stirred solution of (XV, where R2 is ethyl) (100 mg, 0.52 mmol) and aniline (120 mg, 1.3 mmol) in THF (5.0 mL) under nitrogen at -78° C. was treated with a solution (1.2 mL, 1.8 mmol) of lithium diisopropylamide (1.5 M in cyclohexane), then the temperature was allowed to rise slowly to 20° C. overnight. The resulting solution was treated with 3 drops of glacial acetic acid and concentrated to a brown residue that was purified by silica gel chromatography eluting with EtOAc. The product fractions were pooled and concentrated to a solid that was crystallized to give 1-ethyl-7-phenylamino-1H -[1,6]naphthyridin-2-one (33 mg, 24%): mp (8:1 hexanes/dichloromethane) 174-175° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:19]([O:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[CH:10]=1)(=[O:21])[CH3:20]
Reactant: O=C(O)c1ccc(O)cc1F
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(C(=O)O)c(F)c1

Procedure:
A stirred mixture of 2-fluoro-4-hydroxybenzoic acid (5 g) (G. W. Gray et al. Mol. Cryst. Liq. Cryst. 67, 1981, 1-24), 4-dimethylaminopyridine (0.010 g) and triethylamine (11 mL) in DCM (100 mL) was treated with acetic anhydride (6.35 mL). After 2 h the solution was evaporated and the residue redissolved in EtOAc, washed with 5% citric acid, water (3×), dried (Na2SO4) and evaporated to give the title compound as a white solid (4.92 g); APCI m/z 199.1 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[CH:18]=[C:17]([C:19]([O-:21])=O)[NH:16][C:13]3=[N:14][CH:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=N1.N1CCCC1.C(N(CC)C(C)C)(C)C>>[N:30]1([C:19]([C:17]2[NH:16][C:13]3=[N:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:11]=[C:12]3[CH:18]=2)=[O:21])[CH2:31][CH2:36][CH2:35][CH2:34]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C([O-])c1cc2cc(OCCCN3CCCC3)cnc2[nH]1
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNC1
Product: O=C(c1cc2cc(OCCCN3CCCC3)cnc2[nH]1)N1CCCC1
Yield: 53 %

Procedure:
The title compound was synthesized in analogy to example 1 from lithium 5-(3-pyrrolidin-1-yl-propoxy)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, pyrrolidine and N,N-diisopropylethylamine to give the desired product as a light yellow solid (53%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:11]3([C:17]([F:19])([F:18])[CH2:16][O:15][CH2:14][C:13]([NH2:20])=[N:12]3)[CH2:10][CH:9]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[N:33][CH:34]=1)#[N:28]>>[NH2:20][C:13]1[CH2:14][O:15][CH2:16][C:17]([F:19])([F:18])[C@@:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([C:31]4[CH:32]=[N:33][CH:34]=[C:29]([CH:30]=4)[C:27]#[N:28])[CH:3]=3)[O:8][CH:9]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:10]2)[N:12]=1
Reactant: N#Cc1cncc(B(O)O)c1
Reactant: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(F)(F)COC1
Product: N#Cc1cncc(-c2ccc3c(c2)[C@@]2(CC(c4ccccc4)O3)N=C(N)COCC2(F)F)c1
Yield: 15 %

Procedure:
The cross coupling reaction of (2RS,4R)-6-bromo-6′,6′-difluoro-2-phenyl-6′,7′-dihydro-2′H-spiro[chroman-4,5′-[1,4]oxazepin]-3′-amine (intermediate C3.4) with 5-cyanopyridin-3-ylboronic acid yielded the title compound (15% yield) as a colorless solid. MS (ISP): m/z=447.4 [M+H]+.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:14]=[C:15]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:16]([O:21][CH2:22][O:23][CH3:24])=[C:17]([CH:20]=1)C=O>C(Cl)Cl>[Br:12][C:13]1[CH:14]=[C:15]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:16]([O:21][CH2:22][O:23][CH3:24])=[C:17]([OH:9])[CH:20]=1
Reactant: COCOc1c(C=O)cc(Br)cc1C(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COCOc1c(O)cc(Br)cc1C(C)(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
After adding 70% mCPBA (25 g) to a solution of 5-bromo-3-(tert-butyl)-2-(methoxymethoxy)benzaldehyde (30 g, 97 mmol) in methylene chloride (200 ml), the mixture was stirred at 50° C. for 2 hours. The organic layer was washed with a saturated sodium thiosulfate solution and saturated sodium hydrogencarbonate solution and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (17 g) as a light yellow oil.
Reaction SMILES: CN(C)C=O.[I:6]N1C(=O)CCC1=O.[NH2:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][N:16]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C>[NH2:14][C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([I:6])=[CH:17][N:16]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1cc(Cl)ccn1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)c(I)cn1
Reaction time: 8 h
Yield: 74.9 %

Procedure:
N,N-Dimethylformamide (47 ml) and N-iodosuccinimide (10.7 g, 47.6 mmol) were added to 2-amino-4-chloropyridine (4.72 g, 36.7 mmol); and the reaction mixture was stirred overnight. An aqueous solution of sodium thiosulfate and ethyl acetate were added thereto; the organic layer was separated, concentrated, and dried over anhydrous sodium sulfate. This was concentrated under reduced pressure; a solvent mixture (ether: hexane=1:1) was added to the residue; and the solid was filtered off to yield the title compound (7.0 g, 27.5 mmol).