Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)(Cl)=O.[NH4+:18].[OH-]>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH2:18])=[O:8]
Reactant: [NH4+]
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
5-Fluoro-2-nitro-benzoic acid (17.9 g, 96.8 mmol) was heated in thionyl chloride (35 mL, 5 mol eq.) for two hours at 85° C. (oil bath temperature). The reaction mixture was evaporated, taken up and evaporated twice with dry toluene. The resulting acid chloride was dissolved in dry dioxane (180 mL) and added to an ice-water bath cooled solution of 33% NH4OH (23.5 mL, 2 mol eq.) in dioxane (180 mL). The reaction was allowed to warm up gradually to room temperature and then evaporated to dryness. The crystalline residue was triturated in water (50 mL), collected by filtration, washed with a small amount of water and dried in vacuo at 80° C. to constant weight (17.56 g, 98.5%).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:18]([NH:20][C@H:21]([C:32]([NH:34]N)=[O:33])[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:19])[CH2:12][C:13]1[N:17]=[CH:16][NH:15][CH:14]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6].Cl.[O:37]1CCOCC1.N[C@H:44]([C:47]([NH:49][C@H:50]([C:59]([NH:61][C@@H:62]([C:69]([NH:71][C@H:72]([C:77]([NH:79][C@H:80]([C:88]([N:90]1[CH2:99][CH2:98][CH2:97][C@H:91]1[C:92]([NH:94][CH2:95][CH3:96])=[O:93])=[O:89])[CH2:81][CH2:82][CH2:83][NH:84][C:85](=[NH:87])[NH2:86])=[O:78])[CH2:73][CH:74]([CH3:76])[CH3:75])=[O:70])[CH2:63][O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:60])[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([OH:58])=[CH:54][CH:53]=1)=[O:48])[CH2:45][OH:46].Cl.C(N1CCOCC1)C>CN(C)C=O.O1CCOCC1>[NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:18]([NH:20][C@H:21]([C:32]([NH:34][C@H:44]([C:47]([NH:49][C@H:50]([C:59]([NH:61][C@@H:62]([C:69]([NH:71][C@H:72]([C:77]([NH:79][C@H:80]([C:88]([N:90]1[CH2:99][CH2:98][CH2:97][C@H:91]1[C:92]([NH:94][CH2:95][CH3:96])=[O:93])=[O:89])[CH2:81][CH2:82][CH2:83][NH:84][C:85](=[NH:86])[NH2:87])=[O:78])[CH2:73][CH:74]([CH3:76])[CH3:75])=[O:70])[CH2:63][O:64][C:65]([CH3:67])([CH3:68])[CH3:66])=[O:60])[CH2:51][C:52]1[CH:53]=[CH:54][C:55]([OH:58])=[CH:56][CH:57]=1)=[O:48])[CH2:45][OH:46])=[O:33])[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:19])[CH2:12][C:13]1[N:17]=[CH:16][NH:15][CH:14]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6].[CH3:2][C:3]([CH2:4][C:5]([OH:6])=[O:7])=[O:37]
Reactant: NNC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](N)CCC(=O)O
Reactant: C1COCCO1
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)CO
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)CC(=O)O
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](N)CCC(=O)O
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
To a solution of 500 mg of Glu-His-Trp-NH-NH2 in 6 ml of dimethyl formamide were added, at -30° C, 0.66 ml of a 6.05 N HCl/dioxane solution and 1.2 ml of a 10% tert.-butyl nitrile solution in absolute dioxane. The solution was stirred for 20 minutes at -10° C and 877.8 mg of crude H-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-NH-C2H5 . 2 HCl and 0.78 ml of N-ethyl morpholine were added at -40° C. The mixture was allowed to stand overnight at 4° C. It was concentrated and the residue was triturated with ether. The substance was dissolved in water and chromatographed over Dowex(R) 1×2 (acetate form). The eluate was concentrated and purified over a carboxymethyl cellulose column (90 × 1.5 cm), that was equilibrated with 0.002 m NH4 -acetate solution. The substance was added as a solution in a 0.002 m NH4 -acetate solution. It was eluted with a 0.002 m NH4 -acetate solution in which the gradient of a 0.1 m NH4 -acetate solution was established (mixed volume 250 ml).
Reaction SMILES: [CH3:1][O:2][C:3]1[C@@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[CH2:7][N:8]=1.[Li][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:19][O:20][C:21]1[CH:22]([CH:29]([CH3:31])[CH3:30])[N:23]=[C:24]([O:27][CH3:28])[CH2:25][N:26]=1>C1COCC1>[CH3:1][O:2][C:3]1[C@@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[C@H:7]([CH2:18][C:17]#[C:16][CH2:15][C@H:25]2[C:24]([O:27][CH3:28])=[N:23][C@H:22]([CH:29]([CH3:31])[CH3:30])[C:21]([O:20][CH3:19])=[N:26]2)[N:8]=1
Reactant: [Li]CCCC
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Reactant: COC1=NC(C(C)C)C(OC)=NC1
Solvent: C1CCOC1
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1CC#CC[C@@H]1N=C(OC)[C@@H](C(C)C)N=C1OC
Temperature: -78 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
(2R)-(-)-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine 2.76 g (15mmol) was dissolved in 100 ml dry THF and cooled to -78° C., then 9.5 ml of a 1.6M solution BuLi (15 mmol) was added dropwise with stirring. After 1 hour 0.92 g (7.5 mmol) of 1,4-dichloro-2,3-butyne was introduced slowly. TLC and gas chromatography (GC) of the reaction mixture 1 hour later showed substantial amounts of unreacted 2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine and the monoalkylated product. The reaction was allowed to continue overnight and reach ambient temperature gradually. THF was evaporated off under reduced pressure and the residue partitioned between ether and water. The water phase was extracted twice with ether, dried (MgSO4) and evaporated. Kugelrohr distillation of the reaction mixture to give 2.3g (77%) pure product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][N:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12])[CH:5]=[CH:6][CH:7]=1.FC1C=C(C=CC=1)N.C(CC(OC1CCCCC1)=O)#N.[OH2:35].[NH2:36]N>C(O)C>[NH2:14][C:13]1[C:10](=[N:9][NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[C:11](=[O:35])[NH:12][N:36]=1
Reactant: NN
Reactant: N#CC(C#N)=NNc1cccc(F)c1
Reactant: O
Agent: N#CCC(=O)OC1CCCCC1
Agent: Nc1cccc(F)c1
Solvent: CCO
Product: NC1=NNC(=O)C1=NNc1cccc(F)c1
Temperature: 25 °C

Procedure:
This compound was prepared using 2-[(3-fluorophenyl)hydrazono]malononitrile (145 mg, 0.5 mmole), which was derived from 3-fluoroaniline (111 mg, 1 mmole)) and cyclohexyl cyanoacetate (217 mg, 1.3 mmole) as described in Example 8, and hydrazine hydrate (25 mg, 0.5 mmole) in ethanol. Solids had not formed after heating the reaction at 80° C. for 40 minutes, however, analysis of the reaction solution by TLC indicated that no starting material remained. The solution was allowed to cool to room temperature and concentrated. The product was obtained after filtration as a yellow solid (73 mg). 1H NMR (ppm, DMSO-d6): 5.95 (br., s, 2H), 6.90 (m, 1H), 7.20-7.65 (m, 3H), 10.56 (br., s, 1H) 12.77 (br., s, 1H).
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH3:18])=[CH:12][CH:11]=1)[C:6](=[N:8][OH:9])[CH3:7])[CH3:2].[H-].[Na+].[CH3:28][O:29][C:30](=[O:43])[C:31]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41]Br)=[CH:32][O:33][CH3:34]>CN(C)C=O>[CH3:28][O:29][C:30](=[O:43])[C:31]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][O:9][N:8]=[C:6]([CH3:7])[C:5](=[N:4][O:3][CH2:1][CH3:2])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[CH3:18])=[CH:12][CH:11]=1)=[CH:32][O:33][CH3:34]
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Reactant: CCON=C(C(C)=NO)c1ccc(OC(C)c2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCON=C(C(C)=NOCc1ccccc1C(=COC)C(=O)OC)c1ccc(OC(C)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
7 g of 1-[4-(1-{4-chlorophenyl)-ethoxy}-phenyl]-1,2-propanedione-[ethyloxime]-2-oxime dissolved in 25 ml of N,N-dimethylformamide are added dropwise to a suspension of 0.9 g of sodium hydride (55% in oil) in 40 ml of N,N-dimethylformamide and the reaction mixture is then stirred for 10 minutes at room temperature. 5.5 g of 2-(bromomethyl)-α-(methoxymethylene)-phenylacetic acid methyl ester in 20 ml of N,N-dimethylformamide are then added dropwise and the reaction mixture is stirred for a further 1 hour at room temperature. The mixture is then rendered acidic with acetic acid and concentrated by evaporation in vacuo. The residue is dissolved in ethyl acetate and the solution is washed three times with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation in vacuo. Purification by flash chromatography (silica gel, ethyl acetate/hexane 1:3) yields the E isomer of the title compound having a melting point of 107-109° C. (compound 1-4.2).
Reaction SMILES: OC[C@H](NC(=O)[C@H](C)CCCC1C=CC=CC=1)C1C=CC=CC=1.[CH3:24][C@@H:25]([CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]([OH:28])=[O:27]>>[CH3:24][C@H:25]([CH2:29][CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]([OH:28])=[O:27]
Reactant: C[C@@H](CCCc1ccccc1)C(=O)O
Agent: C[C@H](CCCc1ccccc1)C(=O)N[C@@H](CO)c1ccccc1
Product: C[C@H](CCCc1ccccc1)C(=O)O

Procedure:
-(−)-2-Methyl-5-phenylpentanoic acid was prepared from 19mc(i) (30 g) in the same manner (S)-(+)-2-methyl-5-phenylpentanoic acid was prepared from 19mb(i) as described above. The residue was purified by silica gel chromatography. Elution with ethyl acetate-heptane-acetic acid (20:80:0.4 v/v/v) afforded the title compound (20.8 g) as a clear oil; TLC Rf 0.51 (solvent system: 30:70:1 v/v/v ethyl aceate-hepatane-acetic acid; HPLC retention time 24.46 min; Chiralpak IA 4.6×25 mm 5μ, at a wavelength of 208 nm 0.75 mL/min, 99:1:0.5 heptane: 2-propanol: acetic acid, chiral purity 99.32% (R), 0.68% (S); MS (ESI−) m/z 191.1 (M−H)−; 1H-NMR (CDCl3) δ 7.31-7.26 (m, 2H), 7.21-7.15 (m, 3H), 2.67-2.57 (m, 2H), 2.54-2.44 (m, 1H), 1.79-1.59 (m, 3H) 1.58-1.41 (m, 1H), 1.18 (d, J=6.96 Hz, 3H).
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-:17].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC>ClCCl>[Br:17][CH2:15][C:14]([C:11]1[CH:12]=[N:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:9][CH:10]=1)=[O:16]
Reactant: [Br-]
Reactant: CC(=O)c1cnc(Oc2ccccc2)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C(CBr)c1cnc(Oc2ccccc2)nc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 68.4 %

Procedure:
To a solution consisting of 1-(2-phenoxypyrimidin-5-yl)ethanone (Step B, 400 mg, 1.87 mmol) in dichloromethane (14 mL) was added tetrabutylammonium tribromide (990 mg, 2.05 mmol). The reaction mixture was sealed with a screw top and warmed at 40° C. overnight and allowed to cool to room temperature. Hexane (4 mL) was subsequently added. After three hours and little precipitation, additional (150 mg) tetrabutylammonium tribromide was added and the reaction mixture was stirred overnight at room temperature. The pale yellow precipitate that formed was collected on a filter and washed with 1:1 dichloromethane-hexane to afford the title intermediate (375 mg, 68%); Rf 0.43 with 3:1 v/v hexanes-ethyl acetate; MS (ESI+) m/z 295, 293 (M+1, Br isotopes).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[CH:28]=O)[CH:7]=2)[CH2:3][CH2:2]1.[NH:31]1[CH2:36][CH2:35][CH:34]([NH:37]C(=O)OC(C)(C)C)[CH2:33][CH2:32]1>>[NH2:37][CH:34]1[CH2:35][CH2:36][N:31]([CH2:28][C:16]2[C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:8]4[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=4[CH3:12])[C:5]([NH:4][CH:1]4[CH2:2][CH2:3]4)=[O:30])[CH:14]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=2)[CH2:32][CH2:33]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCC(N)CC3)c2c1

Procedure:
The title compound was prepared as a solid by the method of Example 63 using product of Example 59 step iii) and piperidin-4-yl-carbamic acid, tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:11]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].I[CH2:31][CH2:32][CH2:33][CH3:34].O>CN(C)C=O.C1COCC1>[CH2:31]([O:16][C:13]1[CH:14]=[CH:15][N:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:11]2[CH:12]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCI
Reactant: Oc1ccn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CCCCOc1ccn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2c1
Temperature: 25 °C
Yield: 58 %

Procedure:
2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-ol (Example 24. 0.5 g, 1.63 mmol) was dissolved in dimethylformamide (10 mL) and potassium tert butoxide (2.5 mL of a 1 M solution in THF, 2.5 mmol) was added dropwise to the stirred solution. After 10 minutes iodobutane (2 mmol) was added and the reaction stirred at room temperature. Second additions of iodobutane (0.88 mmol) and 1M potassium tertbutoxide (2.5 mL, 1 mmol) were made after 4 h and reaction stirred further until complete by TLC. Water (100 mL) was added and the resulting aqueous solution was extracted with with dichloromethane (4×100 mL), the combined organic solution was dried (MgSO4), filtered and concentrated to give the crude product. This was purified either by silica gel chromatography to give the title compound (58%). 1H NMR (d6-DMSO) δ 0.93 (t, J=7.3 Hz, 3H), 1.43 (quintet, J=7.3 Hz, 2H), 1.74 (quintet, J=7.3 Hz, 2H), 4.13 (t, J=6.9 Hz, 2H), 6.84 (dd, J=2.4, 7.5 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 7.28 (t, J=8.8 Hz, 2H), 7.53 (dd, J=0.5, 8.8 Hz, 2H), 7.73 (d, J=6.4 Hz, 2H), 8.65 (d, J=6.4 Hz, 2H), 8.74 (d, J 7.5 Hz, 1H); APESI-MS m/z 362 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH:10]([C:12]1[C:20]2[C:15](=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[CH:18][CH:19]=2)[N:14]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[N:13]=1)=[CH2:11].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:8][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([CH:11]=[CH:10][C:12]2[C:20]3[C:15](=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[CH:18][CH:19]=3)[N:14]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[N:13]=2)[CH:7]=1
Reactant: Cc1cc(C)nc(Br)c1
Reactant: C=Cc1nn(C2CCCCO2)c2cc([N+](=O)[O-])ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(C=Cc2nn(C3CCCCO3)c3cc([N+](=O)[O-])ccc23)c1
Temperature: 110 °C
Yield: 68 %

Procedure:
A suspension of 2-bromo-4,6-dimethylpyridine (2.42 g, 13 mmol), 3-vinyl-6-nitro-1-(tetrahydro -pyran-2-yl)-1H-indazole (2.37 g, 8.67 mmol), palladium acetate (0.145 g, 0.65 mmol), tri-ortho-tolylphosphine (0.791 g, 2.6 mmol), and diisopropylethylamine (2.4 mL, 13.8 mmol) in aqueous DMF (85%, 34.5 mL) was degassed with Argon bubbling for 5 minutes followed by sonication for 5 minutes before heating in microwave apparatus (300 watts, 10% power) at 110° C. for 40 minutes. After cooling, the mixture was dropped into cold water. The resulting yellow ppt was collected by filtration. The solids were dissolved in ethyl acetate, dried (sodium sulfate), and concentrated under reduced pressure. The residue was purified on silica gel using a gradient of 0 to 20% ethyl acetate in a mixture of chloroform and hexanes (1:1) as eluent. Product from chromatography was triturated with MTBElhexanes to obtain clean product as yellow solid. Mother liquor was repurified in a similar fashion on silica gel followed by trituration to obtain product in a 68% yield. 1H NMR (CDCl3): δ 8.54 (1H, s), 8.15 (1H, d, J=9.4 Hz), 8.08 (1H, dd, J=9.04,1.9 Hz), 7.87 (1H, d, J=16.6 Hz), 7.55 (1H, d, J=16.6 Hz), 7.14 (1H, s), 6.90 (1H, s), 5.82 (1H, dd, J=9.0, 3.0 Hz), 4.08–4.01 (1H, m), 3.84–3.76 (1H, m), 2.56 (3H, s), 2.62–2.54 (1H, m), 2.34 (3H, s), 2.24–2.10 (2H, m), 1.88–1.68 (3H, m).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].Cl[S:17]([N:20]=C=O)(=[O:19])=[O:18]>C1(C)C=CC=CC=1>[C:5]([C:4]1[CH:3]=[C:2]([O:1][S:17](=[O:19])(=[O:18])[NH2:20])[CH:15]=[CH:14][CH:13]=1)(=[O:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C(c1ccccc1)c1cccc(O)c1
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1cccc(C(=O)c2ccccc2)c1
Yield: 30.3 %

Procedure:
This compound was prepared according to the procedure used in Example 56. A mixture of 9.9 g (0.05 mole) of 3-hydroxybenzophenone and 4.4 ml (7.1 g, 0.0505 mole) of chlorosulfonyl isocyanate in 75 ml of toluene gave a solid as residue. This residue was recrystallized sucessively from benzene and then methylene chloride to yield 4.2 g (30%) of the title compound as a white solid, mp 72°-74° C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:21]([F:24])([F:23])[F:22])([OH:20])[C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[F:1][C:2]([F:25])([F:26])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:16]([F:17])([F:18])[F:19])([O:20][S:35]([CH3:34])(=[O:37])=[O:36])[C:21]([F:23])([F:22])[F:24])=[CH:11][CH:10]=1)([O:8][S:35]([CH3:34])(=[O:37])=[O:36])[C:4]([F:7])([F:6])[F:5]
Reactant: OC(c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1)(C(F)(F)F)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC(c1ccc(C(OS(C)(=O)=O)(C(F)(F)F)C(F)(F)F)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.5 %

Procedure:
4.1 g (10 mmol) of 1,4-bis-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethylethyl)-benzene were dissolved in 50 ml of methylene chloride, and 2.5 g (25 mmol) of triethylamine were added. 2.86 g (25 mmol) of methanesulfonyl chloride were added dropwise at 5° to 10° C. The mixture was stirred for 48 hours at room temperature, separated off from the precipitated salt, washed with water, dried and evaporated down. The residue was chromatographed over a silica gel column with methylene chloride/n-hexane (1:1). 3.2 g of 1,4-bis-(2,2,2-trifluoro-1-methanesulfonyloxy-1-trifluoromethylethyl)-benzene were obtained (colorless crystals, m.p.: 151° C. [from diisopropyl ether]).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8]([NH:11][CH2:12][CH2:13][C:14]3[S:18][C:17]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)=[O:21])=[N:16][CH:15]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].C([O-])([O-])=O.[Na+].[Na+]>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.CN(C=O)C.O>[C:33]([O:37][C:38]([N:40]1[CH2:41][CH:42]=[CH:43][CH2:44][CH2:45]1)=[O:39])([CH3:36])([CH3:34])[CH3:35].[N:5]1[C:4]2[CH:3]=[CH:2][S:10][C:9]=2[C:8]([NH:11][CH2:12][CH2:13][C:14]2[S:18][C:17]([NH:19][C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=3)=[O:21])=[N:16][CH:15]=2)=[N:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)Nc1ncc(CCNc2ncnc3cc(Br)sc23)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=CCC1
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1ncc(CCNc2ncnc3ccsc23)s1

Procedure:
A 100 mL vial was charged with compound 34.1 (125 mg, 100 mol %), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (86 mg, 120 mole %), and PdCl2(PPh3)2 (33 mg, 20 mol %). To this was added DMF/H2O (4:1, 1 mL) along with 2N Na2CO3 (0.3 mL). The vial was flushed with nitrogen, sealed, and subjected to microwave irradiation (10 minutes, 300 W, 100° C.). The contents were cooled and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (aqueous 0.1% CF3COOH/MeCN gradient) resulting in a 1:1 mixture of 1-{5-[2-(thieno[3,2-d]pyrimidin-4-ylamino)-ethyl]-thiazol-2-yl}-3-(3-trifluoromethyl-phenyl)-urea; compound with 3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (compound 50.1) and the titled compound. This mixture was dissolved in 4N HCl/dioxane (2 mL), stirred at room temperature for 15 minutes, and concentrated in vacuo to provide exclusively the HCl salt of the titled compound as a yellow powder LCMS [M+H]+ m/z 546.1.
Reaction SMILES: C([NH:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][N:10]([C:15]1[C:16]([F:33])=[CH:17][C:18]3[C:28](=[O:29])[C:27]([C:30]([OH:32])=[O:31])=[CH:26][N:20]4[CH:21]([CH3:25])[CH2:22][O:23][C:24]=1[C:19]=34)[CH2:9]2)(=O)C.Cl.O.O1C2C=CC(C(O)=O)=CC=2C=CN1>C(O)C>[NH2:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][N:10]([C:15]1[C:16]([F:33])=[CH:17][C:18]3[C:28](=[O:29])[C:27]([C:30]([OH:32])=[O:31])=[CH:26][N:20]4[CH:21]([CH3:25])[CH2:22][O:23][C:24]=1[C:19]=34)[CH2:9]2
Reactant: CC(=O)NCc1ccc2c(c1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn4c3c1OCC4C)C2
Agent: Cl
Agent: O=C(O)c1ccc2c(c1)C=CNO2
Solvent: O
Solvent: CCO
Product: CC1COc2c(N3Cc4ccc(CN)cc4C3)c(F)cc3c(=O)c(C(=O)O)cn1c23

Procedure:
315 mg of 10-(5-acetamidomethyl-2-isoindolinyl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6carboxylic acid was added to a mixed solution of 12 ml of concentrated HCl, 2.5 ml of water, and 5 ml of ethanol, and the mixture was heated under reflux for 15 hours. After the mixture was concentrated under reduced pressure, the residue was recrystallized from ethanol to obtain 170 mg of 10-(5-aminomethyl-2-isoindolinyl)-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]1,4]-benzoxazine-6-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH3:12][C:13]1[C:17](B2OC(C)(C)C(C)(C)O2)=[C:16]([CH3:27])[O:15][N:14]=1.O>CCOC(C)=O>[CH3:12][C:13]1[C:17]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=2)=[C:16]([CH3:27])[O:15][N:14]=1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1noc(C)c1-c1ccc(N)c([N+](=O)[O-])c1
Temperature: 120 °C

Procedure:
4-bromo-2-nitroaniline (1 g, 4.6 mmol) and 3,5-Dimethylisoxazole-4-boronic acid pinacol ester (2 g, 9.2 mmol) was added to a solvent mixture of 1,2-dimethoxymethane (12 ml) and water (6 ml). To the above mixture were added PEPPSI-Ipr (312 mg, 0.46 mmol) and CsCO3 (4.5 g, 13.8 mmol). The reaction mixture was heated at 120° C. for 30 min. The reaction mixture was then diluted with EtOAc (100 ml), washed with bring (50 ml×2). The organic solvent was evaporated and the residue was dissolved in DCM and purified with flash column chromatography (50% EtOAc/Hexane) to afford 4-(3,5-dimethylisoxazol-4-yl)-2-nitroaniline.