Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH2:8][C:9]2[S:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)[C:6](=[O:18])[N:5]=[C:4](SC)[N:3]=1.[N:21]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:1][C:2]1[N:7]([CH2:8][C:9]2[S:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)[C:6](=[O:18])[N:5]=[C:4]([N:24]2[CH2:23][CH2:22][N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25]2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CSc1nc(C)n(Cc2ccc(C(F)(F)F)s2)c(=O)n1
Product: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)nc(=O)n1Cc1ccc(C(F)(F)F)s1
Yield: 97.1 %

Procedure:
6-Methyl-4-(methylthio)-1-{[5-(trifluoromethyl)thiophen-2-yl]methyl}-1,3,5-triazin-2(1H)-one (309 mg, 0.962 mmol) synthesized in Reference Synthesis Example 292 and tert-butyl piperazine-1-carboxylate (269 mg, 1.44 mmol) were used to obtain the title compound (429 mg, yield 97%) by synthesis in a similar manner to Reference Synthesis Example 348.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[C:10](=[O:26])[N:11]([CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[NH:12][C:13](=[O:14])[C:8]=2[N:7]=[C:6]1[Cl:27])[C:2]#[C:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]#[N:37].[Cl-].[Na+]>CN(C)C=O>[CH2:1]([N:5]1[C:9]2[C:10](=[O:26])[N:11]([CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[N:12]([CH2:35][C:36]#[N:37])[C:13](=[O:14])[C:8]=2[N:7]=[C:6]1[Cl:27])[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1c(Cl)nc2c(=O)[nH]n(Cc3ccc4ccccc4n3)c(=O)c21
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCn1c(Cl)nc2c(=O)n(CC#N)n(Cc3ccc4ccccc4n3)c(=O)c21
Temperature: 40 °C
Reaction time: 2 h

Procedure:
0.20 g 1-(but-2-ynyl)-2-chloro-6-(quinolin-2-ylmethyl)-5,6-dihydro-1H-imidazo[4,5-d]-pyridazine-4,7-dione and 0.25 g potassium carbonate are placed in 4 ml of dimethylformamide. Then 53 μl of bromoacetonitrile are added and the mixture is stirred for 2 h at 40° C. After the addition of aqueous saturated sodium chloride solution the mixture is extracted three times with ethyl acetate, the combined organic phases are dried over sodium sulphate, and then the solvent is removed. The residue is purified over silica gel (cyclohexane/ethyl acetate 1:1).
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:17][CH2:18][CH2:19][CH3:20])=[C:6]([CH:14]=[CH:15][CH:16]=1)[CH2:7][N:8]([CH3:13])[C:9](=[O:12])[CH:10]=[CH2:11])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Br[C:31]1[CH:44]=[N:43][C:34]2[NH:35][C:36](=[O:42])[C:37]([CH3:41])([CH3:40])[NH:38][CH2:39][C:33]=2[CH:32]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:40][C:37]1([CH3:41])[C:36](=[O:42])[NH:35][C:34]2[N:43]=[CH:44][C:31](/[CH:11]=[CH:10]/[C:9]([N:8]([CH2:7][C:6]3[CH:14]=[CH:15][CH:16]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=3[O:17][CH2:18][CH2:19][CH3:20])[CH3:13])=[O:12])=[CH:32][C:33]=2[CH2:39][NH:38]1
Reactant: CC1(C)NCc2cc(Br)cnc2NC1=O
Reactant: C=CC(=O)N(C)Cc1cccc(C(C)C)c1OCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCC#N
Product: CCCOc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CNC(C)(C)C(=O)N3)cccc1C(C)C
Yield: 31 %

Procedure:
A solution of N-(3-isopropyl-2-propoxybenzyl)-N-methylacrylamide (0.397 g, 1.47 mmol) in propionitrile (5 mL) and DMF (1 mL) was deoxygenated with Ar for 20 min. The solution was treated with diisopropylethylamine (0.40 mL, 2.33 mmol) and 7-bromo-3,3-dimethyl-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (0.300 g, 1.11 mmol). The solution was deoxygenated with Ar for 20 min. Pd(OAc)2 (0.024 g, 0.111 mmol) and P(o-tol)3 (0.067 g, 0.222 mmol) were then added and the mixture deoxygenated with Ar for 20 min. The mixture was heated to reflux for 18 h, then allowed to cool. The solution was diluted with EtOAc (30 mL) and H2O (50 mL). The aqueous layer was extracted with EtOAc (3×50 mL). The combined organics were washed with brine (2×100 mL), dried over Na2SO4, filtered and concentrated to an orange oil. Purification by column chromatography (silica gel, CH2Cl2/MeOH, 100 to 95:5) gave the title compound (0.16 g, 31%) as an off-white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 9.80-9.77 (m, 1H), 8.40-8.35 (m, 1H), 8.01-7.91 (m, 1H), 7.55-7.48 (m, 1H), 7.31-7.20 (m, 2H), 7.10-7.03 (m, 1H), 6.88-6.85 (m, 1H), 4.81-4.66 (m, 2H), 3.90-3.83 (m, 2H), 3.77-3.69 (m, 2H), 3.32-3.25 (m, 1H), 3.12-2.90 (m, 4H), 1.81-1.77 (m, 2H), 1.31-1.28 (m, 6H), 1.19-1.17 (m, 6H), 1.06-1.01 (3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][C:15](=O)[C:14]([CH3:20])([CH3:19])[CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([NH2:27])[C:14]([CH3:20])([CH3:19])[CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N2CCC(=O)C(C)(C)C2)ccc1[N+](=O)[O-]
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COc1cc(N2CCC(N)C(C)(C)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
A solution of 1-(3-Methoxy-4-nitrophenyl)-3,3-dimethylpiperidin-4-one (INTERMEDIATE 39) (278 mg, 1 mmol) and ammonium acetate (771 mg, 10.0 mmol) in MeOH (5 mL) was stirred at RT overnight. Sodium cyanoborohydride (75 mg, 1.2 mmol) were added. The reaction was stirred at RT for 2 h. MeOH (20 mL) and silica gel (5 g) was added. The mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel (5% MeOH and 1% NH4OH in CH2Cl2) to give the title product (0.2 g, 72.0%).
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[C:4]([Cl:18])[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Cl)=[CH:33][CH:32]=1>CN(C=O)C>[Br:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([N:10]([CH2:35][C:34]2[CH:37]=[CH:38][C:31]([O:30][CH3:29])=[CH:32][CH:33]=2)[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[C:4]([Cl:18])[CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)c(Br)cc1Cl
Reactant: COc1ccc(CCl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2cc(C#N)c(Br)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76.2 %

Procedure:
A solution of tert-butyl (4-bromo-2-chloro-5-cyanophenyl)carbamate (1.0 g, 3.02 mmol) in DMF (10 mL) was cooled in an icebath and NaHMDS (1 M solution in THF, 4.52 ml, 4.52 mmol) was added. After 20 min, 4-methoxybenzyl chloride (0.616 ml, 4.52 mmol) was added and the reaction was removed from the bath and left stirring at RT overnight. The reaction was partitioned between EtOAc and sat. aq. NH4Cl solution. The aqueous phase was extracted with EtOAc and the combined organic extracts were washed with brine. After drying with sodium sulfate, the solvents were removed and silica gel chromatography with hexane containing 0 to 30% EtOAc afforded tert-butyl (4-bromo-2-chloro-5-cyanophenyl)(4-methoxybenzyl)carbamate (1.04 g) as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1>>[CH3:8][C@@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: BrCCC1CCCCO1
Reactant: CCC[C@@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 213 from 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 2-(2-bromoethyl)tetrahydro-2H-pyran.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CN(OC)[C:18](=[O:22])[CH2:19][CH2:20][CH3:21].O>C1COCC1.C(OCC)(=O)C>[CH3:9][N:8]([CH3:10])[C:4]1[CH:3]=[C:2]([C:18](=[O:22])[CH2:19][CH2:20][CH3:21])[CH:7]=[CH:6][CH:5]=1
Reactant: CCCC(=O)N(C)OC
Reactant: CN(C)c1cccc(Br)c1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCCC(=O)c1cccc(N(C)C)c1
Temperature: -35 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
To a stirred solution of (3-bromophenyl)dimethylamine (7.5 g, 37.5 mmol) in THF (50 mL) at −78° C., was added n-butyllithium (2.88 g, 45.0 mmol). The resulting solution was stirred at −35° C. for 1 h and was then cooled to −78° C. and treated dropwise with a solution of N-methyl-N-(methyloxy)butanamide (4.92 g, 37.5 mmol) (Description 25) in dry THF (15 mL). The resulting mixture was stirred for 45 min at −78° C. and then worked up using water (100 mL) and ethyl acetate (200 mL). The crude material was purified by chromatography on silica gel, eluting with a gradient of 0-20% ethyl acetate in hexane, to afford the title compound (3.48 g). LCMS (B) m/z: 192 [M+1]+, Rt 2.29 min.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH:26]=[C:25]([OH:27])[C:19]3[CH2:20][C:21]([CH3:24])([CH3:23])[O:22][C:18]=3[CH:17]=2)=[O:15])=[N:9]1.Cl[CH2:29][CH:30]1[CH2:32][CH2:31]1>C(#N)C>[CH3:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH:26]=[C:25]([O:27][CH2:29][CH:30]3[CH2:32][CH2:31]3)[C:19]3[CH2:20][C:21]([CH3:24])([CH3:23])[O:22][C:18]=3[CH:17]=2)=[O:15])=[N:9]1
Reactant: Cn1ccc(NC(=O)c2cc(O)c3c(c2)OC(C)(C)C3)n1
Reactant: ClCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cn1ccc(NC(=O)c2cc(OCC3CC3)c3c(c2)OC(C)(C)C3)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To 60 mg of cesium carbonate (180 μmol) in a test tube (10×95 mm) was added 0.8 mL of 0.1 M solution of 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carbo-xylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) in acetonitrile followed by 1 mL of 0.1 M solution of chloromethyl cyclopropane in acetonitrile and the reaction was stirred at 80° C. for 8 h. After the removal of solid cesium carbonate, the acetonitrile was removed, the residue was reconstituted in 1.2 mL of DMSO and subjected to HPLC purification to obtain the title compound. 1H NMR (500 MHz, DMSO-d6) δ 10.56 (s, 1 H) 7.57 (s, 1 H) 6.92 (s, 1 H) 6.54 (s, 1 H) 3.92-3.93 (d, J=5.00 Hz, 2 H) 2.94 (s, 2 H) 1.42 (s, 6 H) 0.55-0.60 (m, 2 H) 0.30-0.35 (m, 1 H); LCMS for C19H23N3O3 m/z 342 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([S:11][C:12]#[N:13])=O)=[CH:4][CH:3]=1.[BrH:14].C(O)(=O)C>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([Br:14])[S:11][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Br
Reactant: N#CSC(=O)Cc1ccc(Cl)cc1
Solvent: CC(=O)O
Product: Clc1ccc(-c2csc(Br)n2)cc1
Temperature: 80 °C
Yield: 44 %

Procedure:
The compound (40) (2.1 g, 10.0 mmol) was suspended in acetic acid (10 ml) and 47% HBr-acetic acid (1 ml) was added. The mixture was stirred with heating at 80° C. for 2 hrs. The reaction mixture was concentrated under reduced pressure to dryness and the residue was partitioned between ethyl acetate and 5% NaHCO3 aq. The aqueous layer was extracted with ethyl acetate, and the extracts were combined, washed with saturated brine and dried (MgSO4). The solvent was evaporated under reduced pressure and isopropyl ether was added to the obtained residue, which was filtrated to give the title compound (1.2 g, 44%).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([F:14])([F:13])[CH2:10][CH:11]=[CH2:12])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH2:15]([O:17][CH:18]([SiH3:22])[O:19][CH2:20][CH3:21])[CH3:16]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][P:4]([C:9]([F:14])([F:13])[CH2:10][CH2:11][CH2:12][SiH2:22][CH:18]([O:19][CH2:20][CH3:21])[O:17][CH2:15][CH3:16])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOC([SiH3])OCC
Reactant: C=CCC(F)(F)P(=O)(OCC)OCC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Product: CCOC(OCC)[SiH2]CCCC(F)(F)P(=O)(OCC)OCC
Temperature: 60 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
5 g (23.4 mmol) diethyl-1,1-difluorobut-3-enylphosphonate was mixed with 7.5 g (56 mmol) diethoxymethylsilane and several drops of hydrogen hexachloroplatinate (IV) solution (5% in isopropanol). After stirring at 60° C. overnight, the solution was evaporated under reduced pressure to remove the reactants and product [4-(diethoxymethylsilyl)-1,1-difluoro-butyl]-phosphonic acid diethyl ester (DMSFP, 6 g, 16.6 mmol, yield 71%) was provided. See Scheme 7. 1H NMR (CDCl3): δ(ppm) 0.12(3H, s), 0.65 (2H, m), 1.21 (6H, t, JH-H=6.98), 1.35 (6H, 6, JH-H=7.06), 1.65 (2H,m), 2.15 (2H,m), 3.75 (4H, q, JH-H=6.98), 4.26 (4H, q, JH-H=7.06).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O1CCOCC1>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:2]2[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[CH:5]=[CH:6][CH:7]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(S)cc1
Reactant: O=C(O)c1cccc(Br)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc(Sc2cccc(C(=O)O)c2)cc1
Temperature: 25 °C
Yield: 83 %

Procedure:
3-Bromobenzenecarboxylic acid (402 mg, 2 mmol), i-Pr2NEt (700 μL, 4 mmol) and dry 1,4-dioxane (8 mL) were put into a round-bottomed flask, and the round-bottomed flask with the resulting mixture therein was purged repeated three times with nitrogen gas. Next, Pd2(dba)3 (46 mg, 0.05 mmol), Xantphos (58 mg, 0.1 mmol) and 4-methoxythiophenol (246 μL, 2 mmol) were added to it, and this was purged repeatedly twice with nitrogen gas, and then heated under reflux for 6 hours. Next, the completion of the reaction was confirmed through high-performance liquid chromatography, then this was cooled to room temperature, and made to have a pH of 3 to 4 with acetic acid. The insoluble matter was removed through filtration, and the filtrate was concentrated. The resulting concentrate liquid was isolated and purified through flash column chromatography (developer: hexane/ethyl acetate=10/1) with silica gel serving as a carrier, thereby giving 432 mg (yield: 83%) of 3-(4-methoxyphenyl)sulfanylbenzenecarboxylic acid as a white solid.
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:11]=[C:10]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7].[O:21]=[C:22]1[C:26]2[CH:27]=[CH:28][C:29]([CH2:31][CH:32]=O)=[CH:30][C:25]=2[CH2:24][O:23]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:20][CH:2]([F:1])[O:3][C:4]1[CH:11]=[C:10]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH2:32][CH2:31][C:29]3[CH:28]=[CH:27][C:26]4[C:22](=[O:21])[O:23][CH2:24][C:25]=4[CH:30]=3)[CH2:16][CH2:15]2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(CCN2CCNCC2)cc1OC(F)F
Reactant: O=CCc1ccc2c(c1)COC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc(CCN2CCN(CCc3ccc4c(c3)COC4=O)CC2)cc1OC(F)F

Procedure:
A solution of crude 2-(difluoromethoxy)-4-(2-piperazin-1-ylethyl)benzonitrile (15 mg, 0.05 mmol), (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (18 mg, 0.1 mmol) and NaBH(OAc)3 (100 mg, 0.47 mmol) in 10 mL of anhydrous DCM was stirred at ambient temperature overnight. The reaction mixture was added 50 mL of DCM, washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified with prep-TLC to afford 2-(difluoromethoxy)-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile. 1H-NMR (400 MHz, CDCl3) δ 7.82 (d, J=7.8 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.33˜7.36 (m, 2H), 7.13˜7.20 (m, 2H), 6.33 (t, J=71.2 Hz, 1H), 5.26 (s, 2H), 2.99˜3.08 (m, 2H), 2.87˜2.90 (m, 2H), 2.62˜2.84 (m, 12H). (0.15 μm)
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+](=[CH2:13])=[N-]>C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: O=C(O)c1cccnc1Cl
Reactant: C=[N+]=[N-]
Solvent: CCOC(C)=O
Product: COC(=O)c1cccnc1Cl
Temperature: 25 °C

Procedure:
To a suspension of 2-chloronicotinic acid (15.75 g) in ethyl acetate (200 ml) was added excess diazomethane (ether solution) with stirring at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate with addition of charcoal. The title compound (15.5 g) was obtained by filtering the mixture and then evaporating under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([F:12])([F:11])[F:10])=[C:6]([CH:8]=1)[NH2:7].O[CH2:14][CH:15]([CH2:17]O)O.S(=O)(=O)(O)O>C(OCC)(=O)C.[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([F:10])([F:11])[F:12])=[C:6]2[C:8]=1[CH:14]=[CH:15][CH:17]=[N:7]2
Reactant: OCC(O)CO
Reactant: Nc1cc(Br)ccc1C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(Br)c2cccnc12
Temperature: 120 °C
Yield: 34.5 %

Procedure:
To a mixture of 5-bromo-2-(trifluoromethyl)aniline (3.0 g, 12.6 mmol), glycerol (4.64 g, 50.0 mmol), and ferrous sulfate (0.56 g, 2.0 mmol) was added conc. sulfuric acid (2.2 mL) dropwise. The reaction mixture was heated at 120° C. for 4 hr. After cooled to RT, the reaction was diluted with ethyl acetate (150 mL), and 2N aq. NaOH was introduced to adjust pH about 13. The organic layer was separated and washed with brine and dried over Na2SO4 and evaporated to give the crude product, which was purified with flash column chromatography to give 5-bromo-8-(trifluoromethyl)quinoline (1.2 g, 48%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:12]=[N:11][C:10]2[N:13]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[C:14]3[N:19]=[C:18]([NH2:20])[N:17]=[CH:16][C:15]=3[C:9]=2[CH:8]=1)(=O)=O.N#N.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(O)=O.CN(C=O)C>[CH:21]1([N:13]2[C:10]3[N:11]=[N:12][CH:7]=[CH:8][C:9]=3[C:15]3[CH:16]=[N:17][C:18]([NH2:20])=[N:19][C:14]2=3)[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: Nc1ncc2c3cc(OS(=O)(=O)C(F)(F)F)nnc3n(C3CCCC3)c2n1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncc2c3ccnnc3n(C3CCCC3)c2n1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
In a 25 mL single-necked round bottom flask were placed compound 318 (94 mg, 234 μmol, palladium diacetate (21 mg, 93 μmol), and 1,1′-bis(diphenylphosphino)ferrocene (130 mg, 234 μmol). The flask was subjected to 3 cycles of evacuation and back-filling with N2. DMF (3 mL) was added under N2 followed by triethylamine (715 μl, 5140 μmol) and formic acid, 98% (176 μl, 4.67 mmol). The resulting mixture was stirred in an oil bath at 65° C. for 1.5 h. The mixture was poured into ice and saturated NaHCO3 aqueous solution and extracted with 10% i-PrOH/DCM (2×). The combined organics were dried over Na2SO4 and concentrated in vacuo. The residue was subjected to combi-flash column chromatography (methanol/DCM with Et3N) to give compound 319 (48 mg, 80% yield) as an reddish solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.08 (1 H, s), 9.01 (1 H, d, J=5.1 Hz), 8.07 (1 H, d, J=5.1 Hz), 7.28 (2 H, s), 5.42 (1 H, quin, J=8.6 Hz), 2.40-2.49 (2 H, m), 1.92-2.14 (4 H, m), 1.63-1.80 (2 H, m). LCMS-ESI (POS), M/Z, M+1: Found 255.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH2:17][C:18]#C)[C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=2)=[CH:4][N:3]=1.[C:24](=O)([O-])[O-].[K+].[K+]>S1(CCCC1)(=O)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[C:15]3[CH:24]=[C:17]([CH3:18])[O:16][C:14]=3[C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=2)=[CH:4][N:3]=1
Reactant: C#CCOc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: COc1cc(Cc2cnc(N)nc2N)c2cc(C)oc2c1OC

Procedure:
A mixture of 2,4-diamino-5-[3,4-dimethoxy-5-(2-propynyloxy)benzyl]pyrimidine (1.18 g, 3.75 mmol), potassium carbonate (0.518 g, 3.75 mmol) and sulfolane (10 mL) was heated to 220°-230° under nitrogen over a period of 20 minutes and then maintained at this temperature for an additional 15 minutes. The resulting dark mixture was cooled and the precipitate was adsorbed on silica gel. The title compound was eluted with MeOH:CH2Cl2 /1:9 as an off-white powder, after recrystallization from 95% ethanol; mp 209°-212°. Anal. Calcd for C16H18N4O3.1/2H2O: C, 59.43; H, 5.92; N, 17.33. Found: C, 59.22; H, 5.97; N, 17.31.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl>C(O)C.[Pd]>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)c2ccc(N(C)C)cc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(=O)N1CCC(Cc2ccc(N(C)C)cc2)CC1
Reaction time: 48 h
Yield: 74.9 %

Procedure:
In 100 ml of ethanol was dissolved 5.49 g of the 1-acetyl-4-(4-dimethylaminobenzoyl)piperidine (Compound No. 4) prepared in Example 4, followed by addition of concentrated hydrochloric acid (2 ml). Using 10% palladium-on-carbon as the catalyst, catalytic reduction was carried out at atmospheric temperature and pressure for 48 hours. After completion of the reaction, the solvent was distilled off and the residual oil was dissolved in ethyl acetate (100 ml). The solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and water in that order and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residual oil was subjected to silica gel column chromatography (eluent: methanol:dichloromethane=1:19, v/v) to give 3.9 g of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:24]=[C:23]([CH3:25])[C:16]([O:17][CH2:18][CH:19]([OH:22])[CH2:20]O)=[C:15]([CH3:26])[CH:14]=3)[N:9]=2)[CH:5]=[C:4]([CH3:27])[N:3]=1.CC[N:30](C(C)C)C(C)C.CS(Cl)(=O)=O.N>C1COCC1.CO>[NH2:30][CH2:20][CH:19]([OH:22])[CH2:18][O:17][C:16]1[C:15]([CH3:26])=[CH:14][C:13]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([CH3:27])[N:3]=[C:2]([Cl:1])[CH:7]=3)[O:12][N:11]=2)=[CH:24][C:23]=1[CH3:25]
Reactant: Cc1cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(C)c3)no2)cc(Cl)n1
Reactant: CCN(C(C)C)C(C)C
Agent: CS(=O)(=O)Cl
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2nc(-c3cc(C)c(OCC(O)CN)c(C)c3)no2)cc(Cl)n1
Temperature: 65 °C
Reaction time: 16 h

Procedure:
To a solution of (RS)-3-{4-[5-(2-chloro-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol (134 mg, 0.345 mmol) in THF (5 mL), DIPEA (89 mg, 0.69 mmol) followed by methanesulfonylchloride (43 mg, 0.379 mmol) is added at 0° C. The mixture is stirred at it for 2 h before 7 M NH3 in MeOH (1.2 mL) is added. The mixture is stirred at 65° C. for 16 h before the solvent is removed in vacuo to give crude (RS)-1-amino-3-{4-[5-(2-chloro-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propan-2-ol as beige resin; LC-MS: tR=0.80 min, [M+1]+=388.96.