Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.CC(C)([O-])C.[K+].C1(C)C=C(C)C=C(C)[C:17]=1[S:24]([O:27][NH2:28])(=[O:26])=[O:25].CS(O)(=O)=O>CO.ClCCl>[CH3:17][S:24]([OH:27])(=[O:26])=[O:25].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][NH2:28])=[C:4]([I:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1I
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Agent: CC(C)(C)[O-]
Agent: CS(=O)(=O)O
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: NOc1ccc(Br)cc1I
Reaction time: 0.67 h
Yield: 58.4 %

Procedure:
To a solution of product of step A (10.0 g, 33.4 mmol) in methanol (100 mL) at 0° C. was added potassium tert-butoxide (2.59 g, 23.1 mmol) portionwise and the mixture stirred for 40 min. The reaction mixture was concentrated in vacuo, and suspended in dichloromethane. To the suspension was added a solution of O-(mesitylsulfonyl)hydroxylamine (5.53 g, 33.4 mmol) in dichloromethane at 0° C. and the reaction stirred for 1 h. The mixture was then washed with cold 5% KOH solution and dried over anhydrous sodium sulfate. The organic layer was treated with methanesulfonic acid (1.75 mL, 26.72 mmol) then concentrated in vacuo to give crude O-(4-bromo-2-iodophenyl)hydroxylamine methanesulfonic acid salt (8.0 g, 58%) as a brown solid. CAUTION: This compound has potential to be shock sensitive and may be susceptible to decomposition. It should be handled with care and used directly without storage.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1)=[O:8].[C:26](OC(=O)C)(=[O:28])[CH3:27]>CC(O)=O>[C:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([C:20]([F:21])([F:22])[F:23])[CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1)=[O:8])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.7 %

Procedure:
5-Amino-N-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxybenzamide (364.24 mg, 1 mmol) obtained in Example 31 was dissolved in acetic anhydride (0.09 ., 1 mmol), to which AcOH (3 ml) was added, followed by stirring at room temperature for 3 hours. The mixture was extracted by using ethylacetate. The extract was washed with saturated sodium hydrogen carbonate, and dried over MgSO4. After eliminating ethylacetate, the non-purified compound was purified by silica gel column chromatography (ethylacetate:hexane=1:1) to give 340 mg of the target compound (yield: 84%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(F)c(CBr)c1
Reaction time: 16 h

Procedure:
186 g (1.20 mol) of 2-fluoro-5-nitrotoluene are dissolved in 1.2 l of carbon tetrachloride, and 214 g (1.20 mol) of N-bromosuccinimide are added. 19.7 g (120 mmol) of azodiisobutyronitrile are added, and the mixture is heated under reflux. After 16 h, the mixture is allowed to cool, filtered and evaporated to dryness under reduced pressure. The residue is dissolved in 300 ml of dichloromethane, and 300 g of sea sand are added. Once more, the mixture is then concentrated to dryness under reduced pressure, and the residue is applied to a 1 kg silica gel column. The product is chromatographed using a 20:1 mixture of cyclohexane and ethyl acetate, and the product fractions are evaporated to dryness under reduced pressure. The residue is crystallized with cyclohexane and dried under reduced pressure. This gives 92 g (32% of theory) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)#[CH:21]>CCCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:21]#[C:20][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(F)cc(Cl)c2)cc1
Reactant: C#Cc1ccccc1
Solvent: CCCCCCC
Product: Fc1cc(Cl)cc(C#Cc2ccccc2)c1

Procedure:
This product was prepared from toluene-4-sulfonic acid 3-chloro-5-fluoro-phenyl ester and ethynyl-benzene following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane; yield (110 mg, 98%); 1H NMR δ (CDCl3): 7.51 (m, 2H), 7.36 (m, 3H), 7.03 (d, J=7.05 Hz, 2H), 6.79 (t, J=8.35 Hz, 1H); LCMS m/z: 230.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]#[N:13])[CH:8]=2)[N:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].[O:62]=[C:63]1[NH:68][CH2:67][CH2:66][N:65]([C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[CH2:64]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:68]1[CH2:67][CH2:66][N:65]([C:69]([O:71][C:72]([CH3:74])([CH3:73])[CH3:75])=[O:70])[CH2:64][C:63]1=[O:62])[CH:11]=[CH:10]2)#[N:13]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: N#Cc1ccc2nc(Cl)ccc2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3cc(C#N)ccc3n2)C(=O)C1
Temperature: 100 °C

Procedure:
To a 25 mL flask was added a stir bar, 2-chloroquinoline-6-carbonitrile (0.015 g, 0.79 mmol), Pd2 dba3 (0.072 g, 0.08 mmol), Xantphos (0.09 g, 0.16 mmol), cesium carbonate (0.36 g, 1.13 mmol) and tert-Butyl 3-oxopiperazine-1-carboxylate (0.31 g, 1.6 mmol). The resulting mixture was degassed and purged with N2 (3×). To the flask was added 1,4-dioxane (10 mL). The reaction mixture was then refluxed at 100° C. overnight. Analysis of the reaction mixture by LC indicated that reaction had gone to completion. The solution was concentrated in vacuo and the resulting crude was dissolved in EtOAc and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (10% MeOH in DCM) to provide the title product.
Reaction SMILES: C(N(CC)CC)C.C(O)=O.[CH2:11]([O:13][C:14](=[O:32])[CH:15]([CH2:19][C:20]1[C:25](Cl)=[CH:24][N:23]=[C:22]([NH:27][C:28](=[O:30])[CH3:29])[C:21]=1[F:31])[C:16](=[O:18])[CH3:17])[CH3:12]>CC(O)C.O.[Pd]>[CH2:11]([O:13][C:14](=[O:32])[CH:15]([CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:27][C:28](=[O:30])[CH3:29])[C:21]=1[F:31])[C:16](=[O:18])[CH3:17])[CH3:12]
Reactant: CCOC(=O)C(Cc1c(Cl)cnc(NC(C)=O)c1F)C(C)=O
Agent: [Pd]
Solvent: CC(C)O
Solvent: O=CO
Solvent: O
Product: CCOC(=O)C(Cc1ccnc(NC(C)=O)c1F)C(C)=O
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
After cooling the reaction mixture to room temperature, a solution of triethylamine (670 μL, 4.9 mmol) and formic acid (150 μL, 4.0 mmol) in 2-propanol (1.1 mL) and 20% Pd(OH)2 carbon (19 mg; water content: 50%) were added, and after warming to 50° C., the mixture was stirred for 4.5 hours. The reaction mixture was subjected to HPLC analysis under the same conditions as HPLC conditions (2) of Example 10, and the purities of the title compound and its precursor (2-[(2-acetylamino-5-chloro-3-fluoropyridin-4-yl)methyl]-3-oxobutanoic acid ethyl ester) were calculated from their respective area ratios.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1([C:10]([OH:12])=[O:11])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH3:13]O>>[ClH:1].[ClH:1].[NH2:3][C:4]1([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1
Reactant: NC1(C(=O)O)CCNCC1
Reactant: CO
Agent: Cl
Product: COC(=O)C1(N)CCNCC1

Procedure:
Into a heterogeneous mixture of 4-amino-4-carboxypiperidine dihydrochloride (61.0 g, 0.34 mmol) in methanol (600 mL) is bubbled hydrogen chloride gas at room temperature. The reaction mixture is concentrated to dryness in vacuo, dissolved in 1,4-dioxane (200 mL), and concentrated in vacuo. The residue is redissolved in methanol (1600 mL) into which hydrogen chloride gas is bubbled for 45 minutes. The reaction mixture is refluxed for 18 hours. Most of the solvent is then evaporated, the product is collected by filtration, and washed with ethyl acetate to give 4-amino-4-carbomethoxypiperidine dihydrochloride.
Reaction SMILES: Cl.Cl.[F:3][CH2:4][C:5]([NH2:14])([CH2:10][CH2:11][CH2:12][NH2:13])[C:6](OC)=[O:7].C[O-].[Na+].[Na]>CO>[NH2:14][C:5]1([CH2:4][F:3])[CH2:10][CH2:11][CH2:12][NH:13][C:6]1=[O:7]
Reactant: COC(=O)C(N)(CF)CCCN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC1(CF)CCCNC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
To a solution of methyl 2-fluoromethyl-2,5-diaminopentanoate dihydrochloride (2.5 g) in methanol (30 ml) is added under nitrogen a solution of sodium methylate (prepared from 0.46 g of sodium in methanol (20 ml). The reaction mixture is stirred for 1 hour at room temperature and then concentrated in vacuo. The residue is taken up in CH2Cl2. The insoluble material is removed by filtration, and the filtrate is concentrated to give 1 g of 3-amino-3-fluoromethyl-2-piperidone: m.p. 132° C. (from CH2CL2 /pentane).
Reaction SMILES: CC(C)([O-])C.[K+].O.[C:8]1([CH2:14][O:15][C:16]([N:18]2[CH2:23][CH2:22][N:21]3C(=O)[O:25][CH2:26][CH:20]3[CH2:19]2)=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[OH-].[Na+]>>[C:8]1([CH2:14][O:15][C:16]([N:18]2[CH2:23][CH2:22][NH:21][CH:20]([CH2:26][OH:25])[CH2:19]2)=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(OCc1ccccc1)N1CCN2C(=O)OCC2C1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C(OCc1ccccc1)N1CCNC(CO)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a flame dried flask under an inert atmosphere containing potassium tert-butoxide (12.18 g, 108.58 mmol) and water (900 mg, 50.00 mmol) at 0° C. is added (+/-)-tetrahydro-3-oxo-3 H-oxazolo(3,4-a)pyrazin-7(1 H)-carboxylic acid phenylmethylester (Step 3, 10.00 g, 36.19 mmol). The reaction is warmed to ambient temperature, stirred for 2 hours, cooled to 0° C., acidified to pH=2 with conc. HCl, adjusted to pH=9 with 1N NaOH, and extracted with methylene chloride (2×100 mL). The organic extracts are combined, dried over Na2SO4, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 250 mL), eluting with chloroform/methanol (95/5). The appropriate fractions are combined (Rf =0.13, TLC, chloroform/methanol, 90/10) and concentrated in vacuo to give the title compound, NMR (CDCl3) 7.34-7.25, 5.09, 3.95, 3.55-3.53, 3.41, 3.34, 2.92, 2.72-2.70.
Reaction SMILES: FC1C=C(N)C=CC=1OCC1C=CC=C(F)C=1.[F:18][C:19]1[CH:24]=[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[CH:22]=[CH:21][C:20]=1[N+:34]([O-])=O>>[F:18][C:19]1[CH:24]=[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[CH:22]=[CH:21][C:20]=1[NH2:34]
Reactant: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)cc1F
Agent: Nc1ccc(OCc2cccc(F)c2)c(F)c1
Product: Nc1ccc(OCc2cccc(F)c2)cc1F

Procedure:
The title compound is prepared in analogy to 3-fluoro-4-(3-fluoro-benzyloxy)-phenylamine by hydrogenation of 2-Fluoro-4-(3-fluoro-benzyloxy)-nitrobenzene. Yield: 98% of a dark brown oil. MS: m/e=235.0 (M+).
Reaction SMILES: [NH:1]([C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:11])[CH2:2][C:3]([O:5]C(C)(C)C)=[O:4].Cl.CCOC(C)=O>>[NH:1]([C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:11])[CH2:2][C:3]([OH:5])=[O:4]
Reactant: CCCCCCCCCCCCCCCC(=O)NCC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCC(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
To N-palmitoyl-Gly-OtBu (17.4 g, 47.1 mmol), 4M HCl/AcOEt (118 ml, 0.471 mmol) was added and the whole was stirred at room temperature for 1 hour. After concentration under reduced pressure, the residue was washed with hexane to give 11.4 g (77%) of a target compound as colorless powder.
Reaction SMILES: [C:1]([C@@:3]1([CH:32]2[CH2:34][CH2:33]2)[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:27]=[CH:26][C:18]([C:19]([O:21]C(C)(C)C)=[O:20])=[C:17]([O:28][CH2:29][CH3:30])[CH:16]=3)[N:9]=2)[C:4]1=[O:31])#[N:2].[ClH:35]>C(OCC)(=O)C>[ClH:35].[C:1]([C@@:3]1([CH:32]2[CH2:34][CH2:33]2)[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:27]=[CH:26][C:18]([C:19]([OH:21])=[O:20])=[C:17]([O:28][CH2:29][CH3:30])[CH:16]=3)[N:9]=2)[C:4]1=[O:31])#[N:2]
Reactant: CCOc1cc(Nc2nccc(N3CC[C@@](C#N)(C4CC4)C3=O)n2)ccc1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOc1cc(Nc2nccc(N3CC[C@@](C#N)(C4CC4)C3=O)n2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-((4-((3S)-3-cyano-3-cyclopropyl-2-oxopyrrolidin-1-yl)pyrimidin-2-yl)amino)-2-ethoxybenzoate (40 mg) obtained in Step D of Example 139 in ethyl acetate (4.0 mL) was added a solution of 4 M hydrogen chloride in ethyl acetate (4.0 mL), the mixture was stirred at room temperature for 2 hr, and the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate to give the title compound (20 mg).
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:44]([NH:46][C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[C:49]([OH:55])[CH:48]=3)=[O:45])[CH2:20][CH2:21][C:22](=[O:43])[NH:23][C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.[F:56][C:57]1[CH:58]=[C:59]2[C:63](=[CH:64][CH:65]=1)[NH:62][C:61]([C:66]([OH:68])=O)=[CH:60]2>>[F:56][C:57]1[CH:58]=[C:59]2[C:63](=[CH:64][CH:65]=1)[NH:62][C:61]([C:66]([NH:18][C@H:19]([C:44]([NH:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[C:49]([OH:55])[CH:48]=1)=[O:45])[CH2:20][CH2:21][C:22](=[O:43])[NH:23][C:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:68])=[CH:60]2
Reactant: COc1ccc(NC(=O)[C@H](CCC(=O)NC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)OCC2c3ccccc3-c3ccccc32)cc1O
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Product: COc1ccc(NC(=O)[C@H](CCC(=O)NC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)c2cc3cc(F)ccc3[nH]2)cc1O

Procedure:
The title compound was prepared from N-[Nα-(9-fluorenylmethoxycarbonyl)-Nδ-trityl-L-glutaminyl]-3-hydroxy-4-methoxyaniline (605 mg, 0.8 mmol, example 109, step A) as described for example 109 (step B) using 5-fluoroindole-2-carboxylic acid (222 mg, 1.24 mmol) instead of N-(4-fluorobenzyl)indole-2-carboxylic acid. The crude material was purified by flash chromatography using 10, 20 and 40% EtOAc/CH2Cl2 as the eluent. The title compound was obtained as yellow crystals (400 mg, 72%).
Reaction SMILES: [CH3:1][C:2]([NH:25][C:26](=O)[O:27]C(C)(C)C)([CH3:24])[C:3](=[O:23])[NH:4][C:5]1[CH:6]=[N:7][C:8]([O:11][C:12]2[C:17]3[C:18]4([CH2:21][O:22][C:16]=3[CH:15]=[CH:14][CH:13]=2)[CH2:20][CH2:19]4)=[CH:9][CH:10]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:24][C:2]1([CH3:1])[NH:25][C:26](=[O:27])[N:4]([C:5]2[CH:6]=[N:7][C:8]([O:11][C:12]3[C:17]4[C:18]5([CH2:21][O:22][C:16]=4[CH:15]=[CH:14][CH:13]=3)[CH2:19][CH2:20]5)=[CH:9][CH:10]=2)[C:3]1=[O:23]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)Nc1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1(C)NC(=O)N(c2ccc(Oc3cccc4c3C3(CC3)CO4)nc2)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
To a solution of 2-methyl-N1-[6-(spiro[1-benzofuran-3,1′-cyclopropan]-4-yloxy)-3-pyridinyl]alaninamide (Reference Intermediate 219, 34 mg) in dry dichloromethane (6 mL) TEA (0.070 mL, 0.501 mmol) was added and the mixture was cooled to 0° C. A solution of triphosgene (13.38 mg, 0.045 mmol) in dry dichloromethane (2 mL) was slowly added and the reaction mixture was stirred for 1 hour at the same temperature. The reaction was quenched with water (3 ml) and two phases were separated. The organic layer was dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column SNAP and cyclohexane/ethyl acetate 7:3 to cyclohexane/ethyl acetate 3:7 as eluents affording the title as a white solid (23 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8]C)[C:3]1=[O:10].B(Br)(Br)Br.CO>C(Cl)Cl>[CH3:1][N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]1=[O:10]
Reactant: COc1cccn(C)c1=O
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Cn1cccc(O)c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 141a (0.1 g, 0.68 mmol) in dry CH2Cl2 (8 mL) was slowly added 1M BBr3 (0.82 mL) at −30° C. under inert atmosphere. The reaction mixture was stirred for 48 h at room temperature. The mixture was again cooled to −30° C. & then MeOH (5 mL) was slowly added to the mixture. After evaporation of solvent, the residue was adjusted to pH 7 with 1M NaOH and then extracted with CHCl3 (3×30 mL). The combined organic layer dried over Na2SO4. After evaporation of solvent, the residue was purified by prep-TLC with CH2Cl2:Acetone:MeOH (10:1:0.2) to give 61 mg (72%) of pure off white solid. 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 6.78 (dd, J=11.1, 7.1 Hz, 2H), 6.10 (t, J=7.0 Hz, 1H), 3.57 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 158.82, 146.67, 127.63, 114.36, 106.68, 37.28. HRMS (EI) calcd for C6H7NO2 [M]+ 125.0477. found 125.0477.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[NH:20]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11]C.COC1N(C2CCCCO2)C2C(N=1)=C(N)N=C(O[C@@H](C)CC)N=2>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:24][O:23][C:19]1[N:20]=[C:21]2[C:17]([N:18]=1)=[C:16]([NH2:25])[NH:15][C:14]([O:13][C@@H:9]([CH3:8])[CH2:10][CH3:11])=[N:22]2
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)[nH]c2n1
Agent: CC[C@H](C)Oc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1

Procedure:
Prepared similarly to Intermediate 12 from 8-(methyloxy)-2-{[(1S)-1-methylpropyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([F:29])[C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[CH:14]([CH3:20])[C:15]([O:17]CC)=[O:16])=[CH:7][CH:6]=1.[OH-].[Na+]>C1COCC1.C(O)(C)C>[Cl:1][C:2]1[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[C:21]([F:29])[C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[CH:14]([CH3:20])[C:15]([OH:17])=[O:16])=[CH:7][CH:6]=1
Reactant: CCOC(=O)C(C)n1ncc2ccc(Oc3c(F)cc(C(F)(F)F)cc3Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C(=O)O)n1ncc2ccc(Oc3c(F)cc(C(F)(F)F)cc3Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-[6-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)indazol-1-yl]propionate prepared as described in Example 2 (30 mgs) was dissolved in THF (0.1 cm3) and isopropanol (0.28 cm3). 1.73M sodium hydroxide (0.04 cm3) was added and the mixture stirred at room temperature for 8 hours and left to stand overnight. The solvent was removed under vacuum and the residue dissolved in water (2 cm3). 2M hydrocloric acid (0.035 cm3) was added dropwise with stirring. After 1.5 hours the solid product was filtered off, washed with water and air dried to give 2-[6-(2-chloro-6-fluoro-4-trifluoromethylphenoxy) indazol-1-yl]propionic acid (11 mgs) as a white solid. Compound No 4 was prepared by an analogous process using appropriate reactants.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=2)[N:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+:30]1C=CC=CC=1.C(OCC)C>ClCCl>[NH2:30][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[CH:19][CH:18]=2)[N:3]=1
Reactant: c1cc[nH+]cc1
Reactant: Cc1ccc(Cl)cc1-c1nc(Cl)nc(Nc2ccc(CO)cc2)n1
Agent: O=[Cr](=O)([O-])Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(Cl)cc1-c1nc(N)nc(Nc2ccc(C=O)cc2)n1
Reaction time: 6 h
Yield: 6.7 %

Procedure:
To a suspension of the title compound of Example 41 (375 mg, 1.1 mmol) in dichloromethane (100 ml) was added pyridinium chlorochromate (810 mg, 2.7 mmol) and crushed molecular sieves (1.25 g, 3A). After stirring for 6 hours, diethyl ether (150 ml) was added and the mixture was filtered through a pad of silica gel under suction. The filtrate was concentrated under reduced pressure and purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:3 followed by 1:2 followed by 1:1) to provide the title compound (25 mg, 7% yield). 1H NMR (DMSO-d6) 10.10 (s, 1H), 9.86 (s, 1H), 8.07 (d, J=8.6 Hz, 2H), 7.84 (d, J=8.6 Hz, 2H), 7.79 (s, 1H), 7.43 (m, 2H), 7.34 (m, 2H), 2.53 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([C:12]1[N:21]=[CH:20][C:19]2[CH2:18][CH2:17][C:16]3[N:22]=[C:23]([CH3:25])[S:24][C:15]=3[C:14]=2[N:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[CH3:1][N:2]([C:12]1[N:21]=[CH:20][C:19]2[CH:18]=[CH:17][C:16]3[N:22]=[C:23]([CH3:25])[S:24][C:15]=3[C:14]=2[N:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Cc1nc2c(s1)-c1nc(N(C)c3cccc([N+](=O)[O-])c3)ncc1CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: Cc1nc2ccc3cnc(N(C)c4cccc([N+](=O)[O-])c4)nc3c2s1
Yield: 63.2 %

Procedure:
Under dry conditions, a mixture of methyl-(2-methyl-4,5-dihydro-thiazolo[4,5-h]quinazolin-8-yl)-(3-nitro-phenyl)-amine (16 mg, 0.045 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (10.2 mg, 0.045 mmol) in dry toluene (2 mL) was heated under reflux for 16 h. The solvent was evaporated under vacuum and the residue was purified by flash column chromatography (10% EtOAc:hexane) to afford the title product as a yellow solid (10 mg, 68%). mp 209-210° C. Anal. RP-HPLC: tR 23.4 min (10-70% MeCN, purity 98%). 1H-NMR (CDCl3): δ 9.09 (s, 1H, Py-H), 8.41 (t, 1H, J 2.3, Ph-H), 8.09 (ddd, 1H, J 8.2, 2.3, 1.0, Ph-H), 7.85 (d, 1H, J 8.7, Ph-H), 7.79 (ddd, 1H, J 8.2, 2.3, 1.0, Ph-H), 7.72 (d, 1H, J 8.7, Ph-H), 7.58 (t, 1H, J 8.2, Ph-H), 3.78 (s, 3H, N—CH3), 2.94 (s, 3H, Me). 13C-NMR (CDCl3): δ 171.04, 161.09, 158.53, 157.16, 148.54, 148.04, 146.25, 131.74, 129.31, 125.29, 121.01, 119.85, 119.30, 116.97, 38.39, 20.48 missing 1 quat signal. MS (ESI+): m/z 352.08 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[CH:14][N:15]3[CH2:18][CH3:19])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[C:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(OC(N1CCN(C2C=CC(C(=O)NC3C=CC(C)=C(I)C=3)=CN=2)CC1)=O)(C)(C)C>>[C:25]([O:24][C:22]([N:29]1[CH2:34][CH2:33][N:32]([C:2]2[CH:21]=[CH:20][C:5]([C:6](=[O:7])[NH:8][C:9]3[CH:17]=[C:16]4[C:12]([CH:13]=[CH:14][N:15]4[CH2:18][CH3:19])=[CH:11][CH:10]=3)=[CH:4][N:3]=2)[CH2:31][CH2:30]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCn1ccc2ccc(NC(=O)c3ccc(Cl)nc3)cc21
Agent: Cc1ccc(NC(=O)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc1I
Product: CCn1ccc2ccc(NC(=O)c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)cc21

Procedure:
4-[5-(1-Ethyl-1H-indol-6-ylcarbamoyl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester was prepared from 6-chloro-N-(1-ethyl-1H-indol-6-yl)-nicotinamide and 1-Boc-piperazine following a method similar to the one described in the synthesis of 4-[5-(3-iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester above. The product was obtained after silica gel column purification with 10-30% Et2O in toluene gradient. HRMS m/z calcd for C25H31N5O3 [M+H]+: 450.2500. Found: 450.2497.