Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.NN.[CH3:4][C:5]1[C:12]2[N:11]3[CH:13]=[CH:14][CH:15]=[C:10]3/[C:9](=[N:16]/[O:17][CH2:18][CH2:19][N:20]3C(=O)C4=CC=CC=C4C3=O)/[C:8]=2[S:7][CH:6]=1>C(O)C.C(O)(C)C>[CH3:4][C:5]1[C:12]2[N:11]3[CH:13]=[CH:14][CH:15]=[C:10]3/[C:9](=[N:16]/[O:17][CH2:18][CH2:19][NH2:20])/[C:8]=2[S:7][CH:6]=1
Reactant: Cc1csc2c1-n1cccc1/C2=N/OCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: CC(C)O
Solvent: O
Product: Cc1csc2c1-n1cccc1/C2=N/OCCN
Yield: 36.8 %

Procedure:
Add 0.3 ml (6.1 mmol) of hydrazine hydrate to a solution of 0.85 g (2.2 mmol) of (Z)-3-methyl-8-[(2-phthalimido-ethoxy)imino]thieno[2,3-d]pyrrolo[1,2-a]pyrrole in 50 ml of a mixture of ethanol/isopropanol, 1:1. The reaction mixture is heated to reflux. After refluxing the mixture for 30 minutes, add 0.3 ml of hydrazine hydrate and heat at reflux again for 90 minutes. Add 0.5 ml of hydrazine hydrate during the course of the 90 minutes' refluxing. After cooling the reaction mixture, the precipitate formed is removed by filtration and the filtrate is concentrated under reduced pressure. The residue is extracted with diethyl ether and the ethereal phase is washed with water, dried over magnesium sulfate, treated with animal charcoal and concentrated to yield 200 mg of the title product in the form of an oil (base).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:15][C:16]([OH:18])=O)[N:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)=[CH:48][C:47]=1[CH3:58].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:57][CH2:56][N:55]([C:16](=[O:18])[CH2:15][N:8]3[C:9]4=[N:10][CH:11]=[CH:12][CH:13]=[C:14]4[C:6]([C:2]4[NH:1][CH:5]=[CH:4][N:3]=4)=[N:7]3)[CH2:54][CH2:53]2)=[CH:48][C:47]=1[CH3:58]
Reactant: Cc1cc(N2CCNCC2)ccc1Cl
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4cccnc43)CC2)ccc1Cl
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A vial was charged with 2-(3-(1H-imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)acetic acid (55 mg, 0.226 mmol), HBTU (125 mg, 0.33 mmol), 1-(4-Chloro-3-methyl-phenyl)-piperazine dihydrochloride (142 mg, 0.50 mmol), anhydrous DMF (2.0 mL), and DIPEA (0.5 mL). The vial was capped, heated to 45° C., and stirred overnight. The following day, the volatiles were removed in vacuo and separation by preparative hplc (reverse phase, acetonitrile-water gradient) gave 1-[4-(4-Chloro-3-methyl-phenyl)-piperazin-1-yl]-2-[3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]-ethanone: MS (ES) [M+H]+ found: 436.4
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:32])=[C:21]([NH:25]C(=O)OCC=C)[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.CC(O)=O.C([SnH](CCCC)CCCC)CCC>C(Cl)Cl.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>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:32])=[C:21]([CH:22]=[CH:23][CH:24]=2)[NH2:25])[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To a solution of 2-propen-1-yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}carbamate (28 g, 59 mmol) in DCM (300 mL), HOAc (8.5 g, 141.6 mmol), Pd(PPh3)2Cl2 (0.827 g, 1.18 mmol) were added. Then tri-n-butyl tin hydride (27 g, 88.5 mmol) was added dropwise to the mixture at 0° C. The mixture was stirred at rt for 30 min. The reaction was quenched by added the saturated NaHCO3 (200 mL) slowly. The two layers were separated. The aqueous layer was extracted with DCM (300 mL×2). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was washed with petroleum ether (200 mL) to afford the title compound, which was used to the next step directly. (22.5 g, 97.8% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.35 (d, J=5.3 Hz, 1H), 7.01-7.08 (m, 1H), 6.98 (d, J=5.3 Hz, 1H), 6.85-6.92 (m, 1H), 6.79-6.85 (m, 1H), 4.05-4.12 (m, 2H), 3.79-3.86 (br, 2H), 3.51-3.59 (m, 2H), 3.23-3.34 (m, 1H), 2.07-2.15 (m, 2H), 1.89-2.01 (m, 2H).
Reaction SMILES: [O:1]1[CH2:23][CH:2]1[CH2:3][CH:4]([CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CO>[OH:1][CH:2]([CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[CH2:3][CH:4]([CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)C(Cc1cccc2ccccc12)CC1CO1
Solvent: CO
Product: CC(C)(C)OC(=O)C(Cc1cccc2ccccc12)CC(O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.6 %

Procedure:
A mixture of 2 g (6.4 mmole) of t-butyl 4,5-epoxy-2-(1-naphthylmethyl)pentanoate (prepared as described in Preparation 11), 0.84 ml of morpholine and 50 ml of methanol was stirred at room temperature for 6 hours and then allowed to stand overnight. The reaction mixture was then concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel (eluent: a 10 : 90 by volume mixture of methanol and methylene chloride), to afford 1.96 g (76.6%) of the title compound as a pale yellow oil.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:33])[NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][CH:25]=4)=[CH:17][CH:16]=3)[N:12]=[C:11]3[N:34]([CH:37]([CH2:41][O:42][CH3:43])[CH2:38][O:39][CH3:40])[N:35]=[CH:36][C:10]=13)[CH2:2]2.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[CH3:62][N:63]([CH3:65])[NH2:64].Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH3:62][N:63]([CH3:65])[NH:64][C:28]([C:27]1[CH:31]=[CH:32][C:24]([NH:23][C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([C:13]3[N:12]=[C:11]4[N:34]([CH:37]([CH2:38][O:39][CH3:40])[CH2:41][O:42][CH3:43])[N:35]=[CH:36][C:10]4=[C:9]([N:3]4[CH2:2][CH:1]5[O:8][CH:5]([CH2:6][CH2:7]5)[CH2:4]4)[N:14]=3)=[CH:16][CH:17]=2)=[O:33])=[CH:25][CH:26]=1)=[O:30]
Reactant: COCC(COC)n1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(C(=O)O)cc4)cc3)nc21
Reactant: CN(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COCC(COC)n1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(C(=O)NN(C)C)cc4)cc3)nc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.3 %

Procedure:
A mixture of 4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(1,3-dimethoxypropan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)ureido)benzoic acid (0.11 g, 0.19 mmol), 1-hydroxybenzotriazole hydrate (HOBT, 51 mg, 0.37 mmol), N-methylmorpholine (63 μL, 0.57 mmol), and N,N-dimethylhydrazine (63 μL, 0.57 mmol) in dimethylformamide (3 mL) was treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC, 72 mg, 0.37 mmol). After approximately 20 minutes, additional quantities of N,N-dimethylhydrazine (100 μL) and EDC (100 mg) were added. The mixture was stirred overnight at room temperature and then purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 75% acetonitrile to provide 1-{4-[(2,2-dimethylhydrazino)carbonyl]phenyl}-3-(4-{1-[2-methoxy-1-(methoxymethyl)ethyl]-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl}phenyl)urea (114 mg, 95%). MS (ES+): 630.3 (M+H)+
Reaction SMILES: [CH3:1]N(C)C=O.[Br:6][C:7]1[CH:8]=[C:9]([OH:15])[C:10]([OH:14])=[CH:11][C:12]=1[F:13].C(=O)([O-])[O-].[Cs+].[Cs+].BrCCl>CCOCC>[Br:6][C:7]1[C:12]([F:13])=[CH:11][C:10]2[O:14][CH2:1][O:15][C:9]=2[CH:8]=1
Reactant: CN(C)C=O
Reactant: Oc1cc(F)c(Br)cc1O
Agent: ClCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Product: Fc1cc2c(cc1Br)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To N,N-dimethylformamide (25 mL) in a 50 mL flask was added 4-bromo-5-fluorobenzene-1,2-diol (2 g, 9.66 mmol), cesium carbonate (4.72 g, 14.49 mmol) and bromochloromethane (1.875 g, 14.49 mmol). The reaction mixture was allowed to stir at room temperature for 1 h and was then heated to an external temperature of 80° C. for 3 h. Upon cooling, the reaction mixture was diluted with Et2O (75 mL) and washed with water (50 mL) followed by a wash with saturated NaCl solution (50 mL). The organic layer was dried over MgSO4 and filtered. Concentration of the organic solution gave 5-bromo-6-fluorobenzo[d][1,3]dioxole as a light orange solid (1.8 g, 85%): 1H NMR (400 MHz, CDCl3) δ 6.94 (d, J=5.9 Hz, 1H), 6.67 (d, J=7.9 Hz, 1H), 6.00 (s, 2H); 19F NMR (376 MHz, CDCl3) δ −113.82 (s); ESIMS m/z 220 ([M+H]+), 218 ([M−H]−).
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].[F:15][C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[CH2:24][NH2:25]>>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:25]([CH2:24][C:17]2[CH:18]=[C:19]([F:23])[C:20]([F:22])=[CH:21][C:16]=2[F:15])[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: NCc1cc(F)c(F)cc1F
Product: Cl
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1cc(F)c(F)cc1F

Procedure:
According to the method of Example 160, 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide was reacted with 1-(2,4,5-trifluorophenyl)methanamine to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:5]=[CH:4][C:3]=1[NH2:20].[CH3:21][C:22]1([CH3:31])[CH2:27][CH2:26][C:25](B(O)O)=[CH:24][CH2:23]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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>[C:14]([Si:11]([CH3:13])([CH3:12])[O:10][CH2:9][C:8]([C:6]1[CH:5]=[CH:4][C:3]([NH2:20])=[C:2]([C:25]2[CH2:26][CH2:27][C:22]([CH3:31])([CH3:21])[CH2:23][CH:24]=2)[CH:7]=1)([CH3:19])[CH3:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)c1ccc(N)c(Br)c1
Reactant: CC1(C)CC=C(B(O)O)CC1
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: C1COCCO1
Solvent: CCOC(C)=O
Product: CC1(C)CC=C(c2cc(C(C)(C)CO[Si](C)(C)C(C)(C)C)ccc2N)CC1
Temperature: 90 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a mixture of 2-bromo-4-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-phenylamine (as prepared in the previous step, 1.50 g, 4.19 mmol), 4,4-dimethylcyclohexen-1-ylboronic acid (1.09 g, 4.61 mmol) and Pd(PPh3)4 (484 mg, 0.419 mmol) in 50 mL of 1,4-dioxane was added aqueous Na2CO3 (16.8 mL, 33.5 mmol, 2.0 M). The resulting mixture was stirred at 90° C. for 16 h under Ar. After cooling to RT, the mixture was treated with 150 mL of EtOAc and washed with H2O (3×30 mL) and brine (30 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (5-10% EtOAc/hexane) to afford 1.46 g (90%) of the title compound as a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C24H41NOSi, 388.3 (M+H). found 388.3.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[Cl:13]C1C=C(C(OCC)=O)NC=1C>>[Cl:13][C:6]1[C:2]([CH3:1])=[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:4][C:5]=1[CH3:7]
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Reactant: CCOC(=O)c1cc(Cl)c(C)[nH]1
Product: CCOC(=O)c1[nH]c(C)c(Cl)c1C

Procedure:
Title compound was synthesized from ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate (commercially available) by an analogous method to Intermediate 9.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.N[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19].C[N:21](C)C=O>>[OH:19][C:14]1[CH:15]=[CH:16][C:17]([N:21]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])=[CH:18][CH:13]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1ccccc1O
Reactant: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1c1ccc(O)cc1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
360 g (2.43 mol) of phthalic anhydride are used as initial charge in 1.2 l of DMF (dimethylformamide) in a round-bottomed flask. 264 g (2.42 mol) of aminophenol are added slowly to this mixture. The mixture is stirred at 140° C. for 8 hours. During this period, water is removed by distillation by way of the head of a column. The mixture is permitted to cool to room temperature, and the precipitated solid is removed by suction filtration. The solid is washed first with water and then with ethanol, and is then dried in vacuo. This gives 445 g of a beige-coloured solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5](Br)=[CH:6][CH:7]=1.CO.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[C:11]1([C:5]2[N:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(-c2ccccc2)nc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 86.3 %

Procedure:
To a solution of 3-amino-6-bromopyridine (1.1 g, 6.4 mmol) in THF (7 mL)-MeOH (7 mL) at RT was added phenylboronic acid (1.60 g, 12.8 mmol), PXPd (69 mg, 0.13 mmol), followed by K2CO3 (3.54 g, 25.6 mmol). The reaction mixture was stirred at 70° C. in a preheated oil bath for 16 h. After cooling to RT, the reaction mixture was poured into water (10 mL), and the resultant mixture was extracted with EtOAc (3×40 mL). The combined organic layers were washed with saturated NaCl, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by silica gel (40 g) column chromatography eluting with a gradient of EtOAc (30-100%) in hexane to give the title compound as an off-white solid (940 mg, 86%). LC/MS (method A): retention time=1.28 min, (M+H)+=171.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[S:10][C:11]3[CH:17]=[C:16]([OH:18])[C:15]([F:19])=[CH:14][C:12]=3[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27]([NH:29][CH3:30])=[O:28])[CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[CH:1]1([CH2:7][NH:8][C:9]2[S:10][C:11]3[CH:17]=[C:16]([O:18][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([C:27]([NH:29][CH3:30])=[O:28])[CH:22]=4)[C:15]([F:19])=[CH:14][C:12]=3[N:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Oc1cc2sc(NCC3CCCCC3)nc2cc1F
Reactant: CNC(=O)c1cc(Cl)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CNC(=O)c1cc(Oc2cc3sc(NCC4CCCCC4)nc3cc2F)ccn1
Temperature: 85 °C
Reaction time: 12 h
Yield: 4.3 %

Procedure:
To the solution of 2-(cyclohexylmethylamino)-5-fluorobenzo[d]thiazol-6-ol (25 mg, 0.089 mmol, 1.0 eq) in 2 mL of NMP was added 4-chloro-N-methylpicolinamide (18 mg, 0.107 mmol, 1.2 eq) and cesium carbonate (86 mg, 0.267 mmol, 3.0 eq) at room temperature. The reaction mixture was stirred at 85° C. for 12 hours, thereafter the mixture was purified on reverse phase HPLC giving 1.6 mg of product as TFA salt in ca. 3.5% yield. LC/MS (m/z) [415.1] (MH+)
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Mg]Br)C.C(OCC)C.[CH3:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=1)=[O:19]>C1COCC1>[I:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)([OH:19])[CH3:17])=[CH:21][CH:22]=1
Reactant: Ic1cccnc1
Reactant: CC(=O)c1ccc(I)cc1
Agent: CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)(c1ccc(I)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-iodopyridine (0.3 g, 1.463 mmol) in THF (4 ml) was added ethylmagnesium bromide in diethylether (3M) (0.976 ml, 2.93 mmol). The mixture was stirred at room temperature overnight. GC-MS after overnight showed no starting material and the reaction mixture was cooled in an ice-bath. 4-Iodoacetophenone (0.468 g, 1.902 mmol) was added. The ice-bath was removed after 15 minutes and the reaction was stirred at room temperature for 5 hrs. The reaction mixture was quenched with aqueous saturated NH4Cl solution before dilution with ethyl acetate. The organic phase was separated and washed with brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product which was purified by preparative HPLC (reversed phase). Fractions containing product were pooled and worked up (addition of NaHCO3, removal of acetonitrile followed by extraction with DCM) to obtain the title compound as yellowish oil.
Reaction SMILES: [OH:1][CH:2]([C:4]1[N:5]=[C:6]([CH2:14][CH2:15][CH3:16])[NH:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:3].[C:17]([N:36]1[C:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]2[CH:54]=[CH:53][C:50]([CH2:51]Br)=[CH:49][CH:48]=2)=[N:39][N:38]=[N:37]1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(C)([O-])C.[K+]>>[OH:1][CH:2]([C:4]1[N:5]=[C:6]([CH2:14][CH2:15][CH3:16])[N:7]([CH2:51][C:50]2[CH:49]=[CH:48][C:47]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[C:40]3[N:36]([C:17]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:37]=[N:38][N:39]=3)=[CH:54][CH:53]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:3]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1nc(C(C)O)c(C(=O)OCC)[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCc1nc(C(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 72.6 %

Procedure:
Following a procedure similar to that described in Example 35(a), but using 113 mg of ethyl 4-(1-hydroxyethyl)-2-propylimidazole-5-carboxylate [prepared as described in Preparation 23(iii)], 280 mg of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide and 60 mg of potassium t-butoxide, 255 mg of the title compound were obtained as a viscous oil. The Nuclear Magnetic Resonance Spectrum of this compound was identical with that of the compound obtained as described in Example 40(b).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[Cl:19][CH2:20][CH2:21][CH2:22][N:23]1[C:28](=[O:29])[C:27]([CH3:30])=[CH:26][N:25]([CH2:31][C:32]2[O:33][CH:34]=[CH:35][CH:36]=2)[C:24]1=[O:37]>>[ClH:19].[F:18][C:2]([F:1])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:20][CH2:21][CH2:22][N:23]2[C:28](=[O:29])[C:27]([CH3:30])=[CH:26][N:25]([CH2:31][C:32]3[O:33][CH:34]=[CH:35][CH:36]=3)[C:24]2=[O:37])[CH2:13][CH2:12]1
Reactant: Cc1cn(Cc2ccco2)c(=O)n(CCCCl)c1=O
Reactant: FC(F)(F)COc1ccccc1N1CCNCC1
Product: Cc1cn(Cc2ccco2)c(=O)n(CCCN2CCN(c3ccccc3OCC(F)(F)F)CC2)c1=O
Product: Cl

Procedure:
substituting 1-[2-(2,2,2-trifluoroethoxy)phenyl]piperazine and 3-(3-chloropropyl)-1-fur-2-ylmethyl-5-methyl-2,4(1H,3H)-pyrimidinedione gave 3-(3-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazine-1-yl}propyl)-1-fur-2-ylmethyl-5-methyl-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 132°-134° C.; Anal.: Calcd. for C25H29F3N4O4.(HCl)2 : C, 51.81; H, 5.39; N, 9.66%; Found: C, 51.89; H, 5.44; N, 9.55%;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=[C:12]([C:15]3[N:16]4[C:20]([C:21]([C:24](O)=[O:25])=[CH:22][CH:23]=3)=[CH:19][CH:18]=[CH:17]4)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:65][CH2:66][CH2:67][C:68]1[CH:69]=[CH:70][C:71]2[C:75]([CH3:77])([CH3:76])[O:74][B:73]([OH:78])[C:72]=2[CH:79]=1>CN(C=O)C.O>[Cl:9][C:6]1[CH:5]=[C:4]([C:10]2([C:27]([F:30])([F:28])[F:29])[O:14][N:13]=[C:12]([C:15]3[N:16]4[C:20]([C:21]([C:24]([NH:65][CH2:66][CH2:67][C:68]5[CH:69]=[CH:70][C:71]6[C:75]([CH3:76])([CH3:77])[O:74][B:73]([OH:78])[C:72]=6[CH:79]=5)=[O:25])=[CH:22][CH:23]=3)=[CH:19][CH:18]=[CH:17]4)[CH2:11]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[F:8]
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Reactant: CC1(C)OB(O)c2cc(CCN)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2cc(CCNC(=O)c3ccc(C4=NOC(c5cc(Cl)c(F)c(Cl)c5)(C(F)(F)F)C4)n4cccc34)ccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.9 mmol) and HATU (513 mg, 1.35 mmol) in DMF (18 mL), DIPEA (350 mg, 2.7 mmol) can be added. The reaction mixture can be stirred at rt for 10 min and crude 6-(2-aminoethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (1 mmol) can be added. The reaction mixture can be continued to stir overnight. Water can be added and the mixture can be extracted three times with ethyl acetate. The combined organic layers can be washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue can be purified by prep-HPLC to give the final title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:8]2[CH:9]=[C:10]([CH:27]=[CH:28][C:29]=2F)[C:11]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[O:12])=[C:5]([CH3:7])[N:6]=1.Cl.[NH:32]1[CH2:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.CC#N>[N:32]1([C:29]2[CH:28]=[CH:27][C:10]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)[CH2:17][CH2:18]3)=[O:12])=[CH:9][C:8]=2[C:4]2[NH:3][C:2]([CH3:1])=[N:6][C:5]=2[CH3:7])[CH2:35][CH2:34][CH2:33]1
Reactant: Cc1nc(C)c(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)ccc2F)[nH]1
Reactant: C1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CC#N
Solvent: O
Product: Cc1nc(C)c(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)ccc2N2CCC2)[nH]1
Temperature: 120 °C
Reaction time: 48 h
Yield: 27.1 %

Procedure:
Into a 10-mL sealed tube, was placed a solution of 4-(1-(3-(2,4-dimethyl-1H-imidazol-5-yl)-4-fluorobenzoyl)piperidin-4-yl)benzonitrile (compound 25.1, 200 mg, 0.50 mmol) in 1,4-dioxane (4 mL). Azetidine hydrochloride (50 mg, 0.53 mmol) and cesium carbonate (500 mg, 1.53 mmol) were added and the mixture was stirred for 48 h at 120° C. behind a blast shield. The mixture was cooled and the solids were removed by filtration. The filtrate was concentrated under reduced pressure and the crude product was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, Water with 50 mmol NH4HCO3 and CH3CN (33.0% CH3CN up to 46.0% in 10 min, up to 100.0% in 3 min, down to 33.0% in 1 min); Detector, Waters 2489, 254 & 220 nm. The fractions containing pure compound were combined and lyophilized to yield 59.6 mg (27%) of the title compound as a white solid m/z (ES+) 440 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=1.[CH2:12](Br)[CH:13]=[CH2:14]>>[OH:1][C:2]1[C:7]([CH2:12][CH2:13][CH3:14])=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: C=CCBr
Reactant: COc1ccc(O)cc1OC
Product: CCCc1cc(OC)c(OC)cc1O

Procedure:
Following the procedure as in Example 3B, the same product can be obtained starting from 1-hydroxy-3,4-dimethoxybenzene and allyl bromide, Claisen rearrangement and hydrogenation