Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C@@H:24]1[CH2:28][C@H:27]([C:29](=[O:33])[N:30]([CH3:32])[CH3:31])[CH2:26][C@@H:25]1[NH:34]C(=O)OC(C)(C)C)[N:17]=[CH:16]2.Cl>C(Cl)Cl.O1CCOCC1>[NH2:34][C@@H:25]1[C@H:24]([NH:23][C:18]2[N:17]=[CH:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:3]4[C:4]([Cl:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=4[Cl:1])[CH:14]=3)[N:19]=2)[CH2:28][C@@H:27]([C:29]([N:30]([CH3:32])[CH3:31])=[O:33])[CH2:26]1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4C[C@H](C(=O)N(C)C)C[C@@H]4NC(=O)OC(C)(C)C)ncc3c2)c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4C[C@@H](C(=O)N(C)C)C[C@@H]4N)ncc3c2)c1Cl
Reaction time: 3 h

Procedure:
tert-butyl ((1S,2R,4S)-2-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-4-(dimethylcarbamoyl)cyclopentyl)carbamate (0.062 g, 0.103 mmol) was taken up in DCM (2 ml) and treated with 4M HCl in dioxane (3 ml) and stirred for 3 hours. The solvent was removed to give crude (1S,3S,4R)-3-amino-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-N,N-dimethylcyclopentane-1-carboxamide, quantative yield. MS (ES+) C24H27Cl2N5O3 requires: 504, found: 505 [M+H]+.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C@@H:19]1([NH2:29])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1>>[N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([NH:29][C@@H:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21][CH2:20]2)=[O:15])(=[O:8])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: N[C@H]1CCCc2ccccc21
Product: O=C(N[C@H]1CCCc2ccccc21)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 73 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine as the starting materials.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:17])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[N+:14]([O-])=O)[CH:2]=[CH2:3].OC1C=CC(C(O)=O)=C([N+]([O-])=O)C=1.CI.C(N)C=C>CO.O.C(O)C>[CH2:1]([N:4]1[C:5](=[O:17])[C:6]2[C:7](=[CH:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=2)[NH:14]1)[CH:2]=[CH2:3]
Reactant: C=CCNC(=O)c1ccc(OC)cc1[N+](=O)[O-]
Agent: O=C(O)c1ccc(O)cc1[N+](=O)[O-]
Solvent: CI
Solvent: CO
Solvent: C=CCN
Product: C=CCn1[nH]c2cc(OC)ccc2c1=O
Yield: 33 %

Procedure:
Using a similar procedure to that described in Examples 2-16, but starting from N-allyl-4-methoxy-2-nitrobenzamide (itself prepared from 4-hydroxy-2-nitrobenzoic acid using the procedure described in the portion of Example 82 which is concerned with the preparation of starting material except that methyl iodide was used in place of butyl iodide and allylamine was used in place of benzylamine), using a mixture of ethanol and water (4/1 v/v) in place of aqueous methanol as the reaction solvent and having a reaction duration of 3 hours, there was obtained 1,2-dihydro-2-allyl-6-methoxy-3H-indazol-3-one (Ex. 178) as a solid, m.p. 126° C. in 33% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([N:12]1[CH:15](SC)[CH:14]([NH:18][C:19](=[O:27])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]1=[O:28])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4]>O1CCOCC1.[Ni]>[CH3:1][O:2][C:3]([CH:5]([N:12]1[CH2:15][CH:14]([NH:18][C:19](=[O:27])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]1=[O:28])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:4]
Reactant: COC(=O)C(c1ccccc1)N1C(=O)C(NC(=O)Cc2ccccc2)C1SC
Agent: [Ni]
Solvent: C1COCCO1
Product: COC(=O)C(c1ccccc1)N1CC(NC(=O)Cc2ccccc2)C1=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
1-(α-Methoxycarbonylbenzyl)-4-methylthio-3-(2-phenylacetamido)-2-azetidinone (mixture of two trans isomers at the third and fourth positions of the azetidine ring) (0.50 g) was dissolved in dried dioxane (10 ml), and to the solution, there was added an dioxane solution (10 ml) containing Raney nickel (5 ml). The mixture was stirred at 60° C. for 2 hours. Raney nickel was removed by filtration to give a filtrate, which was evaporated to dryness under reduced pressure. The residue obtained was subjected to column chromatography on silica gel (10 g) and elution was carried out with chloroform. The fractions containing a desired compound were collected and the solvent was distilled off from the solution under reduced pressure to give 1-(α-methoxycarbonylbenzyl)-3-(2-phenylacetamido)-2-azetidinone (mixture of two isomers at the third position of the azetidine ring, 320 mg). Additionally this mixture was subjected to column chromatography on silica gel and elution was carried out with chloroform. The eluate was treated in a conventional manner to give each isomer a: 180 mg and b: 140 mg of the above compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1F)[C:5]1[C:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[C:24]5[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=5[N:22]=4)[CH:17]=3)[N:12]=2)=[CH:9][C:8]([O:39][CH3:40])=[CH:7][CH:6]=1.[CH3:45]OC(C1C=CC2N(C3CCCCC3)C(C3C=C4C(=CC=3)N=C(C3C=C(OC)C=CC=3Br)C=C4)=NC=2C=1)=O.B(O)(O)C1C=CC(C)=CC=1>>[CH:26]1([N:25]2[C:24]3[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=3[N:22]=[C:21]2[C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([C:10]2[C:5]([C:4]4[CH:3]=[CH:2][C:43]([CH3:45])=[CH:42][CH:41]=4)=[CH:6][CH:7]=[C:8]([O:39][CH3:40])[CH:9]=2)[CH:20]=[CH:19]3)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
Agent: Cc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(C)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Yield: 12 %

Procedure:
Following the full procedure and workup for Compound 366, Compound 365b (100 mg, 0.175 mmol) was reacted with p-tolylboronic acid (36 mg, 0.2625 mmol) to produce the title compound (12 mg, 12% yield).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:9][C:8]2[C:10]3[C:15]([CH:16]=[CH:17][C:7]=2[CH2:6]1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N+]=[N-]>[Pd]>[O:9]1[CH:5]([CH2:4][NH2:1])[CH2:6][C:7]2[CH:17]=[CH:16][C:15]3[C:10]([C:8]1=2)=[CH:11][CH:12]=[CH:13][CH:14]=3
Reactant: [N-]=[N+]=NCC1Cc2ccc3ccccc3c2O1
Agent: [Pd]
Product: NCC1Cc2ccc3ccccc3c2O1
Yield: 103.9 %

Procedure:
Treatment of (±)-2-(azidomethyl)-2,3-dihydronaphtho[1,2-b]furan (1.61 g, 7.15 mmol) with palladium on carbon (10 wt. %, 0.160 g) generally according to the procedure described for Example 2 afforded 1.48 g (88%) of (±)-1-(2,3-dihydronaphtho[1,2-b]furan-2-yl)methanamine as a white solid, hydrochloride salt. mp>250° C. (dec.); Anal. calcd. for C13H13NOHCl: C, 66.24; H, 5.99; N, 5.94. Found: C, 66.23; H, 6.07; N, 5.77.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]1[C:16]2[CH2:15][S:14][N:13]=[C:12]([N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]3=[N:32][N:33]([CH2:35][C:36]4[C:41]([CH3:42])=[C:40]([O:43][CH3:44])[C:39]([CH3:45])=[CH:38][N:37]=4)[N:34]=[C:9]([C:10]=23)[CH2:8]1.ClCCl>C(N(CC)CC)C>[CH3:1][S:2]([O:6][CH:7]1[C:16]2[CH2:15][S:14][N:13]=[C:12]([N:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:11]3=[N:32][N:33]([CH2:35][C:36]4[C:41]([CH3:42])=[C:40]([O:43][CH3:44])[C:39]([CH3:45])=[CH:38][N:37]=4)[N:34]=[C:9]([C:10]=23)[CH2:8]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(C)cnc(CN2N=C3CC(O)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C)cnc(CN2N=C3CC(OS(C)(=O)=O)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Reaction time: 2 h
Yield: 93 %

Procedure:
Methanesulfonyl chloride (39 μL) was added dropwise to a mixture composed of di-tert-butyl {8-hydroxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 32 (240 mg), dehydrated dichloromethane (6 mL) and triethylamine (88 μL) under cooling in an ice bath. The ice bath was removed and the mixture was stirred for two hours. After confirming that the raw material disappeared, the reaction mixture was diluted with chloroform and washed with water. The organic layer was dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. Dichloromethane and hexane were added to the residue, and the precipitated solid was collected by filtration to obtain the title compound (253 mg, 93%). The resulting compound was directly used for the next reaction without purification.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:15])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:7])[CH3:3].CN1CCOCC1.[C:23]1(=[O:42])[N:27]([C@@H:28]([CH2:32][CH2:33][CH2:34][CH2:35][OH:36])[C:29](O)=[O:30])[C:26](=[O:37])[C:25]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:24]12.OC1C2N=NNC=2C=CC=1.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:26]1(=[O:37])[N:27]([CH:28]([CH2:32][CH2:33][CH2:34][CH2:35][OH:36])[C:29]([NH:7][C@@H:6]([C:5]([O:4][CH2:2][CH3:3])=[O:15])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:30])[C:23](=[O:42])[C:24]2=[CH:41][CH:40]=[CH:39][CH:38]=[C:25]12
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](Cc1ccccc1)NC(=O)C(CCCCO)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of L-phenylalanine ethyl ester hydrochloride salt (998 mg., 4.3 mmol) in dimethylformamide (10 mL.) was added with 4-methylmorpholine (575 μl, 529 mg., 5.2 mmol.). After stirring at room temperature for 5 minutes, the solution was cooled to 0° C. and treated successively with (S)-2-phthalimido-6-hydroxyhexanoic acid (1.002 g., 3.6 mmol.), hydroxybenzotriazole (582 mg., 4.3 mmol.) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (770 mg., 4.0 mmol.). The resulting mixture was stirred at 0° C. for 0.5 hour and at room temperature for 1.5 hours. The solution was partitioned between ethyl acetate and water and the organic extract was washed successively with 0.5N hydrochloric acid, water, 50% saturated sodium bicarbonate, and brine, then dried (sodium sulfate), filtered and stripped to give 1.63 g. of essentially pure title product as an oil/foam. TLC (1:1--acetone:hexanes) Rf =0.30.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][NH:33][C:34]([C@H:36]1[CH2:41][NH:40][CH2:39][CH2:38][NH:37]1)=[O:35]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:25])[N:19]=[C:20]([N:40]5[CH2:39][CH2:38][NH:37][C@@H:36]([C:34]([NH:33][CH3:32])=[O:35])[CH2:41]5)[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: CNC(=O)[C@H]1CNCCN1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CNC(=O)[C@H]1CN(C2=NC(=O)/C(=C/c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CCN1

Procedure:
(2R)-4-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-N-methylpiperazine-2-carboxamide was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (2R)-piperazine-2-carboxylic acid methylamide following General Procedure C.
Reaction SMILES: [CH3:1][N:2]([CH2:15][CH2:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[CH:18]=1)[CH:3]([CH2:5][CH2:6]O[Si](C(C)(C)C)(C)C)[CH3:4].[F-].C([N+:32](CCCC)(CCCC)CCCC)CCC.O.NN>O1CCCC1.C(O)C>[CH3:1][N:2]([CH:3]([CH3:4])[CH2:5][CH2:6][NH2:32])[CH2:15][CH2:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[CH:18]=1
Reactant: COc1cc(CCN(C)C(C)CCO[Si](C)(C)C(C)(C)C)cc(OC)c1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: NN
Agent: [F-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CCN(C)C(C)CCN)cc(OC)c1
Reaction time: 3 h
Yield: 36 %

Procedure:
3.33 g of N-methyl-N-(4-(tert-butyldimethylsiloxy)-butan-2-yl)-[2-(3,5-dimethoxyphenyl)ethyl]amine was dissolved in 13 ml of tetrahydrofuran to obtain a solution. 13 ml of a solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1 mmol/ml) was slowly dropwise added to the solution. The obtained mixture was stirred at a room remperature for 3 hours and distilled to remove the solvent. The residue was extracted with ether thrice and the ether phase was dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The residue was dissolved in 25 ml of tetrahydrofuran, followed by the addition of 1.29 g of phthalimide and 2.29 g of triphenylphosphine. 1.52 g of diethyl azodicarboxylate was slowly added to the obtained mixture at a room temperature. The obtained mixture was stirred overnight and distilled to remove the solvent. The residue was made acidic with 0.5N hydrochloric acid and washed with ether. The aqueous phase was made basic with lithium hydroxide and extracted with ethyl acetate. The ethyl acetate phase was dried over anhydrous sodium sulfate and the filtrate was concentrated under a reduced pressure to obtain a residue. This resiude was dissolved in 20 ml of ethanol, followed by the addition of 200 mg of hydrazine monohydrate. The obtained mixture was heated under reflux for 2 hours and cooled. The white precipitate thus formed was filtered out and the filtrate was concentrated under a reduced pressure, followed by the addition of 20 ml of a 10% solution of sodium hydroxide. The obtained mixrure was extracted with chloroform thrice. The chloroform phase was washed with a saturated aqueous solution of common salt, dried over anhydrous sodium sulfate and concentrated under a reduced pressure to obtain 830 mg of the title compound as a yellow oil (yield: 36%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=3)[C:10]([S:21][CH3:22])=[CH:9]2)=[N:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:47]1[CH:52]=[C:51]([CH3:53])[CH:50]=[CH:49][N:48]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].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>[CH3:53][C:51]1[CH:50]=[CH:49][N:48]=[C:47]([C:2]2[CH:3]=[N:4][C:5]([N:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=4)[C:10]([S:21][CH3:22])=[CH:9]3)=[N:6][CH:7]=2)[CH:52]=1
Reactant: COC(=O)c1ccc2c(SC)cn(-c3ncc(Br)cn3)c2c1
Reactant: Cc1ccnc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(SC)cn(-c3ncc(-c4cc(C)ccn4)cn3)c2c1
Temperature: 25 °C

Procedure:
PdCl2(dppf) (0.325 g, 0.397 mmol) was added to a suspension of methyl 1-(5-bromopyrimidin-2-yl)-3-(methylthio)-1H-indole-6-carboxylate (3.0 g, 7.96 mmol), bis(pinacolato)diboron (2.26 g, 8.91 mmol) and potassium acetate (2.34 g, 23.87 mmol) in dioxane (80 mL) that was stirred under an argon atmosphere. The reaction mixture was stirred for 1 h at 110° C. and then cooled to room temperature. 2-Bromo-4-methyl-pyridine (2.05 g, 11.93 mmol), 2M potassium carbonate solution (8.0 mL) and tetrakis(triphenylphosphine)palladium(0) (0.46 g, 0.398 mmol) were added at this temperature and the resulting mixture was stirred for 16 h at 100° C. The reaction mixture was filtered through a pad of celite, the filter was washed with dichloromethane/methanol (9:1) and the filtrate was concentrated under reduced pressure. The remnant was purified by column chromatography [100-200 mesh silica; dichloromethane ethyl acetate/hexane=5/20/75]. Yellow solid. Yield: 2.0 g (64% of theory)
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:17][CH:16]=3)[CH:13]=[C:12]([CH:28]3[CH2:33][CH2:32][CH:31]([O:34][Si](C(C)(C)C)(C)C)[CH2:30][CH2:29]3)[C:10]=2[N:11]=1)[CH2:2][CH2:3][CH3:4].Cl>CO>[CH2:1]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:17][CH:16]=3)[CH:13]=[C:12]([CH:28]3[CH2:29][CH2:30][CH:31]([OH:34])[CH2:32][CH2:33]3)[C:10]=2[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ncc2c(n1)c(C1CCC(O[Si](C)(C)C(C)(C)C)CC1)cn2-c1ccc(CN2CCOCC2)cc1
Agent: Cl
Solvent: CO
Product: CCCCNc1ncc2c(n1)c(C1CCC(O)CC1)cn2-c1ccc(CN2CCOCC2)cc1
Reaction time: 8 h
Yield: 100.1 %

Procedure:
A solution of N-butyl-7-(4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-5-(4-(morpholinomethyl)phenyl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (84 mg, 0.14653 mmol) in MeOH (3.0 mL) was added 0.15 mL of concentrated HCl. The reaction mixture was stirred overnight and the solvent was removed. The residue was purified by ISCO to provide the desired product (UNC2221A) (68 mg, 99%). 1H NMR (400 MHz, CD3OD) δ 8.69 (s, 1H), 8.13 (s, 1H), 7.74 (d, J=8 Hz, 2H), 7.25 (d, J=8 Hz, 2H), 4.38 (s, 2H), 4.01-3.92 (m, 2H), 180-3.70 (m, 2H), 3.59-3.52 (m, 2H), 3.48 (t, J=8 Hz, 2H), 3.37-3.29 (m, 2H), 3.18-3.11 (m, 1H), 2.78 (tt, J1=12 Hz, J2=4 Hz, 1H), 2.02 (t, J=16 Hz, 4H), 1.68-1.57 (m, 4H), 1.43-1.13 (m, 4H), 0.91 (t, J=8 Hz, 3H). MS m/z 464.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:26]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[CH:13][C:14]([CH3:25])=[C:15]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:16]=3)=[CH:9][N:4]2[N:3]=1.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1>CN(C)C(=O)C.C(=O)([O-])O.[Na+]>[CH:27]1([C:30]([NH:1][C:2]2[N:26]=[C:5]3[CH:6]=[CH:7][C:8]([O:10][C:11]4[CH:12]=[CH:13][C:14]([CH3:25])=[C:15]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH:16]=4)=[CH:9][N:4]3[N:3]=2)=[O:31])[CH2:29][CH2:28]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccc(Oc2ccc3nc(N)nn3c2)cc1NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 84 h
Yield: 102.5 %

Procedure:
To a solution of tert-butyl {5-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]-2-methylphenyl}carbamate (3.52 g, 8.92 mmol) in N,N-dimethylacetamide (30 mL) was added cyclopropanecarbonyl chloride (0.811 mL, 8.93 mmol) at 0° C., and the mixture was stirred at room temperature for 84 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=100/0→425/75) to give the title compound (3.87 g, 97%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].[I-].[Na+]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: Oc1cccc(Br)c1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)COc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
A solution of 3-bromophenol (17.3 g, 100 mmol) in 30 ml of THF is added at ambient temperature to a 50% solution of sodium hydride dispersed in mineral oil (5 g, 125 mmol) in 50 ml of anhydrous THF. The mixture was stirred at ambient temperature for 30 minutes before successively adding a solution of methyl bromoacetate (10.4 ml, 110 mmol) in 33 ml of anhydrous THF and sodium iodide (3.75 g, 25 mmol). The reaction medium is stirred for 30 minutes at ambient temperature and then treated with 30 ml of water at 0° C. The raw product is purified by chromatography on silica (eluent petroleum ether:ether 100:10). 19.66 g of methyl 3-bromophenoxyacetate is obtained (yield=80%).
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.F[C:26]1[C:31]([F:32])=[CH:30][C:29]([C:33]([F:36])([F:35])[F:34])=[CH:28][N:27]=1>CN1CCCC1=O>[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][N:22]([C:26]3[C:31]([F:32])=[CH:30][C:29]([C:33]([F:36])([F:34])[F:35])=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:11][CH:12]=2)[CH2:4][CH2:3]1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: Fc1cc(C(F)(F)F)cnc1F
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2ncc(C(F)(F)F)cc2F)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrochloride and 2,3-difluoro-5-trifluoromethyl-pyridine following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 16): tR=0.56 min; Mass spectrum (ESI+): m/z=475 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.O>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)cc1
Reactant: Fc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Brc1ccc(COc2ccccn2)cc1
Temperature: 54 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a solution of 4-bromobenzyl alcohol (25 g, 130 mmol) in N,N-dimethyl formamide (125 mL) was added potassium tert-butoxide (15.8 g, 141 mmol) at room temperature, which was stirred at 54° C. for 10 minutes. To this reaction solution was added 2-fluoropyridine (15 mL, 154 mmol) at from 40° C. to 58° C., which was further stirred for 30 minutes at 65° C. The reaction solution was allowed to room temperature, water and ethyl acetate were added, and liquid separation was carried out. The aqueous layer was further extracted with ethyl acetate (twice). The ethyl acetate layers were combined, washed with water (3 times) and sodium chloride water (once), dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under a reduced pressure. Diethyl ether was added to the residue, which was concentrated under a reduced pressure to obtain the title compound (34 g) as a crude product.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][C:9](=[O:14])[CH2:8]2)=[CH:3][CH:2]=1.[C:16]([O-])(=[O:18])[CH3:17].[Na+].C(C1C(=O)CC(C2C=CC(F)=CC=2)CC1=O)(=O)C>>[C:16]([CH:10]1[C:9](=[O:14])[CH2:8][CH:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:15])=[CH:6][CH:5]=2)[CH2:12][C:11]1=[O:13])(=[O:18])[CH3:17]
Reactant: Cc1ccc(C2CC(=O)CC(=O)C2)cc1
Reactant: CC(=O)[O-]
Agent: CC(=O)C1C(=O)CC(c2ccc(F)cc2)CC1=O
Agent: [Na+]
Product: CC(=O)C1C(=O)CC(c2ccc(C)cc2)CC1=O

Procedure:
The title compound was prepared from 5-p-tolyl-cyclohexane-1,3-dione (1.6 g, 5.74 mmol), from example 1/c stage 2, and sodium acetate (470 mg, 5.74 mmol), following the procedure describing the synthesis of 2-acetyl-5-(4-fluoro-phenyl)-cyclohexane-1,3-dione (example 3/a stage 1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14].Cl.[F:18][CH:19]1[CH2:22][NH:21][CH2:20]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:21]2[CH2:22][CH:19]([F:18])[CH2:20]2)=[O:8])=[CH:4][C:3]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14]
Reactant: FC1CNC1
Reactant: O=C(O)c1ccc(Br)c(OCC(F)(F)F)c1
Agent: Cl
Product: O=C(c1ccc(Br)c(OCC(F)(F)F)c1)N1CC(F)C1

Procedure:
Starting with 4-bromo-3-(2,2,2-trifluoroethoxy)benzoic acid and 3-fluoroazetidine hydrochloride, Int06.04 was prepared analogously to the procedure for the preparation of Int02.06.