Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C@H:14]1[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([Cl:33])[CH:27]=1.[Cl:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=1>>[Cl:33][C:28]1[CH:27]=[C:26]([C@H:14]2[C@H:13]([NH:12][C:39]([C:38]3[CH:42]=[CH:43][C:35]([Cl:34])=[CH:36][CH:37]=3)=[O:40])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:15]2)[CH:31]=[CH:30][C:29]=1[F:32]
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](c2ccc(F)c(Cl)c2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2ccc(Cl)cc2)[C@H](c2ccc(F)c(Cl)c2)C1

Procedure:
sing the compound obtained in step 1 and 4-chlorobenzoic acid, and by the reaction and purification in the same manner as in Reference Example 1, step 5, the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.N>ClCCl.CO>[Cl:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3c(Cl)cccc32)CC1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: O=c1[nH]c2c(Cl)cccc2n1C1CCNCC1
Reaction time: 5 h

Procedure:
tert-butyl 4-(4-chloro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-1-carboxylate from Step B (2.17 g, <6.17 mmol) was dissolved in dichloromethane (10 mL) and trifluoacetic acid (5 mL) was added at room temperature. After 5 h, additional trifluoacetic acid (5 mL) was added and the reaction stirred overnight. To this solution was added 2.0 M ammonia in methanol, the mixture was filtered and the volatiles removed in vacuo. The crude product was purified by chromatography (silica gel, 1 to 25% methanol containing 1% NH3 in methylene chloride gradient elution), which gave the title compound (1.12 g). MS 352.2 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][C:6]2([CH3:15])[CH3:14])#[CH:2].[O:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>C(N(CC)CC)C.C(OCC)C.[Cu]I.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>[CH2:9]([O:13][C:20](=[O:16])[C:19]1[CH:3]=[CH:1][C:2]([C:2]#[C:1][C:3]2[CH:12]=[CH:11][C:10]3[C:9](=[O:13])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=3[CH:4]=2)=[CH:17][CH:18]=1)[CH3:8]
Reactant: C1CCOC1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
A solution of 6-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-one (Intermediate 13, 0.23 g, 1.1 mmol) and ethyl-4-iodo benzoate (Reagent A, 0.36 g, 1.3 mmol) in triethyl amine (7 mL) and anhydrous tetrahydrofuran (3 mL) was treated with copper(I)iodide (0.1 14 g, 0.6 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (0.23 g, 0.33 mmol) was added and the reaction mixture was stirred overnight at room temperature. It was diluted with diethyl ether and filtered over a bed of celite. The filtrate was evaporated in vacuo to a brown oil that was subjected to flash column chromatography over silica gel (230-400 mesh) using 6-7% ethyl acetate in hexane as the eluent to afford the title compound (0.29 g, 72%) as a pale brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.[H-].[Na+].[CH3:12][O:13][CH2:14]Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([O:8][CH2:12][O:13][CH3:14])[CH:7]=1
Reactant: Oc1cc(Br)ccc1F
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cc(Br)ccc1F
Reaction time: 0.17 h
Yield: 95.8 %

Procedure:
To a stirred solution of 5-bromo-2-fluorophenol (5 g, 26.2 mmol) in DMF (50 mL) at 0° C. was added sodium hydride (1.571 g, 39.3 mmol). After stirring for 10 min, chloromethyl methyl ether (2.386 mL, 31.4 mmol) was added dropwise to mixture and the mixture was then stirred for 1 hour at 0° C. The reaction was quenched with addition of saturated NH4Cl aq. and the mixture was poured into water (150 mL). The mixture was extracted with ethyl acetate (30 mL×2). The organic layers were combined, washed with brine (100 mL), dried over MgSO4, filtered and evaporated in vacuo. The crude residue was purified by chromatography on silica, eluting with a gradient of 0-10% ethyl acetate in cyclohexane to give the title compound (5.90 g). 1H NMR (CDCl3, 400 MHz) δ ppm: 3.55 (3H, s), 5.24 (2H, s), 6.95-7.02 (1H, m), 7.08-7.14 (1H, m), 7.36-7.40 (1H, m).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH:12]1([C:15](=[O:22])[CH2:16][C:17]([CH:19]2[CH2:21][CH2:20]2)=[O:18])[CH2:14][CH2:13]1.O>FC(F)(F)C(O)=O>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:16]([C:15]([CH:12]2[CH2:14][CH2:13]2)=[O:22])[C:17]([CH:19]2[CH2:21][CH2:20]2)=[O:18])=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: O=C(CC(=O)C1CC1)C1CC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(C=C(C(=O)C2CC2)C(=O)C2CC2)cc1
Temperature: 20 °C

Procedure:
The procedure described in Example 19 was repeated by using 3.0 g 4-carboxybenzaldehyde and 3.06 g 1,3-dicyclopropyl-1,3-propanedione. Yield 1.7 g, mp 175°-178° C. in trifluoroacetic acid (10 ml) thionylchloride (4 ml) and catalytic amount of water (0,05 ml) were added at room temperature. The solution was stirred over right at 20° C. The solvent was evaporated and the residue was destilled in vacuo, bp 110° C./1,5 mbar. Yield 5,3 g (41%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:19]=[C:18]4[Cl:31])[N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[Cl:31][C:18]1[C:17]2[C:21](=[CH:22][CH:23]=[C:15]([C:12]3[N:11]=[C:10]([C:4]4[CH:3]=[C:2]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:7]([O:8][CH3:9])=[CH:6][CH:5]=4)[O:14][N:13]=3)[CH:16]=2)[N:20]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:19]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)CCn1cc(Cl)c2cc(-c3noc(-c4ccc(OC)c(Br)c4)n3)ccc21
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
Product: CCOC(=O)CCn1cc(Cl)c2cc(-c3noc(-c4ccc(OC)c(-c5ccccc5)c4)n3)ccc21
Temperature: 90 °C

Procedure:
Ethyl 3-(5-{5-[3-bromo-4-(methyloxy)phenyl]-1,2,4-oxadiazol-3-yl}-3-chloro-1H-indol-1-yl)propanoate (D106) (212 mg, 0.42 mmol), phenyl boronic acid (104 mg, 0.84 mmol), Pd(PPh3)4 (20 mg) and 2N aq. sodium carbonate solution (3 ml, 6 mmol) were suspended in DME (6 ml) and heated at 90° C. for 2 hours. Added phenyl boronic acid (30 mg, 0.24 mmol) and Pd(PPh3)4 (20 mg) and heated at 90° C. for a further 2 hours. Added EtOAc (70 ml) and washed with water (100 ml). Dried over MgSO4 and evaporated off the solvent. The residue was crystallised from ethanol to yield the title compound as 90 mg of light tan solid. MS (ES) C28H2435ClN3O4 requires 501; found 502 (MH+).
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[N:60]([CH2:63][CH2:64][CH2:65][C@H:66]([NH:73][C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[C:67](OCC#N)=[O:68])=[N+:61]=[N-:62]>O.O1CCCC1>[N:60]([CH2:63][CH2:64][CH2:65][C@@H:66]([NH:73][C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[C:67]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:68])=[N+:61]=[N-:62]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN=[N+]=[N-])C(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CCCN=[N+]=[N-])C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.1 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (77 mg, 0.121 mmol) in water (0.3 mL) and a solution of (S)-cyanomethyl 5-azido-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk70) (144 mg, 0.484 mmol) in tetrahydrofuran (0.3 mL) were added to buffer A (18 mL), and the mixture was stirred at room temperature for 0.5 hour. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 5-azido-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk71) (24.5 mg, 23%).
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]#[N:11])[CH:5]=[CH:4]1.[Cl:18][C:19]([Cl:24])([Cl:23])[C:20](Cl)=[O:21].C(N(CC)CC)C>O1CCCC1>[Cl:18][C:19]([Cl:24])([Cl:23])[C:20]([O:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10]#[N:11])[CH:5]=[CH:4]1)=[O:21]
Reactant: N#CC(=C1C=CC(=NO)C=C1)c1ccccc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CC(=C1C=CC(=NOC(=O)C(Cl)(Cl)Cl)C=C1)c1ccccc1
Temperature: 5 °C
Reaction time: 0.83 h

Procedure:
8 g (36 mmol) of (4-Hydroxyimino-cyclohexa-2,5-dienylidene)-phenyl-acetonitrile, prepared as described in example 1.1, are dissolved in 90 ml of tetrahydrofuran (THF) and cooled in an ice bath. After adding 7.2 g (39 mmol) of trichloroacetyl chloride to the solution, 5.4 g (54 mmol) of triethylamine are added dropwise, keeping the temperature below 5° C. While the reaction mixture is stirred at 5° C. for 50 min, a precipitate is formed. The precipitate is filtered off and washed with THF. The filtrate is concentrated by a rotary evaporator. The residue is diluted with 2-propanol (2-PrOH) and stirred at room temperature overnight. After cooling the mixture in an ice bath, the solid is isolated by filtration and washed with 2-PrOH. The product is obtained in the form of an orange solid,mp 147-148° C.(Dec). The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 6.97 (dd, 1H), 7.30 (dd, 1H), 7.38 (dd, 1H), 7.52 (s, 5H), 7.65 (dd, 1H). 1H-NMR reveals the presence of a single isomer.
Reaction SMILES: Br[CH2:2][CH:3]([OH:16])[CH2:4][O:5][C:6]1[S:7][C:8]([C:11](=[O:15])[N:12]([CH3:14])[CH3:13])=[CH:9][N:10]=1.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K]>CN(C)C=O>[C:17]1(=[O:27])[N:21]([CH2:2][CH:3]([OH:16])[CH2:4][O:5][C:6]2[S:7][C:8]([C:11](=[O:15])[N:12]([CH3:14])[CH3:13])=[CH:9][N:10]=2)[C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12
Reactant: CN(C)C(=O)c1cnc(OCC(O)CBr)s1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cnc(OCC(O)CN2C(=O)c3ccccc3C2=O)s1

Procedure:
By a procedure analogous to Example 2 the product from Example 7 can be reacted with potassium phthalimide in N,N-dimethylformamide to give the solid title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:18][CH3:19])[C:7]([O:16][CH3:17])=[N:8]2.[CH3:20][CH:21]1[NH:23][CH2:22]1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[CH3:17][O:16][C:7]1[C:6]([O:18][CH3:19])=[N:5][C:4]2[C:9](=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:3]=2[CH2:2][N:23]2[CH2:22][CH:21]2[CH3:20])[N:8]=1
Reactant: COc1nc2cc([N+](=O)[O-])cc(CBr)c2nc1OC
Reactant: CC1CN1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: ClCCl
Product: COc1nc2cc([N+](=O)[O-])cc(CN3CC3C)c2nc1OC

Procedure:
200 mg (0.61 mmol) of 5-bromomethyl-2,3-dimethoxy-7-nitro-quinoxaline, 0.086 ml (2 equiv.) of propyleneimine and 0.295 ml (0.3 equiv.) of an aqueous 40% tetrabutylammonium hydroxide solution are stirred in 8 ml of dichloromethane for 20 hours at room temperature. The mixture is concentrated by evaporation and the residue is extracted with ethyl acetate and a 5% sodium carbonate solution. The combined organic phases are washed once with brine, dried over magnesium sulfate and concentrated by evaporation.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[CH:8][C:7]([OH:17])=[CH:6][CH:5]=2.[CH2:18]([O:20][C:21](=[O:26])[C:22](Br)([CH3:24])[CH3:23])[CH3:19]>>[CH2:18]([O:20][C:21](=[O:26])[C:22]([CH3:24])([O:17][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([CH3:1])=[C:10]2[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[CH3:23])[CH3:19]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1[nH]c2ccc(O)cc2c1-c1ccncc1
Product: CCOC(=O)C(C)(C)Oc1ccc2[nH]c(C)c(-c3ccncc3)c2c1

Procedure:
The above compound was prepared from 2-methyl-3-(4-pyridyl)-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[N+:13]([CH3:16])[C:12]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:6]=2[C:17]([O:19][CH3:20])=[O:18].C(O)C.[BH4-].[K+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]([C:17]([O:19][CH3:20])=[O:18])[C:7]3[C:12]([N:13]([CH3:16])[C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: COC(=O)c1c2ccccc2[n+](C)c2cc(Cl)ccc12
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COC(=O)C1c2ccccc2N(C)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.3 gm of the methosulfate of 3-chloro-9-methoxycarbonyl-10-methyl-acridinium were added to a mixture of 50 cc of ethanol and 2.5 cc of water and after the addition of 5.3 gm potassium borohydride while maintaining a 25°C temperature, the mixture was stirred for 30 minutes and poured into water. After stirring for 30 minutes, the mixture was extracted with ether and the ether phase was washed with water, dried over magnesium sulfate and distilled to dryness in vacuo. The residue was dissolved in 30 cc of refluxing isopropyl ether, filtered and concentrated to 20 cc. The mixture was iced for 30 minutes and filtered. The precipitate was washed with iced isopropyl ether and dried in vacuo to obtain 3.18 gm of 3-chloro-9-methoxycarbonyl-10-methyl-acridane which was used as is for the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([NH:43][C:44]([C@H:46]3[CH2:50][CH2:49][CH2:48][N:47]3C(OCC3C4C=CC=CC=4C4C3=CC=CC=4)=O)=[O:45])=[CH:39][CH:38]=2)[CH2:9][C:10]2[CH:35]=[CH:34][C:13]3[NH:14][C:15]([C@@H:17]4[CH2:21][CH2:20][CH2:19][N:18]4[C:22](=[O:33])[C@@H:23]([NH:28][C:29]([O:31][CH3:32])=[O:30])[C:24]([OH:27])([CH3:26])[CH3:25])=[N:16][C:12]=3[CH:11]=2)=[CH:4][CH:3]=1.C(NCC)C>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:9][C:10]2[CH:35]=[CH:34][C:13]3[NH:14][C:15]([C@@H:17]4[CH2:21][CH2:20][CH2:19][N:18]4[C:22](=[O:33])[C@@H:23]([NH:28][C:29](=[O:30])[O:31][CH3:32])[C:24]([OH:27])([CH3:25])[CH3:26])=[N:16][C:12]=3[CH:11]=2)[CH2:36][C:37]2[CH:42]=[CH:41][C:40]([NH:43][C:44]([C@H:46]3[CH2:50][CH2:49][CH2:48][NH:47]3)=[O:45])=[CH:39][CH:38]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2cc(CN(Cc3ccc(NC(=O)[C@H]4CCCN4C(=O)OCC4c5ccccc5-c5ccccc54)cc3)c3ccc(F)cc3)ccc2[nH]1)C(C)(C)O
Solvent: CC#N
Solvent: CCNCC
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2cc(CN(Cc3ccc(NC(=O)[C@H]4CCCN4)cc3)c3ccc(F)cc3)ccc2[nH]1)C(C)(C)O

Procedure:
The product from Example 99G (0.115 g, 0.127 mmol) was dissolved in acetonitrile (2 mL) at ambient temperature and treated with diethylamine (1 mL) for 1 hour. The solution was concentrated to dryness to give the crude title compound.
Reaction SMILES: Cl.[CH2:2]([NH2:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[P:15](Cl)([Cl:18])([Cl:17])=[O:16].Cl>>[CH2:2]([NH:14][P:15]([Cl:18])([Cl:17])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCCCCCCCCN
Agent: Cl
Product: CCCCCCCCCCCCNP(=O)(Cl)Cl
Reaction time: 5 h

Procedure:
n-Dodecylamine hydrochloride (44.4 g, 0.2 mol) and phosphorus oxychloride (91.4 mL, 1.0 mol) were reacted under nitrogen. A clear solution formed within 30 minutes, and the evolution of hydrogen chloride was observed. Heating at reflux was continued for 5 hours. Excess phosphorus oxychloride was removed by distillation in vacuum (40 to 5 torr, 24° to 50° C.) forming N-(n-dodecyl)phosphoramidic dichloride as a viscous liquid. The following spectroscopic data were obtained from the liquid:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: BrCCc1ccccc1
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)ccc1OCCc1ccccc1
Temperature: 25 °C
Reaction time: 38 h

Procedure:
66.02 g of 5-bromosalicylaldehyde was dissolved in 260 ml of N,N-dimethylformamide. Then 113.35 g of anhydrous potassium carbonate and 111.71 ml of (2-bromoethyl)benzene were added thereto and the resulting mixture was stirred at room temperature for 38 hours. After evaporation of the solvent under reduced pressure, ethyl acetate and water were added to the residue and the mixture was separated. The organic layer was collected and dried over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, the residue was recrystallized from isopropanol to give 82.62 g of 5-bromo-2-(2-phenylethoxy)benzaldehyde. m.p. 79°-80° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([CH3:12])[CH:3]=1.[NH2:13][C:14]1[C:15]([CH3:21])=[N:16][N:17]([CH3:20])[C:18]=1[CH3:19]>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:13][C:14]2[C:15]([CH3:21])=[N:16][N:17]([CH3:20])[C:18]=2[CH3:19])(=[O:10])=[O:9])=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(Br)ccc1S(=O)(=O)Cl
Reactant: Cc1nn(C)c(C)c1N
Solvent: c1ccncc1
Product: Cc1cc(Br)ccc1S(=O)(=O)Nc1c(C)nn(C)c1C
Yield: 93.3 %

Procedure:
Prepared from 4-bromo-2-methylbenzenesulfonyl chloride (0.736 g, 2.7 mmol) and 4-amino-1,3,5-trimethyl-1H-pyrazole (0.35 g, 2.8 mmol) in pyridine (4.5 ml) according to the method of intermediate 1, to give the title compound as an orange solid (906 m, 2.52 mmol, 93%). δH (D-6 DMSO, 300K) 9.24 (1H, s), 7.70 (1H, d, J=1.5 Hz), 7.54 (1H, dd, J=8.5 Hz 1.5 Hz), 7.48 (1H, d 8.5 Hz), 3.55 (3H, s), 2.57 (3H, s), 1.82 (3H, s), 1.59 (3H, s). m/z (ES+, 70V) 360.0 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]1>>[Br:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][CH2:24][C@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:22]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cccnc1
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Yield: 41 %

Procedure:
(S)-tert-Butyl 1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (63 mg, 41%) was prepared as described in Example 1, Step J, using N-(5-bromo-4-fluoro-1H-pyrrolo[2, 3-1)]pyridin-3-yl)nicotinamide (100 mg, 0.298 mmol, Example 1, Step I) and substituting (S)-tert-butyl piperidin-3-ylcarbamate (179 mg, 0.895 mmol) for tert-butyl piperidin-3-ylcarbamate.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C[O-].[Na+].[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH2:28]Cl)[C:23]=1[CH3:30])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CO.C(OCC)(=O)C>[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH2:28][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)[C:23]=1[CH3:30])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CCCCCCCOc1ccnc(CCl)c1C
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Yield: 38.7 %

Procedure:
To a liquid prepared by dissolving with stirring 8.7 g (0.058 mol, 0.95 eq.) of 2-mercaptobenzimidazole and 68.2 g (0.354 mol, 5.8 eq.) of a 28% sodium methoxide solution in 400 mL of methanol, a liquid prepared by dissolving the whole amount of 4-heptyloxy-2-chloromethyl-3-methylpyridine in 210 mL of methanol was added at 28° C. Subsequently, the mixture was heated to reflux for one hour and cooled, and then methanol was solid dried under reduced pressure. A yellow brown oily residue resulting therefrom was dissolved in 250 mL of ethyl acetate, and then the organic layer was washed with 100 mL of water. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated to dryness. The resulting residue was purified by silica gel column chromatography, and then was concentrated to dryness, to obtain 17.8 g of an orange-colored oily matter. The orange-colored oily matter was recrystallized from ethyl acetate (7 vol.), to obtain 8.7 g of colorless crystals (HPLC: 99.0 Area %, yield 38.7%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[C:22]([F:23])=[CH:21][C:15]3[NH:16][C:17](=[O:20])[CH2:18][O:19][C:14]=3[CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].[CH2:24](Br)[C:25]#[CH:26]>CS(C)=O.O>[Cl:1][C:2]1[C:3]([C:12]2[C:22]([F:23])=[CH:21][C:15]3[N:16]([CH2:26][C:25]#[CH:24])[C:17](=[O:20])[CH2:18][O:19][C:14]=3[CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:9])([F:8])[F:10]
Reactant: Cn1nc(-c2cc3c(cc2F)NC(=O)CO3)c(Cl)c1C(F)(F)F
Reactant: C#CCBr
Solvent: O
Solvent: CS(C)=O
Product: C#CCN1C(=O)COc2cc(-c3nn(C)c(C(F)(F)F)c3Cl)c(F)cc21
Temperature: 45 °C
Reaction time: 16 h
Yield: 90.4 %

Procedure:
At 25° C., 2.7 g (7.7 mmole) the product of step A, 1.1 g (8.0 mmole) KCO3 and 0.9 mL (8.0 mmole) 80% propargyl bromide were slurried in 25 mL DMSO. The mixture was stirred at 45° C. for 16 hours. The mixture was cooled, diluted with 100 mL cold water and extracted four times with ethyl acetate. The ethyl acetate extracts were washed with brine, dried over anhydrous MgSO4 and stripped in vacuo. The residue was purified chromatographically using methylene chloride as the eluent to give 2.7 g (90%) of 7-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-6-fluoro-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one as a white solid, mp 184° C.