Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:21]=[CH:22]/[C:23](O)=[O:24])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:10]1.[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][NH2:33].CCN=C=NCCCN(C)C.C(OCC)(C)=O.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:21]=[CH:22]/[C:23]([NH:33][O:32][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][O:26]2)=[O:24])[CH:5]=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:10]1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1cnc(N[C@@H]2CCN(CC3CCCCC3)C2)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(/C=C/c1cnc(N[C@@H]2CCN(CC3CCCCC3)C2)c(Cl)c1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.7 %

Procedure:
A mixture of (2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid (306 mg), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (108 mg) HOBt (119 mg) and EDCI (137 mg) in DMF (15 ml) was stirred at ambient temperature for 15 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (9:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give (2E)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (100 mg).
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[CH3:9][C:10]([C:13]1[CH:14]=[C:15]([SH:23])[CH:16]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:18]=1)([CH3:12])[CH3:11].C(N(CC)CC)C>O1CCCC1>[CH3:12][C:10]([C:13]1[CH:14]=[C:15]([S:23][CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2=[O:8])[CH:16]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:18]=1)([CH3:9])[CH3:11]
Reactant: O=C1CCCCC1Cl
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(SC2CCCCC2=O)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-Chlorocyclohexanone (0.6 g, 0.0045 moles) was added to a cold (+5° C.) solution of 3,5-bis (1,1-dimethylethyl)benzenethiol (Example 2)(1.0 g, 0.0045 moles) in tetrahydrofuran (50 ml). The solution was stirred for 15 minutes. Triethylamine (1.25 ml) was added, the cold bath was removed and the mixture was stirred at room temperature for 20 hours and then at 50° C. for 2 hours. The mixture was cooled to room temperature and filtered to remove a white solid. The filtrate was concentrated to an oil. The product was purified by silica gel chromatography to give a white solid which was recrystallized from hexane (DSC 81.49° C.). The structure was supported by NMR and Ir.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH2:9][CH2:10]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]=2[N:22]=1.C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>C(Cl)(Cl)Cl>[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][N:18]([CH2:10][CH2:9][CH:8]=[CH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:19][CH2:20][C:21]=2[N:22]=1
Reactant: BrCCC=Cc1ccccc1
Reactant: Nc1nc2c(s1)CCNCC2
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Nc1nc2c(s1)CCN(CCC=Cc1ccccc1)CC2
Yield: 39 %

Procedure:
Prepared analogously to Example 8 from 4-phenyl-3-buten-1-yl-bromide [boiling point 93° C./1,5 torr; prepared from 1-cyclopropyl-1-phenyl-carbinol with phosphorous tribromide] with 4 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in pure chloroform during 8 hours at 60° C. Yield: 39% of theory, Melting point: 157°-158° C. (chloroform/toluene)
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:22]=[CH:21][C:10]([C:11]([NH:13][CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:23][S:24]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])=[O:25].C(O)(=O)C.[CH3:37][CH:38]([CH3:41])[CH:39]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[O:12])=[CH:21][CH:22]=2)=[N:4][C:3]=1[CH2:23][S:24]([CH:27]1[CH2:28][CH2:29][N:30]([CH2:37][CH:38]([CH3:41])[CH3:39])[CH2:31][CH2:32]1)(=[O:25])=[O:26]
Reactant: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCNCC1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCN(CC(C)C)CC1
Temperature: 30 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
A solution of 4-[5-methyl-4-[(piperidine-4-sulfonyl)methyl]-1,3-oxazol-2-yl]-N-(pyridin-3-ylmethyl)benzamide (300 mg, 0.66 mmol, 1.00 equiv), acetic acid (59.3 mg, 0.99 mmol, 1.50 equiv) and 2-methylpropanal (57 mg, 0.79 mmol, 1.20 equiv) in 1,2-dichloroethane (3 mL) was stirred at room temperature for 4 h. Sodium triacetoxyborohydride (420 mg, 1.98 mmol, 3.00 equiv) was added in small batches and the resulting solution was stirred overnight at 30° C. The resulting mixture was concentrated under vacuum and the residue was diluted with 2 mL of methanol. The solution was loaded onto a C18 column and eluted with acetonitrile/water to give 200 mg (59%) of 4-(5-methyl-4-[[1-(2-methylpropyl) piperidine-4-sulfonyl]methyl]-1,3-oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide as a white solid. LC-MS (ES, m/z): 511 [M+H]+, 306, 256; 1HNMR (300 MHz, CD3OD, ppm) δ 8.60 (s, 1H), 8.47 (d, 1H), 8.11 (d, 2H), 7.99 (d, 2H), 7.89 (d, 1H), 7.47-7.43 (m, 1H), 4.65 (s, 2H), 4.41 (s, 2H), 3.33-3.08 (m, 3H), 2.50.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[NH:6][N:5]=1)(=[O:3])[CH3:2].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.CN(C=O)C.[CH2:50]([O:52][C:53](=[O:74])[C@H:54]([OH:73])[CH2:55][C@H:56]([NH2:72])[CH2:57][C:58]1[CH:63]=[CH:62][C:61]([C:64]2[CH:69]=[C:68]([Cl:70])[CH:67]=[CH:66][C:65]=2[F:71])=[CH:60][CH:59]=1)[CH3:51]>C(Cl)Cl>[CH2:50]([O:52][C:53](=[O:74])[C@H:54]([OH:73])[CH2:55][C@H:56]([NH:72][C:9]([C:7]1[CH:8]=[C:4]([C:1](=[O:3])[CH3:2])[NH:5][N:6]=1)=[O:11])[CH2:57][C:58]1[CH:59]=[CH:60][C:61]([C:64]2[CH:69]=[C:68]([Cl:70])[CH:67]=[CH:66][C:65]=2[F:71])=[CH:62][CH:63]=1)[CH3:51]
Reactant: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cc(Cl)ccc2F)cc1
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(C(C)=O)[nH]n1
Temperature: 25 °C
Yield: 14.6 %

Procedure:
To a stirred solution of 3-acetyl-1H-pyrazole-5-carboxylic acid (50.9 mg, 330 mol), HATU (125 mg, 330 μmol), and DIPEA (104 μL, 0.6 mmol) in DMF (0.6 mL, 7.7 mmol), was added (2R,4R)-4-amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxypentanoic acid ethyl ester (110 mg, 300 μmol). The resulting mixture was stirred at room temperature until the reaction was complete. The mixture was diluted with DCM and washed with saturated aqueous NaHCO3. The organics were dried over Na2SO4, and the solvent removed. Half of material was then purified by preparative HPLC to yield the title compound (22 mg) as a TFA salt. MS m/z [M+H]+ calc'd for C25H25ClFN3O5, 502.15. found 502.1.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]C(C)(C)C([O-])([O-])[O-]>C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[I:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: Cc1ccc(I)c(C(=O)O)c1
Reactant: CC(C)(C)C([O-])([O-])[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C)ccc1I
Temperature: 25 °C

Procedure:
To a solution of 2-iodo-5-methyl benzoic acid (10.0 g, 0.038 mol) in toluene (200 mL) was added trimethylorthoacetate (25 mL) at room temperature. The reaction mixture was refluxed for 12 hours. The reaction mixture was cooled to room temperature and diluted with saturated sodium bicarbonate and ethyl acetate. The layers were separated and the organic layer washed with brine. The organic layer was dried (MgSO4) and solvent removed to give 10.35 g of methyl 2-iodo-5-methylbenzoate (EX-25A) as a yellow oil with an m/z+1=277.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH:11]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:19][CH2:11][CH2:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:16][CH:15]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=CCc1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=[N+]([O-])c1cccc(CCNCc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.4 %

Procedure:
2-(3-nitrophenyl)acetaldehyde (1.2 g, 7.33 mmol) was dissolved in methanol (50 mL) and 4-fluorobenzylamine (1.88 g, 14.67 mmol) was added at 15° C. followed by 1-2 drops of glacial acetic acid. The reaction was stirred at room temperature for 2 hours then sodium borohydride (0.14 g, 3.6 6 mmol) was added in lots at 0-10° C. and the solution allowed to warm to room temperature and stirred for a further 2 hours. The reaction mixture was poured into sodium bicarbonate solution (75 mL) and stirred for 15 minutes. The mixture was extracted with EtOAc (2×60 mL) then the combined organic extracts were washed with brine (50 mL) and dried (Na2SO4). The solvents were removed under reduced pressure to afford the crude compound which was purified by column chromatography on neutral silica gel using 1-2% methanol in DCM to afford the title compound (0.793 g, 40%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH3:29])=[C:26]([CH:28]=1)[NH2:27]>>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH3:29])=[C:26]([CH:28]=1)[NH:27][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1
Reactant: Clc1cc(-c2ccccn2)nc(-c2ccccn2)n1
Reactant: COc1ccc(C)c(N)c1
Product: COc1ccc(C)c(Nc2cc(-c3ccccn3)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from a mixture 4-chloro-2,6-di(2-pyridinyl)pyrimidine (25 mg, 0.093 mmol) and 5-methoxy-2-methylaniline (19 mg, 0.140 mmol) similar to Example 111 and isolated as a white solid (21 mg, 61%). 1H NMR (CDCl3): 8.88–8.86 (m, 1H), 8.71–8.60 (m, 3H), 7.92–7.83 (m, 2H), 7.62 (s, 1H), 7.44–7.34 (m, 2H), 7.22 (d, J=8.4 Hz, 1H), 7.08 (d, J=2.7 Hz, 1H), 7.06 (s, 1H), 6.78 (dd, J=2.4, 8.4 Hz, 1H), 3.82 (s, 3H), 2.52 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:4]([Cl:10])=[N:5][C:6](Cl)=[N:7][CH:8]=1.[CH3:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.C(N(CC)CC)C>CCOCC.ClCCCl.CC(O)(C)C.[Cl-].[Zn+2].[Cl-]>[Cl:10][C:4]1[C:3]([C:2]([F:12])([F:11])[F:1])=[CH:8][N:7]=[C:6]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([CH3:13])=[CH:15][CH:16]=2)[N:5]=1
Reactant: Cc1ccc(N)cc1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Reaction time: 1 h

Procedure:
To a solution of 5-trifluoromethyl-2,4-dichloropyrimidine (2 g; 9.2 mmol) in 1:1 DCE/t-BuOH (80 mL) was added Zinc chloride (11 mL of a 1M solution in ether; 1.2 eq) at 0° C. After 1 hour, 4-methylaniline (988 mg; 1 eq) was added followed by dropwise addition of a solution of triethylamine (1.03 g; 1.1 eq) in 10 mL of DCE/t-BuOH. After stirring for 1.5 hours the reaction was concentrated. Analytical HPLC analysis revealed that the crude reaction contained <5% of isomer 9. The desired product 8 was obtained as a white solid (2.25 g; 85%) following crystallization from methanol. HPLC ret. Time: 8.169 min. LRMS (M+): 288.2, 290.1.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.B(O)(O)[C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1>>[CH3:17][C:7]1[C:6]2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=[C:2]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]=12
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Product: Cc1ccc(-c2cc(C#N)cc3c(C)c4n(c23)CCCNC4=O)cc1

Procedure:
The title compound, grey solid (20 mg, 24%), MS (ISP) m/z=330.6 [(M+H)+], mp 287° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available p-tolylboronic acid (44.2 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([CH:4]([CH2:48][CH2:49][CH3:50])[C:5]([NH:7][CH2:8][C:9]([O:11][C@@H:12]1[C@@H:16]([CH2:17][O:18][C:19](=[O:31])[CH2:20][NH:21][C:22](=[O:30])[CH:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])[O:15][C@@H:14]([N:32]2[CH:39]=[C:38]([F:40])[C:36](=[O:37])[NH:35][C:33]2=[O:34])[C@@H:13]1[O:41]C1CCCCO1)=[O:10])=[O:6])[CH2:2][CH3:3].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[CH2:1]([CH:4]([CH2:48][CH2:49][CH3:50])[C:5]([NH:7][CH2:8][C:9]([O:11][C@@H:12]1[C@@H:16]([CH2:17][O:18][C:19](=[O:31])[CH2:20][NH:21][C:22](=[O:30])[CH:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])[O:15][C@@H:14]([N:32]2[CH:39]=[C:38]([F:40])[C:36](=[O:37])[NH:35][C:33]2=[O:34])[C@@H:13]1[OH:41])=[O:10])=[O:6])[CH2:2][CH3:3]
Reactant: CCCC(CCC)C(=O)NCC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](OC2CCCCO2)[C@@H]1OC(=O)CNC(=O)C(CCC)CCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CCCC(CCC)C(=O)NCC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1OC(=O)CNC(=O)C(CCC)CCC
Yield: 77.1 %

Procedure:
In 6 ml of ethanol was dissolved 0.5 g of 3',5'-bis-O-[N-(2-n-propyl-n-pentanoyl)glycyl]-2'-O-(2-tetrahydropyranyl)-5-fluorouridine, and after adding 18 mg of pyridinium p-toluenesulfonate at room temperature under stirring, the mixtuer was stirred at 55° C. for 3.5 hours. The residue obtained by condensing the reaction mixture under reduced pressure was applied to silica gel column chromatography to give 0.34 g (Yield: 77%) of the title compound.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([NH2:16])=O)[CH:10]=[CH:11][CH:12]=1>CN(C)C=O>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]#[N:16])[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(CC(N)=O)c1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cccc(CC#N)c1
Reaction time: 2 h

Procedure:
Thionyl chloride (1249 ml) was added dropwise to dry dimethylformamide (400 ml) stirring at 0°-5° C. under nitrogen over a period of about 2 hours. 3-Methoxyphenylacetamide (403.7 g) was added portionwise over a period of 45 minutes to the above solution under nitrogen maintaining the temperature between 0°-5° C. The reaction mixture was then stirred at 0°-5° C. for a further 2 hours. The reaction mixture was poured carefully onto ice/water (6 l). The aqueous mixture was extracted with ether. The extracts were washed with water, dried over magnesium sulphate and evaporated in vacuo to give a red liquid. The crude product was distilled (110°-112° C./12 mm Hg) to give 3-methoxyphenylacetonitrile.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:6]=1.[Li+].[OH-].Cl>C1COCC1>[F:16][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[CH:8]=[CH:9][C:5]([CH2:4][C:3]([OH:17])=[O:2])=[CH:6]2)=[CH:11][CH:12]=1
Reactant: COC(=O)Cc1ccn(-c2ccc(F)cc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccn(-c2ccc(F)cc2)c1
Temperature: 25 °C

Procedure:
To a solution of 2-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]-acetic acid methyl ester (100 mg, 0.43 mmol) in THF (1 mL) at 0° C. was added dropwise 2N aqueous LiOH (0.5 mL). After warming to ambient temperature over 4 hours, the mixture was added dropwise to 0.5N aqueous HCl (10 mL). The resultant light brown solid was collected by filtration, washed with H2O, and dried in vacuo over P2O5 to yield 700 mg (74%) of analytically pure 2-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]-acetic acid as a solid, mp 100-2° C. 1H NMR: δ 7.34-7.30 (m, 2H), 7.10 (t, 2H, J=8.6 Hz), 6.97-6.95 (m, 2H), 6.29 (t, 1H, J=2.2 Hz), 3.60 (s, 2H). Anal. Calculated for C12H10NO2F•0.15 H2O: C, 64.95; H, 4.68; N, 6.31. Found: C, 65.03; H, 4.71; N, 6.25.
Reaction SMILES: I[C:2]1[C:7]([CH:8]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:18])[N:5]=[C:4]2[S:19][C:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:3]=12.C(=O)([O-])[O-].[K+].[K+].[F:32][C:33]1[CH:34]=[C:35](B2OC(C)(C)C(C)(C)O2)[C:36]([CH3:43])=[C:37]2[C:42]=1[O:41][CH2:40][CH2:39][CH2:38]2.C(OCC)(=O)C>COCCOC.O.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>[CH3:18][C:6]1[N:5]=[C:4]2[S:19][C:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:3]2=[C:2]([C:35]2[C:36]([CH3:43])=[C:37]3[C:42](=[C:33]([F:32])[CH:34]=2)[O:41][CH2:40][CH2:39][CH2:38]3)[C:7]=1[CH:8]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1I)CCCC3
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cc(F)c2c1CCCO2
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: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1cc(F)c2c(c1C)CCCO2)CCCC3
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
To a solution of methyl 2-[4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate (0.075 g; 0.158 mmol) in a mixture of DME-water (3:1) (0.480 mL) were added potassium carbonate (0.066 g; 0.475 mmol), tetrakis(triphenylphosphine)palladium(0) (0.018 g; 0.016 mmol) and 2-(8-fluoro-5-methylchroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.069 g; 0.238 mmol). The solution was stirred for 30 min at 140° C. under a microwave irradiation. Ethyl acetate was added to the reaction mixture and the solution was washed with brine. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethylacetate (0-40%) in heptane furnished 0.046 g (57%) of the title compound as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[C:13]([N:15]2[CH:19]=[N:18][N:17]=[N:16]2)[CH:12]=[C:11]([C:20]([OH:22])=O)[CH:10]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:31][CH2:32][NH2:33])[CH:28]=[CH:29][CH:30]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:31][CH2:32][NH:33][C:20]([C:11]2[CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH:14]=[C:13]([N:15]3[CH:19]=[N:18][N:17]=[N:16]3)[CH:12]=2)=[O:22])[CH:28]=[CH:29][CH:30]=1
Reactant: COc1cccc(CCN)c1
Reactant: COc1ccccc1-c1cc(C(=O)O)cc(-n2cnnn2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cccc(CCNC(=O)c2cc(-c3ccccc3OC)cc(-n3cnnn3)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2′-Methoxy-5-tetrazol-1-yl-biphenyl-3-carboxylic acid 0.9 g, 3 mmol), 2-(3-methoxy-phenyl)-ethylamine (0.5 mL), EDCI (0.6 g), HOBt (0.4 g) were added to methylene chloride (9 mL), and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between 1N aqueous HCl and EtOAc, and the combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (3-20%, 5% NH4OH in MeOH/methylene chloride) to give 1.5 g of 2′-methoxy-5-tetrazol-1-yl-biphenyl-3-carboxylic acid[2-(3-methoxy-phenyl)-ethyl]-amide as a white solid, MS (M+H)=430.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[OH:26][C:27]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([N:30]4[CH2:29][CH2:28][C:27]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)([OH:26])[CH2:32][CH2:31]4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Product: CN1CCN(c2cc(N3CCc4ccc(N5CCC(O)(c6ccccc6)CC5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 36 starting from 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and 4-hydroxy-4-phenylpiperidine (Aldrich Cat. No. H52201). LCMS (M+H)+: m/z=500.3.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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(#N)C>[Cl:17][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:19]2[S:18][CH:22]=[CH:21][CH:20]=2)[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Reactant: OB(O)c1cccs1
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: CC#N
Product: NC(=O)C1CCN(c2c(Cl)cncc2-c2cccs2)CC1
Yield: 10.4 %

Procedure:
General procedure E was followed using 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (75 mg, 0.27 mmol), 2-thiophene boronic acid (44 mg, 0.34 mmol), tetrakis(triphenylphosphine)palladium(0) (16 mg, 0.014 mmol), acetonitrile (3 mL) and 0.5 M sodium carbonate (0.77 mL, 0.38 mmol). The crude product was purified by flash column chromatography on silica gel (CH2Cl2, EtOH, 96:4-80:20, biotage 25+S) to yield the a mixture of starting material and product (50 mg, 2:5), along with dehalogenated monochloro starting material (7 mg, 11%). The product/starting material mixture was further purified by preparative hplc (CH3CN, H2O, gradient 1:9 to 9:1, 15 min) to furnish the title compound (9 mg, 10%) as a clear colourless oil, along with recovered 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide (30 mg, 40%) as a white solid, LC-MS (ESI, 4 min) Rt 2.31 min, m/z 322 (100%, [M+H]+); m/z (ESI) C15H16N3OSCl requires 321.0703, found [M+H]+ 321.0700.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH:6]([O: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:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH3:3].[C:23]([C@H:26]([C@@H:28]([C:30]([O-:32])=[O:31])[OH:29])[OH:27])([O-:25])=[O:24]>O1CCCC1.O>[CH3:1][N:2]([CH2:4][CH2:5][C@H:6]([O: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:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH3:3].[C:23]([C@H:26]([C@@H:28]([C:30]([O-:32])=[O:31])[OH:29])[OH:27])([O-:25])=[O:24]
Reactant: CN(C)CCC(Oc1cccc2ccccc12)c1cccs1
Agent: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CC[C@H](Oc1cccc2ccccc12)c1cccs1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(RS)—N,N-dimethyl-3-(naphthyloxy)-3-(2-thienyl)propylamine/D-tartrate (773 g, 1 mole) is dissolved in warm tetrahydrofuran (1500 ml) with addition of water (40 ml). After cooling down to ambient temperature, the mixture is stirred for 24 h. The precipitated crystals are recrystallized once more in tetrahydrofuran (400 ml) with an addition of water (12 ml) following the same procedure. Yield: 170 g (22%). Optical purity: 99.5% ee (CE).