Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:11][CH2:10][S:9][CH:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:22]2[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].COCCOC>CCOC(C)=O.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].C(Cl)Cl>[S:9]1[CH2:10][CH2:11][C:7]([C:22]2[CH:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=2)=[CH:8]1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: O=S(=O)(OC1=CSCC1)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Nc1ccc(C2=CSCC2)cn1
Temperature: 90 °C

Procedure:
To a vial was charged with all reagents: 4,5-dihydrothiophen-3-yl trifluoromethanesulfonate (900 mg, 3.84 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine(1.69 g, 7.69 mmol), K3PO4 (2.45 g, 11.5 mmol), and PdCl2(dppf)-CH2Cl2 adduct (314 mg, 0.384 mmol) and DME (16 mL), and the mixture was purged with Argon, then sealed and heated at 90° C. via external oil bath overnight. The reaction mixture was cooled down to room temperature, and the precipitates in the reaction mixture was removed by filtration, and the filtrate was concentrated under reduced pressure and a black residue was obtained as crude product. The crude product was dissolved in EtOAc (30 mL), washed with water (20 mL), and the slug between the two layers was removed by filtration. The EtOAc layer was collected, stripped with 1N HCl (2×20 mL) and the aqueous layers were combined, scrubbed with EtOAc (20 mL), basified with aqueous NaOH (3 g in 10 mL water), extracted with EtOAc (2×30 mL), and the obtained EtOAc extracts were combined, washed with brine (30 mL), dried (Na2SO4), concentrated and desired product was obtained as light color solid. LCMS (m/z): 179.0 (MH+), 0.41, 0.43 min (for regioisomers).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[C:11]1([NH:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:18][NH:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: NNc1ccccc1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: O=C(NNc1ccccc1)Nc1ccc(Cl)cc1
Yield: 105.5 %

Procedure:
1.1 A solution of 15.35 g of 4-chlorophenyl isocyanate in 50 ml of THF is added to a solution of 9.83 g of phenylhydrazine in 100 ml of THF under a nitrogen atmosphere, and the mixture is refluxed for 2 hours. Conventional work-up gives 25.1 g of N-(4-chlorophenylaminocarbonyl)-N′-phenylhydrazine(“AA”), El 277, m.p. 187-189.
Reaction SMILES: [C:1]([NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16](=[O:18])[CH3:17])=[CH:13][CH:14]=2)[CH2:9][C:8]1=[O:19])=[O:6])(=[O:3])[CH3:2].C(NC(N1C2[C:32](=[CH:33][C:34](C(=O)C)=CC=2)[CH2:31][C:30]1=O)=O)(=O)C(C)(C)C.C(NC(N1C2C(=CC(C(=O)C)=CC=2)CC1=O)=O)(=O)CC>>[C:1]([NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16](=[O:18])[CH3:17])=[CH:13][CH:14]=2)[CH2:9][C:8]1=[O:19])=[O:6])(=[O:3])[C:2]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(=O)NC(=O)C(C)(C)C
Reactant: CC(=O)NC(=O)N1C(=O)Cc2cc(C(C)=O)ccc21
Agent: CCC(=O)NC(=O)N1C(=O)Cc2cc(C(C)=O)ccc21
Product: CC(=O)c1ccc2c(c1)CC(=O)N2C(=O)NC(=O)c1ccccc1

Procedure:
In a similar manner 1-(N-acetylcarbamoyl)-5-acetyloxindole, 1-(N-s-butyrylcarbamoyl)-5-acetyloxindole, 1-(N-pivaloylcarbamoyl)-5-acetyloxindole and 1-(N-propionylcarbamoyl)-5-acetyloxindole are prepared.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:67]=[CH:66][C:53]2[NH:54][C:55]([CH:57]([NH2:65])[CH2:58][N:59]3[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]3)=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:49][C:50]1[CH:67]=[CH:66][C:53]2[NH:54][C:55]([CH:57]([NH:65][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:58][N:59]3[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]3)=[N:56][C:52]=2[CH:51]=1
Reactant: NC(CN1CCCCC1)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(C(=O)NC(CN2CCCCC2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 41 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and rac.-1-(5-chloro-1H-benzimidazol-2-yl)-2-(piperidin-1-yl)-ethylamine in tetrahydrofuran. Yield: 41%; Rf value: 0.56 (silica gel; dichloromethane/ethanol=9:1); Cl27H32ClN5O2 (494.04); mass spectrum: (M+H)+=494/496 (chlorine isotope).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([CH3:14])=[CH:8][N:7]=1)(=O)C.[OH-].[Na+]>C(O)C>[CH3:13][O:12][C:10]1[C:9]([CH3:14])=[CH:8][N:7]=[C:6]([CH2:5][OH:4])[CH:11]=1
Reactant: COc1cc(COC(C)=O)ncc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(CO)ncc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
47.8 g of (4-methoxy-5-methyl-2-pyridyl)methyl acetate were dissolved in 330 ml of ethanol. 165 ml of 3N sodium hydroxide solution were then added dropwise thereto at 0° and the mixture was stirred at room temperature for a further 3 hours. The ethanol was subsequently removed in vacuo, whereupon the residual aqueous solution was extracted three times with 250 ml of methylene chloride. The organic extracts were dried over sodium sulfate and evaporated in vacuo. The residue crystallizes from petroleum ether and there was obtained 4-methoxy-5-methyl-2-pyridylmethanol of melting point 101°-103°.
Reaction SMILES: [OH:1][C:2]1([C:8]2[O:9][C:10]([S:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)=[CH:11][CH:12]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:24]I>>[CH3:24][O:1][C:2]1([C:8]2[O:9][C:10]([S:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)=[CH:11][CH:12]=2)[CH2:3][CH2:4][O:5][CH2:6][CH2:7]1
Reactant: OC1(c2ccc(Sc3ccc4ccccc4c3)o2)CCOCC1
Reactant: CI
Product: COC1(c2ccc(Sc3ccc4ccccc4c3)o2)CCOCC1
Yield: 92 %

Procedure:
Using the procedure described in Example 1, 4-hydroxy-4-[5-(naphth-2-ylthio)fur-2-yl]tetrahydropyran was reacted with methyl iodide to give 4-methoxy-4-[5-(naphth-2-ylthio)fur-2-yl]tetrahydropyran in 92% yield as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[F:13][C:14]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:15]=1[NH2:16]>>[F:13][C:14]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:15]=1[NH:16][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1
Reactant: Cc1nc(Cl)c2ccccc2n1
Reactant: COc1ccc(N)c(F)c1
Product: COc1ccc(Nc2nc(C)nc3ccccc23)c(F)c1

Procedure:
The title compound was prepared from 4-chloro-2-methylquinazoline and 2-fluoro-4-methoxyaniline by a procedure similar to Example 28 (79%). 1H NMR (CDCl3): 8.54 (m, 1H), 7.83 (m, 2H), 7.65 (m, 1H), 7.50 (m, 1H), 7.47 (s, broad, 1H), 6.74-6.81 (m, 2H), 3.83 (s, 3H), 2.70 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@H:9]([CH2:13][OH:14])[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CCN=C=NCCCN(C)C.Cl>ClCCl.C(N(CC)CC)C>[CH2:32]([NH:39][C:10](=[O:11])[C@H:9]([N:8]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:13][OH:14])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)[C@@H](CO)N(Cc1ccccc1)Cc1ccccc1
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1)[C@@H](CO)N(Cc1ccccc1)Cc1ccccc1
Temperature: 22.5 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To the suspension of (R)-2-(dibenzylamino)-3-hydroxypropanoic acid (285.34 g, 1.0 moL) in dichloromethane (2.86 L) was added HOBt (202.68 g, 1.50 moL), triethylamine (111.31 g, 1.1 moL), benzyl amine (117.86 g 1.1 moL) and EDC.HCl (230.04 g, 1.2 moL) at 0-5° C. under constant stirring. The reaction mixture was stirred at below 10° C. for 16 hours. When the reaction was considered complete, the agitation was stopped and the phases were allowed to separate. The organic phase was washed with water (856 mL), saturated sodium bicarbonate (2×713 mL), water (713 mL) and finally with a mixture of 2.85 mL of 30% HCl and 570 mL of water. The organic phase was concentrated under reduced pressure to a final volume of about 485 mL. MTBE (770 mL) was added and distilled again under reduced pressure to a final volume of about 485 mL. The reaction mixture was cooled to 20-25° C., and charged with heptanes (856 mL). The reaction mixture was heated to 28-32° C. and stirred for 1 hour, then cooled to 0-5° C. and stirred for 3 hours. The obtained mixture was filtered and the cake was washed with cold (0-5° C.) heptanes (285 mL). The resulting solid was dried under vacuum at 45-50° C. for 12 hours to provide (R)—N-benzyl-2-(dibenzylamino)-3-hydroxypropanamide as a white solid (353.82 g, yield 95%, HPLC purity >99.95%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][N:5]2[C:14]=1I.[F:16][C:17]1[CH:18]=[CH:19][C:20]2=[C:21]([CH:37]=1)[O:22][CH2:23][C:24]1[CH:34]=[C:33]([CH:35]=[O:36])[CH:32]=[CH:31][C:25]=1/[C:26]/2=[C:27](/[CH3:30])\[C:28]#[N:29]>>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][N:5]2[C:14]=1[CH:35]([OH:36])[C:33]1[CH:32]=[CH:31][C:25]2/[C:26](=[C:27](/[CH3:30])\[C:28]#[N:29])/[C:20]3[CH:19]=[CH:18][C:17]([F:16])=[CH:37][C:21]=3[O:22][CH2:23][C:24]=2[CH:34]=1
Reactant: FC(F)(F)c1ccn2c(I)c(Cl)nc2c1
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Product: C/C(C#N)=C1/c2ccc(C(O)c3c(Cl)nc4cc(C(F)(F)F)ccn34)cc2COc2cc(F)ccc21
Yield: 90.6 %

Procedure:
[step 2] Using 2-chloro-3-iodo-7-(trifluoromethyl)imidazo[1,2-a]pyridine (1.81 g, 5.22 mmol) obtained in step 1 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (0.77 g, 2.6 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 8F, step 4, (E)-2-{8-[(2-chloro-7-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)(hydroxy)methyl]-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (1.21 g, 90%) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@H:13]([O:19][CH3:20])[C@@H:14]([CH3:18])[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl.[CH3:31][O:32][C:33](=[O:43])[C@H:34]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[NH2:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@H:13]([O:19][CH3:20])[C@@H:14]([CH3:18])[C:15]([NH:35][C@H:34]([C:33]([O:32][CH3:31])=[O:43])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CO[C@H]([C@@H](C)C(=O)O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)[C@@H](OC)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 65.5 %

Procedure:
To a mixture of #11 (2.7 g, 9.4 mmol, 1 eq.) in dichloromethane (30 mL, 0.3 M) and N,N-dimethylformamide (3 mL) were added diisopropylethylamine (3.30 mL, 18.8 mmol, 2 eq.), L-phenylalanine methyl ester hydrochloride (2.03 g, 9.40 mmol, 1.2 eq.) and HATU (4.79 g, 12.2 mmol, 1.3 eq.). The reaction was stirred for 18 hours and then concentrated in vacuo. The residue was taken up in ethyl acetate (100 mL) and washed sequentially with 1 M hydrochloric acid (2×50 mL) and brine. The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo. The crude material was taken up in dichloromethane and filtered. The filtrate was purified by silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) to give #37 (2.76 g, 65%) as an off-white solid. LC-MS: m/z 449.3 [M+H+], 349.2 [(M−Boc)+H+] retention time=0.88 minutes; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ 8.28 (d, J=8.2 Hz, 1H), 7.14-7.29 (m, 5H), 4.50 (ddd, J=10.9, 8.1, 4.4 Hz, 1H), 3.64 (s, 3H), 3.23 (s, 3H), 2.15-2.24 (m, 1H), 1.56-1.76 (m, 2H), 1.31-1.55 (m, 11H), 1.02 (d, J=6.6 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([F:21])=[C:9]([CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]#[N:13])[CH:10]=1.[CH3:22][N:23]1[CH:27]=[C:26]([S:28](Cl)(=[O:30])=[O:29])[N:25]=[CH:24]1>ClCCl.CN(C)C1C=CN=CC=1>[CH2:14]([CH:11]([C:12]#[N:13])[C:9]1[CH:10]=[C:5]([CH:6]=[CH:7][C:8]=1[F:21])[O:4][CH2:3][CH2:2][NH:1][S:28]([C:26]1[N:25]=[CH:24][N:23]([CH3:22])[CH:27]=1)(=[O:30])=[O:29])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: N#CC(Cc1ccccc1)c1cc(OCCN)ccc1F
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cn1cnc(S(=O)(=O)NCCOc2ccc(F)c(C(C#N)Cc3ccccc3)c2)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 2-[5-(2-amino-ethoxy)-2-fluoro-phenyl]-3-phenyl-propionitrile (536 mg, 1.885 mmol) in dry dichloromethane was added 4-dimethylaminopyridine (345 mg, 2.83 mmol) followed by 1-methyl-1H-imidazole-4-sulfonyl chloride (409 mg, 2.262 mmol). The mixture was stirred at RT under argon over night. Dichloromethane was added and the mixture was subsequently washed twice with 1N hydrochloric acid, water, sodium bicarbonate solution, brine and then dried over sodium sulfate, filtered and concentrated to obtain the desired product as a pale yellow solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[C:5]#[N:6].[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:2]2[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=2)[C:5]#[N:6])[CH2:17][CH2:16]1
Reactant: N#Cc1cc(F)cc(C(F)(F)F)c1
Reactant: CN1CCNCC1
Product: CN1CCN(c2cc(C#N)cc(C(F)(F)F)c2)CC1

Procedure:
The title compound is prepared using an analogous method as described in Example 1.1, utilising 3-fluoro-5-(trifluoromethyl)-benzonitrile (Lancaster Synthesis GmbH) and 1-methylpiperazine (Fluka, Buchs, Switzerland).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[C:20]([C:22]([N:24]3[CH:33]4[CH:28]([CH2:29][CH2:30][CH2:31][CH2:32]4)[CH2:27][CH2:26][CH2:25]3)=[O:23])[CH:19]=[C:18]([OH:34])[CH:17]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].F[C:37]1[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][CH:38]=1>>[C:1]([O:5][C:6](=[O:35])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:21]=[C:20]([C:22]([N:24]3[CH:33]4[CH:28]([CH2:29][CH2:30][CH2:31][CH2:32]4)[CH2:27][CH2:26][CH2:25]3)=[O:23])[CH:19]=[C:18]([O:34][C:37]3[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][CH:38]=3)[CH:17]=2)=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Oc2cc(O)cc(C(=O)N3CCCC4CCCCC43)c2)cc1
Product: CC(C)(C)OC(=O)NCc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)N3CCCC4CCCCC43)c2)cc1
Yield: 98.6 %

Procedure:
Using 1.34 g (2.79 mmol) of {4-[3-hydroxy-5-(octahydroquinoline-1-carbonyl)phenoxy]benzyl}carbamic acid tert-butyl ester and 4-fluorobenzonitrile (0.84 g, 6.97 mmol) and following the procedure of Example 42(b) afforded 1.6 g of the required product. 1H NMR (DMSO-d6): δ 1.30 (8H, m), 1.40 (9H, s), 1.8 (8H, m), 4.1 (2H, d), 6.68 (1H, s), 6.82 (2H, s), 7.08 (2H, d), 7.22 (2H, d), 7.28 (2H, d), 7.4 (1H, t), 7.88 (2H, d).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 460 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[O:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[C:18](O)=[O:19].C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:18]([CH:14]3[CH2:15][CH2:16][CH2:17][O:13]3)=[O:19])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)C1CCCO1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)C1CCCO1
Temperature: 25 °C
Reaction time: 7 h
Yield: 80.7 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol), tetrahydrofuran-2-carboxylic acid (252 mg, 2.17 mmol), triethylamine (606 μL, 4.35 mmol), and BOP-Cl (203 mg, 2.17 mmol) in CH2Cl2 (10 mL) was stirred at room temperature for 7 hours. 2M LiOH (5 mL) was then added to the mixture and stirred at room temperature for 30 minutes. Water (25 mL) was then added to the mixture and stirred for an additional 30 minutes. The solid formed was filtered, washed with water (3×5 mL) and dried to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydrofuran-2-carboxamide (230 mg, 80.6% yield) as a solid.
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH2:11][C:12]([O:14]C)=O)=[N:8][CH:9]=1>CO>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH2:11][C:12]([NH:2][CH3:1])=[O:14])=[N:8][CH:9]=1
Reactant: CN
Reactant: COC(=O)CNc1ccc(Br)cn1
Solvent: CO
Product: CNC(=O)CNc1ccc(Br)cn1
Reaction time: 24 h
Yield: 100 %

Procedure:
A solution of 2.0 M methylamine in MeOH (75 mL) was added to 5-bromo-2-(methoxycarbonylmethyl)aminopyridine (2.9 g, 12 mmole). The reaction was stirred for 24 h then was concentrated to dryness. The residue was triturated with 10% petroleum ether/Et2O (100 mL), then was collected and dried under vacuum to give the title compound (2.96 g, 100%) as an off-white solid: MS (ES) m/e 244.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[N:9]=2)=[CH:6][N:5]=[C:4]([NH2:21])[N:3]=1.[CH2:22]([O:29]CC(N(OC)C)=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.NC1C=CN=CC=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C(OCC1C(C2C=CN=C(S(C)=O)N=2)=CN=C(N)N=1)C1C=CC=CC=1>C1COCC1>[CH2:22]([O:29][CH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[N:9]=2)=[CH:6][N:5]=[C:4]([NH2:21])[N:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CON(C)C(=O)COCc1ccccc1
Reactant: Cc1nc(N)ncc1-c1ccnc(Nc2ccncc2)n1
Agent: CS(=O)c1nccc(-c2cnc(N)nc2COCc2ccccc2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Nc1ccncc1
Solvent: C1CCOC1
Product: Nc1ncc(-c2ccnc(Nc3ccncc3)n2)c(COCc2ccccc2)n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
This compound was synthesized in an analogous manner to compound 21 utilizing 2-(benzyloxy)-N-methoxy-N-methylacetamide in step one. To a solution of 4-aminopyridine (79 mg, 0.836 mmol) in THF (1114 μl) cooled to −78° C. was added LHMDS (836 μl, 0.836 mmol). The reaction was stirred −78° C. for 15 minutes, after which time 4′-(benzyloxymethyl)-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-amine (99 mg, 0.279 mmol) was added as a solution in THF (2 mL). The reaction was warmed to rt and stirred for 1 hour. The reaction was quenched by slow addition of saturated ammonium chloride and the reaction mixture was diluted with EtOAc. The residue was then partitioned between water and EtOAc. The organic layer was washed with brine, dried with sodium sulfate, and concentrated in vacuo. The crude product was purified by reverse-phase HPLC [30-100% organic phase over 15 minutes] followed by Biotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 10% MeOH/DCM] to obtain the desired product as a pale yellow solid (94 mg, 88% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.42 (s, 2H) 4.68 (s, 2H) 7.07-7.19 (m, 4H) 7.19-7.31 (m, 4H) 7.76 (d, J=6.57 Hz, 2H) 8.34 (d, J=6.06 Hz, 2H) 8.50-8.64 (m, 2H) 10.05 (s, 1H). HRMS (ES+) for C21H19N7O.H+ [MH+]: calculated, 386.1729; found, 386.1731. UV-LC: 100/100% UV purity at 214/254 nm; tR=2.78 minutes over 7.75 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:19](=[O:20])[NH:18][C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=2)=[C:6]([Cl:21])[CH:5]=[CH:4][C:3]=1[NH:22][C:23](=[O:34])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1.[H-].[Na+].I[CH3:38]>CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]2[C:19](=[O:20])[N:18]([CH3:38])[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=2)=[C:6]([Cl:21])[CH:5]=[CH:4][C:3]=1[NH:22][C:23](=[O:34])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=1
Reactant: CSc1ncc2cc(-c3c(Cl)ccc(NC(=O)c4cccc(C(F)(F)F)c4)c3Cl)c(=O)[nH]c2n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ncc2cc(-c3c(Cl)ccc(NC(=O)c4cccc(C(F)(F)F)c4)c3Cl)c(=O)n(C)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
To a solution of N-[2,4-dichloro-3-(2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-phenyl]-3-trifluoromethyl-benzamide (1.14 g, 2.17 mmol) in DMF (35 mL) is slowly added NaH (117.2 mg, 60%, 2.93 mmol) with stirring for 30 minutes a 0° C. Iodomethane (369 mg, 2.60 mmol) is added to above solution with stirring for 40 minutes at 0° C. The solvents are evaporated and diluted with EtOAc and washed with saturated K2CO3, brine and water. The organic layer is dried, filtered and concentrated to give crude product, which is purified by flash silica gel column, eluting with CH2Cl2 (100%) gradient to CH2Cl2/MeOH(NH3, 2N)(93/7), to give the title intermediate as a solid (1.14 g, 98.0%).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([O:9][CH2:10][O:11][CH3:12])=[N:7][O:8][C:4]=2[CH:3]=1.[Br:15]N1C(=O)CCC1=O.C(OCC)(=O)C.O>C1C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:15][CH2:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([O:9][CH2:10][O:11][CH3:12])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCOc1noc2cc(C)ccc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: COCOc1noc2cc(CBr)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.2 %

Procedure:
20.0 g of methoxymethyl 6-methyl-1,2-benzisoxazol-3-yl ether was dissolved in 200 mL of benzene, to which 20.3 g of N-bromosuccinimide and 1.7 g of 2,2′-azobisisobutyronitrile were successively added at room temperature, and this mixture was stirred for 30 minutes while heating it under reflux. The reaction mixture was cooled to room temperature, and added to a mixture of ethyl acetate and water, and then the organic phase was separated therefrom. After the resultant organic phase was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to yield 28.5 g of 6-(bromomethyl)-3-(methoxymethoxy)-1,2-benzisoxazole as light brown oil.