Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([NH:10][C@@H:11]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][N:20]=2)[C:15]([CH2:22][C:23]([O:25]C)=[O:24])=[CH:14][CH2:13][C@H:12]1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[F:34])=[O:9])([CH3:6])([CH3:5])[CH3:4]>O1CCCC1.CO>[C:3]([O:7][C:8]([NH:10][C@@H:11]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][N:20]=2)[C:15]([CH2:22][C:23]([OH:25])=[O:24])=[CH:14][CH2:13][C@H:12]1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[F:34])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)CC1=CC[C@@H](c2cccc(F)c2F)[C@H](NC(=O)OC(C)(C)C)c2nccnc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1c2nccnc2C(CC(=O)O)=CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a 50 mL round-bottomed flask was dissolved methyl 2-((5S,6S)-5-(tert-butoxycarbonylamino)-6-(2,3-difluorophenyl)-6,7-dihydro-5H-cyclohepta[b]pyrazin-9-yl)acetate (5) in 4:1 tetrahydrofuran/methanol (2.5 mL). Lithium hydroxide (0.588 mL, 0.588 mmol) was added and the mixture was stirred at rt for 16 h. LCMS indicated complete conversion. The mixture was concentrated and further dried under a high vacuum to remove water to give a slightly orange solid, which was directly carried on to the next step.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Br[C@H:7]([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:8]([OH:10])=[O:9].C1(NC2CCCCC2)CCCCC1.CCOCC>C(#N)C>[C:1]([S:3][C@@H:7]([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:8]([OH:10])=[O:9])(=[O:4])[CH3:2]
Reactant: O=C(O)[C@H](Br)CC1CCCCC1
Reactant: CC([O-])=S
Agent: C1CCC(NC2CCCCC2)CC1
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: CC(=O)S[C@@H](CC1CCCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred slurry of potassium thioacetate (1.07 g., 9.36 mmol.) in dry acetonitrile (15 ml.) at 0° C. under argon was added a solution of (R)-2-bromo-3-cyclohexylpropanoic acid (2.20 g., 9.36 mmol.) in acetonitrile (3 ml.) over 10 minutes. The reaction was warmed to room temperature and stirred 16 hours. The resulting slurry was filtered and evaporated. The residue was redissolved in ethyl acetate, washed once with 5% potassium bisulfate solution, dried (sodium sulfate) and evaporated. The oily yellow residue (2.21 g.) was dissolved in ether and treated with a solution of dicyclohexylamine (1.8 ml., 9.0 mmol.) in 5 ml. of ether. Scratching the flask surface with a glass rod provided 2.38 g. of white crystalline title product; m.p. 159°-161° C., [α]D =-41.2° (c=1.0, chloroform).
Reaction SMILES: [Mg].[CH3:2]I.[CH3:4][C:5](O)=O.[CH:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2.[Cl-].[NH4+]>CCOCC>[CH:5]([C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)([CH3:4])[CH3:2]
Reactant: CI
Reactant: C1C2CC3CC1CC(C2)C3
Reactant: CC(=O)O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)C12CC3CC(CC(C3)C1)C2
Yield: 93 %

Procedure:
Introduce 0.5 mol of magnesium chips into 50 ml of absolute ether, and drop 0.5 mol of methyl iodide into the solution under moisture-free conditions until the ether boils. Subsequently, heat in a water bath until the magnesium has completely dissolved. Into this solution at room temperature drop 0.2 mol of adamantane methyl carboxylate in absolute ether. Then heat to reflux for 3 hours. After cooling, hydrolize with ice and mix with ammonium chloride solution until the precipitate has dissolved. Separate the ether phase, wash the aqueous phase with 2 portions of ether, and wash the combined organic phases with sodium bicarbonate solution. Then dry and evaporate to dryness under vacuum. (Yield: 93%).
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][N:4]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:3]1.S1C=CC=[CH:22]1.[H][H]>CO.[Pd]>[OH:1][C@H:2]1[C@H:7]([N:8]([CH3:22])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][N:4]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:3]1
Reactant: CCOC(=O)N1CC[C@@H](NCc2ccccc2)[C@H](O)C1
Reactant: c1ccsc1
Reactant: [H][H]
Agent: [Pd]
Agent: *CO*
Solvent: CO
Product: CCOC(=O)N1CC[C@@H](N(C)Cc2ccccc2)[C@H](O)C1
Yield: 79.9 %

Procedure:
(a-2) A mixture of 40 parts of ethyl trans-3-hydroxy-4-[(phenylmethyl)-amino]-1-piperidinecarboxylate, 15 parts of poly(oxymethylene), 2 parts of a solution of thiophene in methanol and 400 parts of methanol was hydrogenated at normal pressure and at room temperature with 4 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in trichloromethane. The organic layer was washed successively with a dilute ammonium hydroxide solution and water, dried, filtered and evaporated in vacuo. The residue was crystallized from 80 parts of acetonitrile The product was filtered off and dried, yielding 32.7 parts (79.9%) of ethyl trans-3-hydroxy-4-[methyl(phenylmethyl)amino]-1-piperidinecarboxylate (interm. 6).
Reaction SMILES: [SH2]=N.[CH2:3]([NH:10][C:11](C1C=CC=CC=1C(O)=O)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.CC(C)=O.[Cl:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1>O.CC(C)=O.C(N(CC)CC)C>[Cl:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:11]([NH:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:12])=[CH:30][CH:29]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(O)c1ccccc1C(=O)NCc1ccccc1
Agent: N=[SH2]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NCc1ccccc1)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.5 %

Procedure:
6.32 g benzylcarbamoyl-benzoic acid sulfimide was suspended in 40 ml of a 1:1 mixture of water and aceton. 2.55 g p-chloroaniline was added to the suspension, then a solution of 2.8 ml triethylamine with 10 ml of a 1:1 water-aceton mixture was added dropwise at ambient temperature during a half hour. The reaction mixture was stirred for 5 hours at room temperature, the obtained product was evacuated, washed with a 1:1 mixture of water and aceton and dried. 4.3 g 1-(4-chlorophenyl)-3-benzylurea was obtained, which melted at 206°-208° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=O)[CH3:6].[CH:9]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[OH2:21]>ClCCl>[CH2:18]1[CH2:17][CH2:16][CH:15]([CH2:9][C:14]([C:13]2[CH:12]=[CH:11][CH:10]=[CH:6][CH:5]=2)=[O:21])[CH2:20][CH2:19]1
Reactant: O
Reactant: c1ccc(C2CCCCC2)cc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CC1CCCCC1)c1ccccc1
Temperature: 0 °C

Procedure:
There was introduced to a 1 liter 3-neck flask under nitrogen atmosphere 41.7 g (0.312 Mol) of aluminum chloride, followed by 250 ml of dichloromethane. The mixture was cooled in an ice bath and 39.3 g (0.5 Mol) of acetyl chloride was added dropwise. This was followed by dropwise addition of 40.0 g of cyclohexylbenzene in 100 ml of dichloromethane. Fifteen minutes after addition was complete, 25 g of ice and then 25 ml of water were added to the reaction mixture, whereupon a thick white solid formed. The dichloromethane was decanted and washed with water, then three times with 30 ml of saturated saline solution, after which it was dried overnight over magnesium sulfate. After filtration, the remaining dichloromethane was evaporated, and the residue crystallized on cooling. The residue was recrystallized from petroleum ether to give 28.1 g. of product, m.p. 65°-67° C. Analysis:
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:29])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][CH3:28].[F:30][C:31]([F:55])([C:51]([F:54])([F:53])[F:52])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]CC1C=C(C)C=CC=1S([O-])(=O)=O.[C:56](=O)(O)[O-].[Na+]>CN(C)C=O>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:29])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH3:56])[CH2:28][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][C:31]([F:30])([F:55])[C:51]([F:52])([F:53])[F:54]
Reactant: O=C([O-])O
Reactant: CNCCCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Reactant: Cc1ccc(S(=O)(=O)[O-])c(CCCCCCCCC(F)(F)C(F)(F)F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCCCCCCCC(F)(F)C(F)(F)F)CCCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F

Procedure:
A solution of 381 mg of 11β-fluoro-3-hydroxy-7α-[6-(methyl-amino)-hexyl)-estra-1,3,5(10)-trien-17-one in 5 ml of dimethylformamide is stirred with 180 mg of 9,9,10,10,10-pentafluoro-decyltosylate for 2 hours at a bath temperature of 100° C. Then, it is added to semi-saturated sodium bicarbonate solution, extracted three times with methylene chloride, dried on magnesium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane/methanol/triethylamine. 121 mg of 11β-fluoro-3-hydroxy-7α-{6-[methyl-(9,9,10,10,10-pentafluoro-decyl)-amino]-hexyl}-estra-1,3,5(10)-trien-17-one is obtained as a foam, [α]D=+59° (c=1.0 in chloroform).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+:12]([O-:15])(O)=[O:13].[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([NH:9][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:11][C:10]=1[N+:12]([O-:15])=[O:13])(=[O:18])[CH3:17]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Yield: 90 %

Procedure:
4-t-Butylaniline (5 g, 33.58 mmol) in acetic anhydride (25 ml) was stirred at ambient temperature for 0.5 h. The mixture was cooled in an ice-bath and nitric acid (6 ml, 65%) was added at such a rate that the temperature did not exceed 18° C. Following the addition the mixture was poured on ice (200 g). The precipitate was filtered off, washed thoroughly with water and dried to yield N-acetyl-4-t-butyl-2-nitroaniline (7.15 g, 90%). Mp. 109°-110° C.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([NH:11][C:12]([C:14]2[C:15]3[CH:16]=[CH:17][N:18]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:19]=3[CH:20]=[C:21](Br)[CH:22]=2)=[O:13])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[CH3:31][S:32]([O-:34])=[O:33].[Na+]>CS(C)=O.[I+].[Cu+]>[CH3:31][S:32]([C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([NH:11][C:12]([C:14]2[C:15]3[CH:16]=[CH:17][N:18]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:19]=3[CH:20]=[C:21]([S:32]([CH3:31])(=[O:34])=[O:33])[CH:22]=2)=[O:13])[CH2:9][CH3:10])=[CH:4][CH:3]=1)(=[O:34])=[O:33]
Reactant: CC[C@H](NC(=O)c1cc(Br)cc2c1ccn2-c1ccc(F)cc1)c1ccc(Br)nc1
Reactant: CS(=O)[O-]
Agent: [Cu+]
Agent: [I+]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC[C@H](NC(=O)c1cc(S(C)(=O)=O)cc2c1ccn2-c1ccc(F)cc1)c1ccc(S(C)(=O)=O)nc1
Temperature: 130 °C
Reaction time: 0.67 h

Procedure:
A microwave tube is charged with 6-bromo-1-(4-fluorophenyl)-1H-indole-4-carboxylic acid [(S)-1-(6-bromopyridin-3-yl)-propyl]-amide (90.0 mg, 0.170 mmol, prepared as described in Example 5), copper (I) iodine (143 mg, 0.75 mmol) and sodium methanesulfinate (77 mg, 0.75 mmol) in DMSO (20 mL). The tube is capped and the solution is degassed with argon for 3 minutes. The mixture is warmed in a microwave reactor at 130° C. After 40 minutes, the reaction is diluted with saturated aqueous ammonium chloride (100 mL), saturated aqueous sodium bicarbonate (50 mL) and extracted with EtOAc. The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture is purified by reversed-phase HPLC to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:12][C:13](O)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]([NH:27][NH2:28])=O)=[CH:24][C:19]=2[NH:18][CH:17]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1.O=P(Cl)(Cl)Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:12][C:13]2[S:38][C:25]([C:23]3[CH:22]=[CH:21][C:20]4[NH:16][CH:17]=[N:18][C:19]=4[CH:24]=3)=[N:27][N:28]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(SCC(=O)O)cc1OC
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(SCc2nnc(-c3ccc4[nH]cnc4c3)s2)cc1OC

Procedure:
The compound was synthesized starting from (3,4-dimethoxyphenylthio)acetic acid (229 mg; 1 mmol), benzimidazol-5-carbohydrazide (176 mg; 1 mmol), Lawesson's reagent (606 mg; 1.5 mmol) and POCl3 (0.137 ml; 1.5 mmol) as described in method 3; yield: 0.042 g (10.9%);
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]3[O:31][CH:30]=[CH:29][C:7]=3[N:8]=[C:9]([NH:11][C:12]3[CH:20]=[C:19]4[C:15]([C:16](C)=[N:17][N:18]4C4CCCCO4)=[C:14](F)[CH:13]=3)[N:10]=2)[CH2:3][CH2:2]1.Cl.O1CCOC[CH2:34]1>>[CH:1]1([NH:4][C:5]2[C:6]3[O:31][CH:30]=[CH:29][C:7]=3[N:8]=[C:9]([NH:11][C:12]3[CH:20]=[C:19]4[C:15]([CH:16]=[N:17][NH:18]4)=[C:14]([CH3:34])[CH:13]=3)[N:10]=2)[CH2:3][CH2:2]1
Reactant: C1COCCO1
Reactant: Cc1nn(C2CCCCO2)c2cc(Nc3nc(NC4CC4)c4occc4n3)cc(F)c12
Agent: Cl
Product: Cc1cc(Nc2nc(NC3CC3)c3occc3n2)cc2[nH]ncc12
Temperature: 50 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
A flask was charged with N4-cyclopropyl-N2-(4-fluoro-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)furo[3,2-d]pyrimidine-2,4-diamine (0.19 g, 0.45 mmol, prepared using B from Preparation #A.1 with Preparation #AN.1) and 4 M HCl in 1,4-dioxane (2 mL). The mixture was stirred at about 50° C. for about 2 h, cooled to rt, concentrated under reduced pressure and purified by reverse phase HPLC (Table 2, Method o) to give N4-cyclopropyl-N2-(4-methyl-1H-indazol-6-yl)furo[3,2-d]pyrimidine-2,4-diamine (0.030, 20%): LC/MS (Table 2, Method h) Rt=1.85 min; MS m/z: 321 (M+H)+. Syk IC50=A
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[H-].[Na+].Cl[C:19]1[CH:24]=[C:23]([N:25]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:22]2[N:42]=[CH:43][C:44]([C:45]3[CH:46]=[N:47][C:48]4[C:53]([CH:54]=3)=[CH:52][CH:51]=[CH:50][CH:49]=4)=[C:21]2[N:20]=1.[Br:55]N1C(=O)CCC1=O>C1COCC1.C(OCC)(=O)C>[CH3:31][Si:30]([CH3:33])([CH3:32])[CH2:29][CH2:28][O:27][CH2:26][N:25]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:23]1[N:22]2[N:42]=[CH:43][C:44]([C:45]3[CH:46]=[N:47][C:48]4[C:53]([CH:54]=3)=[CH:52][CH:51]=[CH:50][CH:49]=4)=[C:21]2[N:20]=[C:19]([O:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[C:24]=1[Br:55]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: O=C1CCC(=O)N1Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2nc3c(-c4cnc5ccccc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
To a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (311 mg, 1.44 mmol) and sodium hydride (60% in mineral oil, 58 mg, 1.44 mmol) in THF (2 ml) under argon at room temperature was added 5-chloro-3-(quinolin-3-yl)-N,N-bis((2(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (400 mg, 0.72 mmol). The mixture was heated at 100° C. for 30 min in microwave. Ethyl acetate (50 ml) was added and the mixture was washed with brine and water, dried over Na2SO4, and concentrated in vacuo. The crude product was dissolved in acetonitrile, followed by the addition of N-bromosuccinimide (193 mg, 1.08 mmol). The reaction mixture was stirred at room temperature for 2 h, concentrated in vacuo and purified via silica gel chromatography (10% to 50% ethyl acetate in hexanes gradient) to yield the title compound (0.56 g, 95% yield). LC-MS: 813 [M+H].
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]5[O:38][CH:37]=[N:36][CH:35]=5)[CH:29]=4)[N:22]=3)=[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N:14]3[N:13]=2)[CH:7]=1)=O.[Li+].[OH-].C1COCC1>O>[NH2:5][C:6]1[CH:7]=[C:8]([C:12]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]5[O:38][CH:37]=[N:36][CH:35]=5)[CH:29]=4)[N:22]=3)=[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N:14]3[N:13]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1
Yield: 78.6 %

Procedure:
A solution of 2,2,2-trifluoro-N-{3-[3-(2-{[3-(1,3-oxazol-5-yl)phenyl]amino}-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}acetamide (0.89 g, 0.002 mols) and 1M LiOH (8.22 mL, 0.008 mols) in 10:1 THF:water (20 mL) was heated at 60° C. for 5 h. The reaction was washed with brine (25 mL), organic layer separated, aqueous layer extracted with EtOAc (25 mL), organic layers combined, filtered through a cotton plug, and solvent removed by rotary evaporation. The crude product was purified by column chromatography (5%-75% EtOAc in hexanes then 100% EtOAc) to provide the aniline (0.70 g, 96%) as a pale yellow foam. ES-LC/MS m/z=446 [M+H]+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[C:15]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=2[Cl:24])=[N:14][CH:13]=[C:12]([NH2:25])[N:11]=1>CS(C)=O.O>[Br:1][C:13]1[N:14]=[C:15]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=2[Cl:24])[C:10]([NH2:9])=[N:11][C:12]=1[NH2:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cnc(-c2cc(Cl)cc(Cl)c2Cl)c(N)n1
Solvent: CS(C)=O
Solvent: O
Product: Nc1nc(N)c(-c2cc(Cl)cc(Cl)c2Cl)nc1Br
Temperature: 15 °C
Reaction time: 1 h

Procedure:
N-Bromosuccinimide (0.194 g, 1.09×10−3 mole) was added over 20 min to a mixture of 2,6-Diamino-3-(2,3,5-trichlorophenyl)pyrazine (0.3 g, 1.04×10−3 mole) in dimethylsulfoxide (10 ml) and water (0.25 ml) below 15° C. The resulting reaction mixture was stirred at 15° C. for 1 hr, poured onto ice water (150 ml) and extracted with ethyl acetate (2×75 ml). The extract was then washed with 2 M sodium carbonate solution (50 ml) and water (100 ml), dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated in vacuo. The residue was purified by ‘flash chromatography’ using 5-13% ethyl acetate in cyclohexane as the eluent. Yield 0.183 g (48%), M.p. 222-224° C.
Reaction SMILES: [CH2:1](O)[CH3:2].[CH2:4]([NH2:16])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>O>[CH2:4]([NH2:16])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:1][CH3:2]
Reactant: CCCCCCCCCCCCN
Reactant: CCO
Solvent: O
Product: CCCCCCCCCCCCCCN

Procedure:
In application Ser. No. 355,979, filed Dec. 14, 1994, describing the assembly of silica molecular sieves in 50:50 (v/v) water:ethanol, it was shown that certain alkylamine surfactants (e.g., dodecylamine) gave derivatives with high textural mesoporosity whereas others afforded relatively low textural pore volumes (e.g., tetradecylamine (Tanev, P.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.[C:16]1([C:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[S:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>ClCCCl>[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([C:23]2[S:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:22]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:12])=[CH:9][CH:8]=1
Reactant: c1ccc(-c2csc3ccccc23)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2sc3ccccc3c2-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a stirred slurry of 14.6 g. (0.11 mole) of aluminum chloride in 1,2-dichloroethane maintained at 0° C. were added 18.7 g. (0.11 mole) of 4-methoxybenzoyl chloride. The mixture was stirred at 0° C. for 10 minutes, and 21.0 g. (0.1 mole) of 3-phenylbenzothiophene in 1,2-dichloroethane were added. The mixture was stirred for two hours, the temperature being maintained at 0° C. The reaction mixture then was poured into a mixture of hydrochloric acid in ice. The resulting mixture was extracted with ether. The ether extract was washed with water, dilute aqueous sodium bicarbonate, and water. The ether layer was dried over magnesium sulfate, and the ether solvent was evaporated. The residue was dissolved in ethanol. The ethanol solution was filtered and maintained at 5° C. for three days. The resulting crystals were filtered and washed with ethanol and petroleum ether to obtain 23.7 g. (70 percent) of the title compound, m.p. 94°-95° C. The nmr spectrum was consistent with the structure of the title compound.
Reaction SMILES: Br[CH2:2][CH:3]=[CH2:4].[N:5]1([C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.CCN(C(C)C)C(C)C>ClCCl>[CH2:2]([N:8]1[CH2:9][CH2:10][CH2:11][N:5]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][CH:22]=2)[CH2:6][CH2:7]1)[CH:3]=[CH2:4]
Reactant: CCOC(=O)c1ccc(N2CCCNCC2)cc1
Reactant: C=CCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCN1CCCN(c2ccc(C(=O)OCC)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.5 %

Procedure:
3-Bromoprop-1-ene (0.433 mL, 5.00 mmol) was added to a stirred solution of ethyl 4-(1,4-diazepan-1-yl)benzoate (1.242 g, 5 mmol) and DIPEA (2.183 mL, 12.50 mmol) in dichloromethane (20 mL). The reaction mixture was stirred under nitrogen at room temperature for 24 h. This was diluted with dichloromethane (20 mL), washed with water (2×25 ml) and saturated sodium chloride solution (20 ml), dried over MgSO4, filtered and evaporated to dryness. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 5% 2.5M ammonia/MeOH in DCM. Pure fractions were evaporated to dryness to afford ethyl 4-(4-allyl-1,4-diazepan-1-yl)benzoate (0.700 g, 48.5%) as a yellow oil.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:23]=[C:22]([C:24]([OH:26])=O)[O:21][N:20]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[C:28]1([S:34]([NH:37][C@@H:38]([CH2:43][NH2:44])[C:39]([O:41][CH3:42])=[O:40])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)CCl.CN(C=O)C>[CH3:42][O:41][C:39](=[O:40])[C@@H:38]([NH:37][S:34]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:36])=[O:35])[CH2:43][NH:44][C:24]([C:22]1[O:21][N:20]=[C:19]([O:18][CH2:17][CH2:16][CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]2)[CH:23]=1)=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCCOc2cc(C(=O)O)on2)CC1
Reactant: COC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CNC(=O)c1cc(OCCCCC2CCN(C(=O)OC(C)(C)C)CC2)no1)NS(=O)(=O)c1ccccc1
Reaction time: 72 h
Yield: 72.3 %

Procedure:
A stirred mixture of 4-5 (147 mg, 0.4 mmol), 2-9a (149 mg, 0.4 mmol), HOBT (61 mg, 0.4 mmol), DIEA (215 μL, 1.2 mmol), and DMF (6 mL) at -15° C. was treated with EDC (77 mg, 0.4 mL) followed by removal of the cooling bath. After 72 h, the reaction mixture was diluted with EtOAc and then washed with 1M NaHSO4 and brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 10% acetone/CH2Cl2) gave 4-6 (176 mg) as a viscous oil. Rf 0.24 (silica, 10% acetone/CH2Cl2).