Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:29]=2[F:35])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([CH2:16][N:17]([CH2:25][CH3:26])C(=O)OC(C)(C)C)([F:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].Cl>C(#N)C.O1CCOCC1>[CH2:25]([NH:17][CH2:16][C:13]1([F:15])[CH2:14][N:11]([C:9]([C:4]2[C:3]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:29]=3[F:35])=[C:2]([F:1])[C:7]([F:8])=[CH:6][CH:5]=2)=[O:10])[CH2:12]1)[CH3:26]
Reactant: CCN(CC1(F)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: CCNCC1(F)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Yield: 27.3 %

Procedure:
To the 1,1-dimethylethyl [{1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-fluoroazetidin-3-yl]methyl}ethylcarbamate (19.0 mg, 0.031 mmol) in acetonitrile (1.0 mL) added a solution 4.0N hydrogen chloride in dioxane (1.0 mL). After 1.5 hr the solution was concentrated in vacuo. The residue was purified by preparative reverse phase HPLC to afford the title compound (4.30 mg, 27%). 1H NMR (400 MHz, CDCl3): 8.25 (s, 1H), 7.33 (dd, 1H), 7.33-7.25 (m, 1H), 7.18-7.14 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.58 (m, 1H), 4.33-4.05 (br m, 4H), 3.07-2.95 (br m, 2H), 2.65 (q, 2H), 1.08 (t, 3H); MS (EI) for C19H18F4IN3O: 508 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:14]([Sn](CCCC)(CCCC)C=C)[CH2:15]CC.CCOC(C)=O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:14]([C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1)=[CH2:15]
Reactant: CCOC(=O)Cc1cccc(Br)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1cccc(CC(=O)OCC)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To a mixture of ethyl 2-(3-bromophenyl)acetate (1.5 g, 6.1 mmol) in anhydrous DMF (15 mL) was added tributyl(vinyl)stannane (2.1 mL, 7.4 mmol) and tetrakis(triphenylphosphine) palladium (400 mg, 0.5 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 110° C. for 8 hours. Followed a standard aqueous/EtOAc workup. Purified by silica gel column chromatography (petroleum: ether/ethyl acetate=15:1) (640 mg, yield 54%).
Reaction SMILES: [C:1]([C:4]1[C:5]([F:13])=[C:6](N)[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[CH3:14][C:15](C1C=CC(OC)=CC=1F)=[O:16].C(O)CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:13][C:5]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=1[C:1]1([CH3:2])[O:16][CH2:15][CH2:14][O:3]1
Reactant: COc1ccc(C(C)=O)c(F)c1N
Reactant: COc1ccc(C(C)=O)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCCO
Solvent: Cc1ccccc1
Product: COc1ccc(C2(C)OCCO2)c(F)c1

Procedure:
Starting material 3-acetyl-2-fluoro-6-methoxyphenyl-amine, was prepared in following manner: A mixture of 2-Fluoro-4-methoxyacetophenone (5 g)(Fluorochem), ethylene glycol (4 ml), and p-toluensulfonic acid (50 mg) in toluene was refluxed 10 hours to give 5.7 g of 2-(2-fluoro-4-methoxyphenyl)-2-methyl-1,3-dioxolane. This was converted to 2-fluoro-6-methoxy-3-(2-methyl-1,3-dioxol-2-yl)-benzaldehyde according to Example 362 of WO 93/03022. This compound was converted to 2-fluoro-6-methoxy-3-(2-methyl-1,3-dioxol-2-yl)-cinnamic acid ethylester according to the methods described in Example 353 of WO 93/03022. 2-Fluoro-6-methoxy-3-(2-methyl-1,3-dioxol-2-yl)cinnamic acid ethylester was then treated with KOH in dioxane and water to yield 2-fluoro-6-methoxy-3-(2-methyl-1,3-dioxol-2-yl)cinnamic acid. Hydrolysis with aqueous HCl in dioxane gave 3-acetyl-2-fluoro-6-methoxycinnamic acid. N-(3-Acetyl-2-fluoro-6-methoxyphenyl)-N′-(5-chloropyrid-2-yl)-urea was then prepared in a manner analogous to the method in Example 7. 1H NMR (250 MHz, CDCl3) δ 9.18 (br s, 1H), 8.97 (br s, 1H), 7.85 (d, 1H), 7.83 (t, 1H), 7.51 (dd, 1H), 6.83 (d, 1H), 6.70 (d, 1H), 3.82 (s, 3H), 3.57 (q, 2H), 3.08-2.92 (m, 2H), 2.51 (d, 3H).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][Br:16])=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccccc1)c1ccc(CBr)cc1
Temperature: 25 °C

Procedure:
To a solution of 4.0 g (20 mmol) of 4-benzoyltoluene and 3.6 g (20 mmol) of N-bromosuccinimide in 120 ml of carbon tetrachloride was added 0.05 g (0.2 mmol) of benzoyl peroxide. The reaction was refluxed for 17 hours, cooled to room temperature and filtered. The filtrate was evaporated and the crude product was taken on without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([OH:17])=O)[S:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:19]([CH3:18])[C:15]([C:13]1[S:14][C:5]2[C:4]3[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]=3[O:8][CH2:7][C:6]=2[CH:12]=1)=[O:17]
Reactant: Cc1ccc2c(c1)-c1sc(C(=O)O)cc1CO2
Reactant: CNc1ccc(F)cc1F
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(c1)-c1sc(C(=O)N(C)c3ccc(F)cc3F)cc1CO2
Reaction time: 24 h

Procedure:
8-Methyl-4H-thieno[3,2-c]chromene-2-carboxylic acid was converted to the acid chloride as in Example 3, then treated with N-methyl-2,4-difluoroaniline (1.5 equiv), and triethylamine (5 equiv) in dichloromethane and N,N-dimethyl-4-aminopyridine (0.2 equiv) at 24° C. After about 24 hr, the reaction mixture was diluted with dichloromethane, and the resulting solution was washed with saturated aqueous sodium bicarbonate. The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (5:2 hexanes/ethylacetate) provided 167bp. 1H NMR (500 MHz, CDCl3) δ 7.29 (m, 1 H), 6.95-6.98 (m, 4 H,), 6.78 (d, J=8.2 Hz, 1 H), 5.04 (s, 2 H), 3.39 (s, 3 H), 2.27 (s, 3 H). LCMS (ESI) m/z: 372.1.
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][N:8]([CH3:30])[CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38](=O)[C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)[N:33]=1.O>O1CCCC1>[Br:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH:38]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)/[CH:10]=[CH:9]\[N:8]([CH3:30])[CH3:7])[N:33]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cccc(Br)n1
Reactant: CN(C)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)/C=C\C(c1ccc(Cl)cc1)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of n-butyllithium (60 mL, 1.55M in hexane) was added dropwise during 45 min to a stirred suspension of (2-dimethylaminoethyl)triphenylphosphonium bromide (38.1 g) in dry tetrahydrofuran (500 mL) under nitrogen. After an additional hour at room temperature, a solution of 2-bromo-6-(4-chlorobenzoyl)pyridine (27.3 g) in dry tetrahydrofuran (200 mL) was added dropwise. The mixture was stirred at room temperature for 20 min, then refluxed for 80 min, cooled to room temperature, and poured into water (500 mL). The ether layer was separated and the aqueous phase extracted with three additional portions of ether. The ether layers were combined, washed once with water, dried (MgSO4) and evaporated to give an oil which was triturated with hexane (500 mL). The hexane layer was decanted and concentrated to give a crude mixture of isomeric Z and E alkenes which were separated by chromatography (Waters Prep 500) on silica gel with 95:5/methylene chloride: methanol (E, 7.53 g; Z, 15.19 g). The individual isomers were then rechromatographed on silica gel with ethyl acetate to yield (Z)-2-bromo-6-(1-(4-chlorophenyl)-3-dimethylaminoallyl)pyridine, m.p. 56°-62°, and (E)-2-bromo-6-(1-(4-chlorophenyl-3-diomethylaminoallyl)pyridine, 69°-70°.
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4](N)=[O:5].S(=O)(=O)(O)[OH:15]>>[F:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([OH:15])=[O:5]
Reactant: Cc1c(F)c(F)cc(C(N)=O)c1F
Reactant: O=S(=O)(O)O
Product: Cc1c(F)c(F)cc(C(=O)O)c1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 2,4,5-trifluoro-3-methylbenzamide (0.38 g) in 18N sulfuric acid (3 ml) was stirred on an oil bath (100° to 110° C.) for 2 hours. After cooling, to the reacting mixture was added ice-water (10 ml), the resulting precipitate was collected by filtration and recrystallized from hexane to give the title compound (0.30 g) as colorless needles, mp 103°-105° C.
Reaction SMILES: [CH2:1]([Sn:9](=[O:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:19](O)[CH2:20][OH:21]>C1(C)C=CC=CC=1>[CH2:1]([Sn:9]1([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:21][CH2:20][CH2:19][O:18]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC[Sn](=O)CCCCCCCC
Reactant: OCCO
Solvent: Cc1ccccc1
Product: CCCCCCCC[Sn]1(CCCCCCCC)OCCO1
Temperature: 60 °C
Reaction time: 25.5 h
Yield: 97.6 %

Procedure:
2.0005 g (5.54 mol) of dioctyltin oxide and 0.344 g (5.54 mmol) of ethylene glycol were introduced into a 100 ml reaction vessel equipped with a Dean-Stark device, and the atmosphere in the reaction vessel was replaced by argon. 70 ml of toluene was added, and the mixture was dehydrated by azeotropic distillation at 135° C. and stirred for 25.5 hours during which it became an uniform solution. After left and cooled to 60° C., the toluene was distilled off under reduced pressure. The resulting white solids were dried at 60° C. for 5 hours in vaccuo to give 1,1-dioctylstanna-2,5-dioxacyclopentane, 2.19 g (97.6% yield).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:18])[C:14]([C:15]([OH:17])=O)=[C:10]2[CH:9]=[C:8]([CH3:19])[CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[NH2:54][CH2:55][C@H:56]1[CH2:61][CH2:60][C@H:59]([C:62]([O:64][CH3:65])=[O:63])[CH2:58][CH2:57]1.C(O)(C(F)(F)F)=O>CN(C=O)C.O>[F:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:18])[C:14]([C:15]([NH:54][CH2:55][C@H:56]3[CH2:57][CH2:58][C@H:59]([C:62]([O:64][CH3:65])=[O:63])[CH2:60][CH2:61]3)=[O:17])=[C:10]2[CH:9]=[C:8]([CH3:19])[CH:7]=1
Reactant: COC(=O)[C@H]1CC[C@H](CN)CC1
Reactant: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)O)c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@H](CNC(=O)c2c(C)nn3c(OCc4c(F)cccc4F)cc(C)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 100 mg (0.30 mmol, 1.0 eq.) of 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid from Example 4A, 116 mg of TBTU (0.36 mmol, 1.2 eq.) and 0.132 ml (1.2 mmol, 4.0 eq.) of 4-methylmorpholine in 2.2 ml of DMF was admixed with 103 mg (0.60 mmol, 2.0 eq.) of methyl trans-4-(aminomethyl)cyclohexanecarboxylate, and the mixture was stirred at RT overnight. The reaction mixture was admixed with water and TFA and purified by means of preparative HPLC (RP18 column, eluent:acetonitrile/water gradient with addition of 0.1% TFA). The product fractions were combined and concentrated. Subsequently, the residue was taken up in dichloromethane and a little methanol, and washed twice with saturated aqueous sodium hydrogencarbonate solution. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered, concentrated and lyophilized. 67 mg of the target compound were obtained (46% of theory).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][N:5]2[C:16]1[C:24]2[C:19](=[C:20]([F:25])[CH:21]=[CH:22][CH:23]=2)[N:18]([CH3:26])[N:17]=1.[CH:27]1([N:30]2[CH:34]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:32]=[N:31]2)[CH2:29][CH2:28]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].O>[CH:27]1([N:30]2[CH:34]=[C:33]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][N:5]4[C:16]3[C:24]4[C:19](=[C:20]([F:25])[CH:21]=[CH:22][CH:23]=4)[N:18]([CH3:26])[N:17]=3)[CH:32]=[N:31]2)[CH2:29][CH2:28]1
Reactant: CC1(C)OB(c2cnn(C3CC3)c2)OC1(C)C
Reactant: CC(=O)N1c2ccc(Br)cc2N(c2nn(C)c3c(F)cccc23)C[C@@H]1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)cc2N(c2nn(C)c3c(F)cccc23)C[C@@H]1C
Temperature: 100 °C
Reaction time: 8 h
Yield: 26.8 %

Procedure:
A 100-mL round-bottom flask was purged with an inert atmosphere of nitrogen and charged with (S)-1-(6-bromo-4-(7-fluoro-1-methyl-1H-indazol-3-yl)-2-methyl-3,4-dihydroquinoxalin-1(2H)-yl)ethan-1-one (46 mg, 0.11 mmol), 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (77.6 mg, 0.33 mmol), [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (8 mg, 0.01 mmol), potassium carbonate (46 mg, 0.33 mmol), 1,4-dioxane (20 mL) and water (2 mL). The resulting mixture stirred overnight at 100° C. After cooling to room temperature, the reaction mixture was filtered through a short pad of celite and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 1:1, ethyl acetate/petroleum ether) to afford (S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-4-(7-fluoro-1-methyl-1H-indazol-3-yl)-2-methyl-3,4-dihydroquinoxalin-1(2H)-yl)ethanone (13.1 mg, 27%) as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 1.01-1.14 (m, 4H), 1.26 (d, J=6.90 Hz, 3H), 2.32 (s, 3H), 3.55-3.65 (m, 1H), 3.67-3.75 (m, 1H), 3.90-4.01 (m, 1H), 4.23 (s, 3H), 6.76 (s, 1H), 6.85-6.98 (m, 2H), 7.01-7.15 (m, 3H), 7.49 (s, 1H), 7.56 (s, 1H). MS (ESI, pos. ion) m/z 445 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.[ClH:10]>CO.[Pd]>[ClH:10].[CH3:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C#N)nn1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1ccc(CN)nn1
Reaction time: 2 h

Procedure:
To a solution of compound 2 (250 mg, 2.38 mmol) in MeOH (20 mL) was added 6N HCl (5 mL) followed by Pd/C (100 mg). The reaction mixture was kept on Parr shaker for 2 h at 40 psi. The reaction mixture was filtered through celite and washed with 5 mL of MeOH and the filtrate was concentrated to give compound 3 as a dark brown solid.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:9][CH2:10][OH:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[C:13]1[C:14]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][S:19][C:15]=2[N:16]=[CH:17][N:18]=1>C1COCC1.O>[C:22]1([C:21]2[C:14]3[C:13]([O:11][CH2:10][CH2:9][N:3]4[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]4)=[N:18][CH:17]=[N:16][C:15]=3[S:19][CH:20]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Clc1ncnc2scc(-c3ccccc3)c12
Reactant: OCCN1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(-c2csc3ncnc(OCCN4CCCCC4)c23)cc1
Reaction time: 0.17 h
Yield: 71.4 %

Procedure:
Sodium hydride (8 mg, 0.16 mmol) was suspended in dry THF (0.5 mL). To this was added 2-(1-piperidyl)ethanol (16 μL, 0.12 mmol) and the reaction stirred for 10 min until effervescence had ceased. Then 4-chloro-5-phenyl-thieno[2,3-d]pyrimidine (20 mg, 0.08 mmol) in dry THF (0.5 mL) was added and the reaction left to stir at room temperature for 72 hrs. The reaction mixture was diluted with water and extracted with DCM. The organic layers were concentrated and the residue purified by preparative TLC (eluent 10% MeOH in DCM) to give 5-phenyl-4-[2-(1-piperidyl)ethoxy]thieno[2,3-d]pyrimidine as a yellow oil (19.4 mg, 72%). LCMS RT=3.03 min. M+1=340.
Reaction SMILES: CCN=C=NCCCN(C)C.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]([C:26]([OH:28])=O)[C:20]2=[O:29])=[CH:15][CH:14]=1.C1C=CC2N(O)N=NC=2C=1.[NH2:40][C:41]1[CH:73]=[CH:72][C:44]([O:45][C:46]2[CH:51]=[CH:50][N:49]=[C:48]3[N:52]([CH2:63][C:64]4[CH:69]=[CH:68][C:67]([O:70][CH3:71])=[CH:66][CH:65]=4)[N:53]=[C:54]([NH:55][CH:56]4[CH2:61][CH2:60][N:59]([CH3:62])[CH2:58][CH2:57]4)[C:47]=23)=[C:43]([F:74])[CH:42]=1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[CH3:71][O:70][C:67]1[CH:66]=[CH:65][C:64]([CH2:63][N:52]2[C:48]3=[N:49][CH:50]=[CH:51][C:46]([O:45][C:44]4[CH:72]=[CH:73][C:41]([NH:40][C:26]([CH:21]5[CH2:22][CH2:23][CH2:24][CH2:25][N:19]([C:16]6[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=6)[C:20]5=[O:29])=[O:28])=[CH:42][C:43]=4[F:74])=[C:47]3[C:54]([NH:55][CH:56]3[CH2:61][CH2:60][N:59]([CH3:62])[CH2:58][CH2:57]3)=[N:53]2)=[CH:69][CH:68]=1
Reactant: O=C(O)C1CCCCN(c2ccc(F)cc2)C1=O
Reactant: COc1ccc(Cn2nc(NC3CCN(C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(NC3CCN(C)CC3)c3c(Oc4ccc(NC(=O)C5CCCCN(c6ccc(F)cc6)C5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.1 %

Procedure:
EDCI (48 mg, 0.25 mmol) was added to a mixture of the 1-(4-fluorophenyl)-2-oxoazepane-3-carboxylic acid (21 mg, 0.084 mmol) and HOBT (34 mg, 0.25 mmol) in DMF (0.5 mL) at ambient temperature, and the reaction mixture was stirred for 10 minutes at ambient temperature. 1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-N-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (20 mg, 0.042 mmol, obtained from Example 101, Step A) and triethylamine (0.035 ml, 0.25 mmol) were added. The resulting mixture was stirred for 12 hours at ambient temperature. The reaction mixture was diluted with EtOAc. The organic layer washed with 10% aqueous LiCl, dried over Na2SO4, and concentrated. The residue was purified by flash column chromatography (5% MeOH in CH2Cl2) to afford the product (20 mg, 67% yield) as a white solid. LRMS (APCI pos) m/e 710.3 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5](=[O:9])[O:6][CH2:7][CH3:8].[Cl:10][C:11]1[CH:26]=[CH:25][C:14]2[N:15]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:16](=[O:18])[NH:17][C:13]=2[CH:12]=1.C(=O)([O-])O.[Na+]>C(O)C>[Cl:10][C:11]1[CH:26]=[CH:25][C:14]2[N:15]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:2][CH2:3][NH:4][C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH2:23][CH2:24]3)[C:16](=[O:18])[NH:17][C:13]=2[CH:12]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Reactant: CCOC(=O)NCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)NCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1

Procedure:
A mixture of 12.94 parts of ethyl (2-bromoethyl)carbamate, 15.68 parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 10.08 parts of sodium hydrogen carbonate and 160 parts of ethanol is stirred and refluxed overnight. The formed precipitate is filtered off and washed with trichloromethane. The layers from the filtrate are separated. The organic phase is dried, filtered and evaporated. The residue is stirred in 2-propanone. The unreacted starting material is filtered off and the filtrate is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from ethanol 70%. The product is filtered off and dried, yielding 6.5 parts of ethyl {2-[4-(5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]-ethyl}carbamate; mp. 187.7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:29])[N:18]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:13][C@H:12]2[C:30]([NH:32][CH2:33][CH2:34][NH:35][CH2:36][C:37](=[O:39])[NH2:38])=[O:31])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:46][O:47][C:48]1[CH:55]=[CH:54][CH:53]=[CH:52][C:49]=1[CH2:50]Cl.CCN(C(C)C)C(C)C>C(#N)C.C(Cl)(Cl)Cl>[CH2:24]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:9](=[O:10])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C@H:12]([C:30]([NH:32][CH2:33][CH2:34][N:35]([CH2:50][C:49]2[CH:52]=[CH:53][CH:54]=[CH:55][C:48]=2[O:47][CH3:46])[CH2:36][C:37](=[O:39])[NH2:38])=[O:31])[CH2:13]1)=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2cccc(Cl)c2)[C@H](C(=O)NCCNCC(N)=O)C1
Reactant: COc1ccccc1CCl
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2cccc(Cl)c2)[C@H](C(=O)NCCN(CC(N)=O)Cc2ccccc2OC)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 23 %

Procedure:
A solution of 74 mg (ca. 0.11 mmole) of 1-(N-(3-chlorophenyl)-N-phenylcarbamoyl)-2-(2-(N-(methylcarboxamido)amino)-N-(methyl)ethylaminocarbonyl)- 4-(N,N-di-n-pentylcarbamoyl)piperazine (from Step E above) in 2 mL of acetonitrile was treated with 72 mg (0.23 mmole) of a 50 wt % solution of 2-methoxybenzyl chloride in chloroform and 60 microliters (0.35 mmole) of DIEA, and the mixture was stirred at room temperature for 24 hours and then at 80° C. for 36 hours. After cooling to room temperature, the mixture was concentrated in vacuo and the residue purified by flash chromatography on 23 g of silica gel eluting with 500 mL of 100:3:0.1 CH2Cl2 :methanol:ammonia water. Impure fractions containing product were resubmitted to the chromatographic conditions given above. The pooled product fractions were then purified by flash chromatography on 23 g of silica gel eluting with 700 mL of 100:2 CH2Cl2 :methanol and then 200 mL of 100:4 CH2Cl2 :methanol to provide 20 mg (23%) of an oil.
Reaction SMILES: O1CCCCC1OC1C[CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[CH:18]3)[CH2:10][CH2:9]1.[NH:24]1C2C(=CC(OC3CCC(O)CC3)=CC=2)C=N1>>[NH:24]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[CH:18]3)[CH2:12]1
Reactant: c1cc2[nH]ncc2cc1OC1CCC(OC2CCCCO2)CC1
Reactant: OC1CCC(Oc2ccc3[nH]ncc3c2)CC1
Product: c1cc2[nH]ncc2cc1OC1CCNC1

Procedure:
The following compound of Example 379 was synthesized by carrying out reactions according to the methods described in Example 372, (b) and Example 377 except for using the tert-butyl 4-hydroxyazepane-1-carboxylate obtained in Example 322, (c), as a reagent.
Reaction SMILES: O[CH2:2][CH2:3][O:4][CH2:5][C:6]1[O:7][CH:8]=[CH:9][CH:10]=1.C(N(C(C)C)CC)(C)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([CH2:2][CH2:3][O:4][CH2:5][C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOCc1ccco1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)CCOCc1ccco1
Reaction time: 1.5 h

Procedure:
Combine fur-2-ylmethyl 2-hydroxyethyl ether (10 mmol), and diisopropylethylamine (4.0 mL, 23 mmol), and dichloromethane (20 mL). Cool in an ice-bath. Add dropwise, methanesulfonyl chloride (1.0 mL, 13 mmol). After 1.5 hours, extract the reaction mixture with 1M aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to obtain fur-2-ylmethyl 2-methanesulfonylethyl ether.