Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:12]=[CH:11][NH:10][C:9]=1[CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]2[S:30][C:29]([CH:31]([CH:35]([CH3:37])[CH3:36])[C:32](O)=[O:33])=[CH:28][C:27]=2[CH:38]=1>CCOCC>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]2[S:30][C:29]([CH:31]([CH:35]([CH3:36])[CH3:37])[C:32]([O:14][CH2:13][C:9]3[NH:10][CH:11]=[CH:12][C:8]=3[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:33])=[CH:28][C:27]=2[CH:38]=1
Reactant: OCc1[nH]ccc1Cc1ccccc1
Reactant: CC(C)C(C(=O)O)c1cc2cc(Cl)ccc2s1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)C(C(=O)OCc1[nH]ccc1Cc1ccccc1)c1cc2cc(Cl)ccc2s1
Reaction time: 1 h

Procedure:
To a stirred solution of 3-benzylpyrrolylmethyl alcohol (0.99 mmol) and triethylamine (0.14 g, 1.38 mmol) in ether (about15 ml), under nitrogen, is added a solution of the acid chloride of 2-(5-chloro-2-benzothienyl)-3-methylbutanoic acid (1.5 mmol) in either. The mixture is stirred for about 60 minutes and then quenched with saturated aqueous NaHCO3. The ether phase is washed with aqueous NaHCO3, water and brine, dried over sodium sulfate and solvent evaporated to give 3-benzylpyrrolylmethyl 2-(5-chloro-2-benzothienyl)-3-methylbutanoate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][NH:9][S:10]([CH:13](S(CC)(=O)=O)[CH3:14])(=[O:12])=[O:11])[CH:5]=[N:6][CH:7]=1.[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1B(O)O>>[CH2:13]([S:10]([N:9]([CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:22]2[N:21]([CH3:20])[C:29]3[C:24]([CH:23]=2)=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:3]=1)[S:10]([CH2:13][CH3:14])(=[O:11])=[O:12])(=[O:12])=[O:11])[CH3:14]
Reactant: Cn1c(B(O)O)cc2ccccc21
Reactant: CCS(=O)(=O)C(C)S(=O)(=O)NCc1cncc(Br)c1
Product: CCS(=O)(=O)N(Cc1cncc(-c2cc3ccccc3n2C)c1)S(=O)(=O)CC

Procedure:
N-((5-Bromopyridin-3-yl)methyl)-1-(ethylsulfonyl)ethanesulfonamide and N-methyl-indole-2-boronic acid are processed according to the procedure described in Example 100 to give N-(ethylsulfonyl)-N-((5-(1-methyl-1H-indol-2-yl)pyridin-3-yl)methyl)ethanesulfonamide. MS (ESI) m/z 422.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]1[N:12]=[N:13][N:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])=[CH:18][CH:17]=2)[CH:15]=1.[CH2:30]([N:37]1[CH2:42][CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH2:39][CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH2:30]([N:37]1[CH2:38][CH:39]=[C:40]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[C:5]3[C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)=[O:23])=[CH:18][CH:17]=3)[CH:15]=2)[CH2:41][CH2:42]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(c1ccc(-n2cc(-c3n[nH]c4ccc(Br)cc34)nn2)cc1)N1CCOCC1
Reactant: CC1(C)OB(C2=CCN(Cc3ccccc3)CC2)OC1(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccc(-n2cc(-c3n[nH]c4ccc(C5=CCN(Cc6ccccc6)CC5)cc34)nn2)cc1)N1CCOCC1
Temperature: 150 °C

Procedure:
A suspension of {4-[4-(5-Bromo-1H-indazol-3-yl)-[1,2,3]triazol-1-yl]-phenyl}-morpholin-4-yl-methanone (100 mg; 0.22 mmol; 1.0 eq.), 1-Benzyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,6-tetrahydro-pyridine; hydrochloride (J&W Pharm Lab, 222 mg; 0.66 mmol; 3.00 eq.), Pd2Cl2(PPh3)2(15 mg; 0.02 mmol; 0.1 eq.), potassium carbonate (91 mg; 0.66 mmol; 3.0 eq.) in dioxane (2 mL) and water (1 mL) was degassed with nitrogen flow and heated in MW at 150° C. for 10 min. The reaction mixture was filtered through a celite pad, water was added to the filtrate. Aqueous phase was extracted three times with DCM using separators tubes. Combined organic phases were concentrated under reduced pressure and the crude was purified by flash chromatography on silica (DCM/MeOH, gradient from 100:0 to 90:10) to give the title compound as yellow powder. 1H NMR (300 MHz, DMSO-d6) δ 13.37 (brs, 1H), 9.39 (s, 1H), 8.30 (s, 1H), 8.22-8.10 (m, 2H), 7.76-7.65 (m, 2H), 7.65-7.50 (m, 2H), 7.42-7.31 (m, 4H), 7.31-7.22 (m, 1H), 6.30-6.10 (m, 1H), 3.78-3.50 (m, 8H), 3.47-3.37 (m, 2H), 3.18-3.07 (m, 2H), 2.77-2.56 (m, 4H). HPLC (Condition A): Rt 2.87 min (purity 97.5%). MS (ESI+): 546.4, MS (ESI−): 544.3.
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][C:7]1[S:8][C:9]([C:12]([F:15])([F:14])[F:13])=[N:10][N:11]=1)=[O:5])[NH2:3].[CH2:16]=O.[OH-].[K+]>CO>[CH3:1][N:2]1[C:4](=[O:5])[N:6]([C:7]2[S:8][C:9]([C:12]([F:15])([F:13])[F:14])=[N:10][N:11]=2)[CH2:16][NH:3]1
Reactant: CN(N)C(=O)Nc1nnc(C(F)(F)F)s1
Reactant: C=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1NCN(c2nnc(C(F)(F)F)s2)C1=O
Temperature: 35 °C

Procedure:
The 2-methyl-4-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)semicarbazide prepared in Example 2 was dissolved in methanol (100 ml) in a glass reaction flask equipped with a mechanical stirrer and thermometer. Aqueous formaldehyde (12 ml; 37% concentration) was then added to the flask with stirring. The reaction mixture warmed to a temperature of about 35°C. Sufficient aqueous potassium hydroxide was then added to adjust the pH of the reaction medium to from about 7 to 8. A solid precipitate was formed. The precipitate was then recovered by filtration, was recrystallized from an ethyl acetate-heptane mixture and was dried under vacuum to yield the desired product 2-methyl-4-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-1,2,4-triazolidin-3-one having a melting point of 187° to 188°C.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11](OC)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][OH:20].[OH-].[K+]>C1COCC1.CO>[OH:20][NH:19][C:11](=[O:12])[C:10]1[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=1[C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccccc1C#Cc1ccccc1
Reactant: NO
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NO)c1ccccc1C#Cc1ccccc1
Temperature: 0 °C
Yield: 42.5 %

Procedure:
In a 100 mL round-bottomed flask was added methyl 2-(phenylethynyl)benzoate 36 (157 mg, 0.665 mmol) in THF (1.33 mL) and MeOH (1.33 mL) and the solution was cooled to 0° C. Then, a 50% aqueous solution of hydroxylamine (2195 mg, 33.2 mmol) was added followed by a 4M aqueous solution of KOH (0.33 mL, 1.329 mmol) and the resulting colorless solution was stirred at 0° C. and allowed to slowly warm to rt for 20 h. The reaction mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (2×) and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The yellow oil was crystallized in Et2O and the filtrate was evaporated and triturated again in Et2O. The solids were combined to afford title compound 37 (67 mg, 43% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.98 (s, 1H), 9.20 (s, 1H), 7.61 (d, J=7.4 Hz, 1H), 7.55-7.43 (m, 814). LRMS (ESI): (calc.) 237.25 (found) 238.2 (MH)+
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)[CH:17]=1>>[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([C:18]3[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=3)=[CH:29][CH:28]=2)[CH:8]=1
Reactant: COC(=O)CCc1cccc(CN)c1
Reactant: O=Cc1ccc(-c2cccnc2)cc1
Agent: Cl
Product: COC(=O)CCc1cccc(CNCc2ccc(-c3cccnc3)cc2)c1

Procedure:
The title compound of Step A was prepared from 3-(3-aminomethyl-phenyl)-propionic acid methyl ester hydrochloride salt, of Preparation 44, and 4-pyridin-3-yl-benzaldehyde, of Preparation 23, using the method described in Example 1, Step A. 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 8.55 (m, 1H), 7.81 (d, 1H), 7.53 (d, 2H), 7.46 (d, 2H), 7.32 (m, 1H), 7.22 (m, 3H), 7.09 (d, 1H), 3.84 (s, 2H), 3.80 (s, 2H), 3.63 (s, 3H), 2.92 (t, 2H), 2.61 (t, 2H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:32][C:33]1[C:38]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:37][CH:36]=[C:35]([C:48]2[CH:53]=[CH:52][C:51]([OH:54])=[CH:50][CH:49]=2)[N:34]=1.[CH2:55]([C@@H:60]1[O:62][C@H:61]1[CH2:63]O)[CH2:56][CH2:57][CH2:58][CH3:59]>O1CCCC1>[F:32][C:33]1[C:38]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:37][CH:36]=[C:35]([C:48]2[CH:49]=[CH:50][C:51]([O:54][CH2:63][C@H:61]3[C@H:60]([CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[O:62]3)=[CH:52][CH:53]=2)[N:34]=1
Reactant: CCCCC[C@@H]1O[C@H]1CO
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)cc2)nc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2ccc(OC[C@@H]3O[C@H]3CCCCC)cc2)nc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
0.91 g (5.25 mmol) of diethyl azodicarboxylate is added dropwise at 0° C. to 1.37 g (5.25 mmol) of triphenylphosphine in 20 ml of tetrahydrofuran, and the mixture is stirred at 0° C. for 30 minutes. 1.11 g (3.50 mmol) of 2-fluoro-6-(4-hydroxyphenyl)-3-octyloxypyridine (prepared as described in EXAMPLE 21) and 0.75 g (5.25 mmol) of (2S,3S)-3-pentyl-2-oxiranylmethanol are then added. After a reaction time of 18 hours at room temperature, the solvent is distilled off, and the residue is purified by chromatography (silica gel, 8:2 hexane/ethyl acetate). Recrystallization from hexane gives 0.85 g of (2S,3S)-3-pentyloxiran-2-ylmethyl 4-(2-fluoro-3-octyloxypyridin-6-yl)phenyl ether having an [α]D20 (2.6% in CH2Cl2) of -18.01°. ##STR71##
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:24][C:25]([F:42])([F:41])[C:26]1[C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:34][C:33]2[CH2:32][CH2:31][NH:30][CH2:29][C:28]=2[N:27]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>C(Cl)CCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22])[CH2:10][C:11]([N:30]1[CH2:29][C:28]2[N:27]=[C:26]([C:25]([F:42])([F:41])[F:24])[C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:34][C:33]=2[CH2:32][CH2:31]1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)ccc1F
Reactant: CCOC(=O)c1cc2c(nc1C(F)(F)F)CNCC2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCOC(=O)c1cc2c(nc1C(F)(F)F)CN(C(=O)C[C@@H](Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C)CC2

Procedure:
(3R)-3-[(tert-Butoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoic acid (intermediate 1) and ethyl 2-(trifluoromethyl)-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carboxylate hydrochloride (intermediate 27) were treated with EDC, HOBt and N,N-diisopropylethylamine according to the procedure described for Example 1, Step A to afford the title compound as a white foam.
Reaction SMILES: [CH2:1]([N:3]([CH2:45][CH3:46])[CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([NH:15][C:16](=[O:36])[CH2:17][N:18]([CH2:26][CH2:27][O:28]CC3C=CC=CC=3)CC3C=CC=CC=3)=[C:10]3[O:37][C:38]4[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][C:39]=4[C:8]([C:9]=23)=[N:7]1)[CH3:2].[H][H].[ClH:49].O>C(O)(=O)C.[OH-].[OH-].[Pd+2]>[ClH:49].[CH2:45]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([NH:15][C:16](=[O:36])[CH2:17][NH:18][CH2:26][CH2:27][OH:28])=[C:10]3[O:37][C:38]4[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][C:39]=4[C:8]([C:9]=23)=[N:7]1)[CH3:46]
Reactant: CCN(CC)CCn1nc2c3c(c(NC(=O)CN(CCOCc4ccccc4)Cc4ccccc4)ccc31)Oc1ccc(O)cc1-2
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCN(CC)CCn1nc2c3c(c(NC(=O)CNCCO)ccc31)Oc1ccc(O)cc1-2

Procedure:
A mixture of 1.3 g of the above acetamide and 0.10 g of 20% palladium hydroxide on carbon in 50 ml of glacial acetic acid stirred under hydrogen at atmospheric pressure until the hydrogen uptake measured 100 ml. The reaction mixture was filtered and coevaporated several times with methanol. The residue was dissolved in methanol and acidified with a solution of hydrogen chloride in 2-propanol. Further dilution with 2-propanol and cooling caused precipitation of a crystalline solid. The solid was isolated and dried to give 0.976 g of the product as a yellow crystalline solid with 2.5 equivalents of hydrogen chloride and 1.5 equivalents of water, mp 285° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([NH:13][CH3:14])[C:5]([C:6](OCC)=[O:7])=[CH:4][N:3]=1.[BH4-].[Li+]>C1COCC1.CO>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[C:11]([NH:13][CH3:14])[CH:12]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1NC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CNc1cc(Cl)ncc1CO
Temperature: 55 °C
Yield: 111.1 %

Procedure:
To a solution of ethyl 6-chloro-4-(methylamino)nicotinate (4.7 g, 21.9 mmol) in THF (30 mL) and methanol (30 mL) was added lithium borohydride (2.4 g, 109.8 mmol), and the reaction mixture was heated at 55° C. overnight. LCMS showed the reaction was completed. The reaction was cooled to RT, quenched with water (1 mL) and filtered. The filtrate was concentrated to afford the title compound (4.2 g, crude) as a white solid, which was directly used in the next step without further purification. MS (ES+) C7H9ClN2O requires: 172, 174. Found: 173, 175 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([F:11])[C:3]=1[F:12].Br[C:14]1[N:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.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>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]2[N:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=2)=[C:4]([F:11])[C:3]=1[F:12]
Reactant: Nc1cnc(Br)cn1
Reactant: OB(O)c1ccc(Br)c(F)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1cnc(-c2ccc(Br)c(F)c2F)cn1
Temperature: 80 °C
Yield: 33 %

Procedure:
A mixture of (4-bromo-2,3-difluorophenyl)boronic acid (400 mg, 1.69 mmol) and 5-bromopyrazin-2-amine (588 mg, 3.38 mmol was suspended in EtOH (5.6 ml) and toluene (5.7 mL) The resulting mixture was treated with aqueous Na2CO3 (2.0 N, 4.2 mL, 8.45 mmol). The resulting mixture was then sparged with nitrogen through the mixture for 10 min, and then Pd(PPh3)4 (98 mg, 0.085 mmol) was added. The reaction vessel was sealed and heated at 80° Celsius for 17 hours. The reaction mixture was cooled to rt and then partitioned between saturated aqueous NH4Cl and EtOAc. The organic layer was dried over MgSO4 and concentrated to dryness. The residue was suspended in DCM and the solid isolated by filtration to afford the title compound (160 mg, 33%), which was used without further purification. MS (ESI): mass calcd. for C10H6BrF2N3, 284.97; m/z found, 286.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.01 (d, J=1.2, 1H), 7.68-7.56 (m, 2H), 6.87 (s, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1>C(Cl)Cl>[NH:21]1[CH2:20][CH2:19][CH:18]([O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][N:9]=[CH:10]3)[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3[nH]ncc3c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc2[nH]ncc2cc1OC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
Trifluoroacetic acid (0.20 ml, 2.60 mmol) was added to a solution of tert-butyl 4-(1H-indazol-5-yloxy)-1-piperidinecarboxylate (70 mg, 0.221 mmol) in methylene chloride (5 ml) at room temperature and stirred overnight at room temperature. Then, the solvent of the reaction solution was distilled off under reduced pressure and the resulting residue was poured into a 1N-aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 5-(4-piperidinyloxy)-1H-indazole (25 mg, 52%).
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH3:11])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([F:22])[CH:16]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(OC2C=CC=CC=2)C=CC=CC=1>[F:22][C:17]1[CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:20]=[CH:19][C:18]=1[O:21][C:2]1[C:3]2[N:10]([CH3:11])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cn1ccc2ncnc(Cl)c21
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cn1ccc2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c21
Temperature: 140 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A suspension of 4-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (28) (300 mg, 1.79 mmol), 4-nitro-2-fluorophenol (422 mg, 2.69 mmol) and cesium carbonate (1.2 g, 3.58 mmol) in diphenyl ether (18 mL) was stirred overnight at 140° C. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and the residue was triturated with Et2O, filtered, and dried to afford the title compound 29 as a grey solid (258 mg, 49% yield). LRMS (M+1) 289.1 (100%).
Reaction SMILES: [OH-:1].[Na+].BrBr.[F:5][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])C)=[CH:11][CH:10]=1>O.O1CCOCC1>[F:5][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([OH:17])=[O:1])=[CH:13][CH:14]=1
Reactant: CCCCCCCCC(F)COc1ccc(C(C)=O)cc1
Reactant: [OH-]
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCCC(F)COc1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.3 %

Procedure:
A solution of 11.3 g of sodium hydroxide in 75 ml of water was charged in a 300 ml-three necked flask and cooled to 0° C., and 12.3 g of bromine was added thereto in 15 minutes under stirring, followed by addition of 30 ml of dioxane. The resultant mixture solution was added dropwise in 40 minutes to a solution which was obtained by dissolving 5.2 g of p-(2-fluorodecyloxy) acetophenone in 170 ml of dioxane followed by addition of 10 ml of water, and subjected to reaction for 3.5 hours while being kept below 10° C. Thereafter, the excessive hypobromite was removed by addition of a hydrosulfite aqueous solution, followed by acidification with addition of 6N-hydrochloric acid aqueous solution, and addition of 500 ml of water to precipitate a crystal, which was then recovered by filtration. The crystal was recrystallized from isopropyl ether to obtain 4.1 g of p-(2-fluorodecyloxy)benzoic acid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[C:9]([O:13][C:14]([NH:16][CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:19]2[CH2:20][CH2:21][CH:17]([NH:16][C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:18]2)[CH:7]=1
Reactant: Cc1ccnc(F)c1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccnc(N2CCC(NC(=O)OC(C)(C)C)C2)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
A suspension of 2-fluoro-4-methylpyridine (1.11 g), 3-(tert-butoxycarbonylamino)pyrrolidine (1.68 g) and potassium carbonate (1.49 g) in N,N-dimethylformamide (20 ml) was stirred at 100° C. for 16 hours. After cooling, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water five times and brine, dried over sodium sulfate and evaporated under reduced pressure to give 1-(4-methylpyridin-2-yl)-3-(tert-butoxycarbonylamino)pyrrolidine (1.36 g).
Reaction SMILES: Cl.[F:2][C:3]([F:28])([F:27])[C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[CH:6]([O:18][CH:19]1[CH2:22][NH:21][CH2:20]1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1.[C:29]([N:33]=[C:34]=[O:35])([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-]>>[F:28][C:3]([F:27])([F:2])[C:4]1[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=1[CH:6]([O:18][CH:19]1[CH2:22][N:21]([C:34]([NH:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:20]1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1
Reactant: CC(C)(C)N=C=O
Reactant: FC(F)(F)Oc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Product: CC(C)(C)NC(=O)N1CC(OC(c2ccc(OC(F)(F)F)cc2)c2ccccc2C(F)(F)F)C1

Procedure:
This material was prepared from 3-[2-(trifluoromethyl)-4′-(trifluoro-methoxy)benzhydryloxy]azetidine hydrochloride (141) (0.234 mmol), tert-butyl isocyanate (0.234 mmol) and MP-carbonate (2.62 mmol/g, 0.702 mmol) using the procedure described for compound (10) (78.7 mg, 69%).
Reaction SMILES: [N:1]1[O:2][C:3]2[CH2:4][CH2:5][CH2:6][CH:7]3[C:16]=2[C:15]=1[C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:8]3.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:8]2[CH:7]3[C:16]4=[C:3]([O:2][N:1]=[C:15]4[C:14]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=4)[CH2:4][CH2:5][CH2:6]3)=[CH:20][CH:19]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: c1ccc2c(c1)NC1CCCc3onc-2c31
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(CN2c3ccccc3-c3noc4c3C2CCC4)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In 40 ml dry DMF were combined 3.00 g 4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine, 8.8 ml 4-fluorobenzylbromide and 3 g milled K2CO3. The mixture was stirred mechanically under nitrogen at ambient temperature for 2 days during which the reaction was complete. The reaction mixture was poured into excess water and extracted with DCM. The DCM layer was concentrated to a residue and the residue was triturated with 1:1 methanol/water and recrystallized from 1:1 DCM/hexanes to yield after drying 2.21 g needles, m.p. 214° C. (dec.).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:20][CH3:21])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=3)[C:6]=2[N:7]=1.[Cl:22][C:23]1[N:24]=[CH:25][N:26]([C:28]2[N:33]=[CH:32][C:31]([NH2:34])=[CH:30][C:29]=2[O:35][CH3:36])[CH:27]=1>C(O)(=O)C.C1COCC1>[Cl:22][C:23]1[N:24]=[CH:25][N:26]([C:28]2[N:33]=[CH:32][C:31]([NH:34][C:2]3[N:3]=[C:4]([NH:20][CH3:21])[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=5)[C:6]=4[N:7]=3)=[CH:30][C:29]=2[O:35][CH3:36])[CH:27]=1
Reactant: COc1cc(N)cnc1-n1cnc(Cl)c1
Reactant: CNc1nc(Cl)nc2c1CCC2c1cc(F)c(F)c(F)c1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNc1nc(Nc2cnc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCC2c1cc(F)c(F)c(F)c1
Temperature: 80 °C

Procedure:
2-Chloro-N-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (100 mg, 0.319 mmol) was added to a solution of 6-(4-chloro-1H-imidazol-1-yl)-5-methoxypyridin-3-amine (107 mg, 0.478 mmol) in acetic acid (2 mL) and THF (2.000 mL). The reaction mixture was heated at 80° C. overnight. Partial formation of the desired product was observed. The reaction mixture was heated at 130° C. for 6 h. The crude reaction mixture was purified by preparative HPLC. The appropriate fractions were evaporated to afford N2-(6-(4-chloro-1H-imidazol-1-yl)-5-methoxypyridin-3-yl)-N4-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine, TFA salt (12.9 mg, 0.021 mmol, 6.50% yield). LC-MS (M+H)+=502.2. 1H NMR (500 MHz, CDCl3) δ ppm 12.33 (1H, s), 8.75 (1H, s), 8.56 (1H, s), 7.61-7.89 (2H, m), 6.85-7.00 (2H, m), 5.62-5.79 (1H, m), 4.36-4.49 (1H, m), 4.02 (3H, s), 3.29 (3H, d, J=4.9 Hz), 2.88-2.98 (1H, m), 2.76-2.85 (2H, m), 2.21-2.38 (1H, m).