Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@@H:11]1[O:15]C(C)(C)[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32](OC(=O)C(F)(F)F)=[CH:31][CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[Cl-].C([Sn](CCCC)(CCCC)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=1)CCC.C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>CN(C=O)C.C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@H:11]([OH:15])[C@@H:12]([NH:13][C:18](=[O:19])[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=2)=[CH:31][CH:30]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1Cc1ccc(OC(=O)C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)OCc1ccccc1
Temperature: 100 °C
Reaction time: 48 h
Yield: 25.4 %

Procedure:
A solution containing the product from Example 23I (2.65 g, 3.75 mmol) in DMF (20 mL) was treated with LiCl (1.6 g, 37.74 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.5 g, 0.71 mmol), and 2-tri-n-butylstannylpyridine (2.6 mL, 11.30 mmol), heated at 100° C. for 16 hours, cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. A solution of the residue in THF (30 mL) and aqueous HCl (30 mL, 1 N) was stirred at 50° C. for 48 hours, cooled to 0° C. and adjusted to pH 8 with 3 N NaOH solution. The reaction mixture was partitioned between ethyl acetate and water, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated. A solution of the residue in THF (30 mL) was treated with triethylamine (1 mL, 13.6 mmol) and di-tert-butyl dicarbonate (0.82 g, 3.75 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and saturated NaHCO3. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane to give the title compound (0.568 g, 25% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[CH3:23][C:24]1[S:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.CCOC(C)=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>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:4]3[CH:3]=[CH:2][CH:7]=[C:6]([C:27]4[S:28][C:24]([CH3:23])=[CH:25][CH:26]=4)[CH:5]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
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: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3ccc(C)s3)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 5-methylthiophene-2-boronic acid pinacol ester (175 mg, 0.784 mmol) and K2CO3 (162 mg, 1.1 mmol) in DME-water (2:1) was added Pd(PPh3)4 (22 mg, 0.019 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(3-(5-methylthiophen-2-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) d (ppm): 7.7 (d, 1H), 7.6 (m, 2H), 7.37 (s, 1H), 7.23 (m, 2H), 7.19 (d, 1H), 7.03 (d, 1H), 6.8 (s, 1H), 4.6 (m, 2H), 3.7 (m, 2H), 3.3 (m, 1H), 3.1-3.2 (m, 4H), 2.5 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [CH:1]([CH:5]1[CH:9]([CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:8][N:7]([CH3:18])[C:6]1=[O:19])=[CH:2][CH2:3]C.[O:20]=[O+][O-].CSC>[Cl-].CO>[CH:3]([CH2:2][CH2:1][CH:5]1[CH:9]([CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:8][N:7]([CH3:18])[C:6]1=[O:19])=[O:20]
Reactant: CCC=CC1C(=O)N(C)CC1COC1CCCCO1
Reactant: O=[O+][O-]
Agent: [Cl-]
Solvent: CO
Solvent: CSC
Product: CN1CC(COC2CCCCO2)C(CCC=O)C1=O

Procedure:
11.0 g (41 m mols) of 3-(butenyl)-1-methyl-4-(2-tetrahydropyranyl-oxy-methyl)-pyrrolidone were dissolved in a mixture of 60 ml of absolute methyle chloride and 30 ml of absolute methanol. At -70° C ozone was introduced into this solution, while stirring, until the solution had a blue color. The reduction of the ozonide with dimethyl sulfide and the isolation of the aldehyde was effected in analogy to Example (5).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[O:21][CH2:20][CH2:19][O:18]2)=[CH:9][CH:8]=1)(=O)=O.[C:24]([O:28][CH2:29][CH3:30])(=[O:27])[CH:25]=[CH2:26].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:29]([O:28][C:24]([CH:25]=[CH:26][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[O:21][CH2:20][CH2:19][O:18]2)=[CH:9][CH:8]=1)=[O:27])[CH3:30]
Reactant: O=S(=O)(Oc1ccc(C2OCCO2)c2ccccc12)C(F)(F)F
Reactant: C=CC(=O)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1ccc(C2OCCO2)c2ccccc12
Temperature: 90 °C
Yield: 53.7 %

Procedure:
Nitrogen was passed through a solution of 2-(4-trifluoromethylsulfonyloxynaphthyl) dioxolane (2.46 g, 7.06 mmol), ethyl acrylate (2.3 mL, 2.1 g, 21.2 mmol), triethylamine (4.3 g, 42.3 mmol) in DMF (6 mL) for 15 min, and bis(triphenylphosphine)palladium dichloride was added. The well stirred solution was heated at 90° C. for 8 hr, and concentrated. The residue was dissolved in ethyl acetate (50 mL), washed with brine (2×50 mL), dried (Na2SO4), and concentrated. Purification by flash chromatography using hexane/ethyl acetate 9:1 as eluent provided a yellow solid (1.13 g, 53%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10](SC)[N:9]=1.C([O-])(O)=[O:17].[Na+]>Cl.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][NH:11][C:10](=[O:17])[N:9]=1
Reactant: CSc1nccc(-c2ccccc2F)n1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=c1nc(-c2ccccc2F)cc[nH]1
Yield: 89 %

Procedure:
A solution of 4-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine (943 mg, 4.28 mmol) in 37% HCl (18 ml) was heated at 100° C. for 21 hours. The mixture was diluted with water then basified with solid NaHCO3. The suspension was extracted with DCM; the organic layer was dried (Na2SO4), filtered and evaporated to give the title compound that was used without further purification in the next step (725 mg, 89% yield)
Reaction SMILES: [CH2:1]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9](Br)[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:15]([OH:21])(=[O:20])[CH2:16][C:17]([OH:19])=[O:18].[Na]>>[O:8]=[C:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH:16]([C:15]([OH:21])=[O:20])[C:17]([OH:19])=[O:18]
Reactant: O=C1CCCCCCCCCCC1Br
Reactant: O=C(O)CC(=O)O
Agent: [Na]
Product: O=C1CCCCCCCCCCC1C(C(=O)O)C(=O)O

Procedure:
Reaction of α-bromocyclododecanone VI with the dialkyl ester of sodium malonic acid to obtain the dialkyl ester of 2-(2-oxocyclododec-1-yl)malonic acid VII.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)#[N:2].[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[CH:26]=[C:25]([C:27]#[N:28])[N:24]([C:29]3[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=3)[N:23]=2)[CH:17]=1>>[C:1]([CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:35][C:32]2[CH:31]=[CH:30][C:29]([N:24]3[C:25]([C:27]#[N:28])=[CH:26][C:22]([C:18]4[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=4)=[N:23]3)=[CH:34][CH:33]=2)=[O:13])=[CH:14][CH:15]=1)#[N:2]
Reactant: N#Cc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Reactant: N#CCCCOc1ccc(C(=O)O)cc1
Product: N#CCCCOc1ccc(C(=O)Nc2ccc(-n3nc(-c4cccnc4)cc3C#N)cc2)cc1

Procedure:
The 4-(cyanopropyloxy)benzoic acid (0.75 mmol) was coupled with 3-(3-pyridyl)-5-cyano-1-(4′-aminophenyl)-pyrazole (0.5 mmol) under standard EDC mediated conditions (Method A). The crude product was recrystallized from hot benzene/methanol, m.p. 193-194° C. 1H NMR(CDCl3): δ 2.04-2.11 (m, 2H), 2.68-2.71 (7, J=7.1 Hz, 2H), 4.14-4.17 (t, J=6 Hz, 2H), 7.11-7.13 (d, J=8.6 Hz, 2H), 7.53-7.56 (m, 1H), 7.79-7.82(d, J=8.7 Hz, 2H), 8.00-8.05 (m, 4H), 8.1 (s, 1H), 8.30-8.32 (d, J=8 Hz, 1H), 8.63-8.64(d, J=4.6 Hz, 1H), 9.15 (s, 1H), 10.4 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=1.[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36]Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36][N:7]1[C:6]2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=[C:2]([CH3:1])[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: ClCc1cccc(OCc2ccccc2)c1
Reactant: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c1[nH]c1ccccc12
Product: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c3ccccc3n(Cc3cccc(OCc4ccccc4)c3)c12
Yield: 78 %

Procedure:
Following a procedure and using relative proportions of starting materials similar to those described in Example 4, but using tert-butyl (4-methyl-1-methylthiocarbazol-2-yl)acetate and 3-benzyloxybenzyl chloride as starting materials, the title compound was obtained in a yield of 78% as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:4]=2[N:3]=1.[C:22](=O)([O-])[O-].[Na+].[Na+].CI>CN(C=O)C>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[N:7]([CH3:22])[C:6](=[O:15])[N:5]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2COCCOC
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCn1c(Cl)nc2c1c(=O)n(C)c(=O)n2COCCOC
Reaction time: 18 h
Yield: 142.3 %

Procedure:
To a solution of 8-chloro-3-({[2-(methyloxy)ethyl]oxy}methyl)-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (2 g, 6.37 mmol) in anhydrous DMF (15 ml) was added sodium carbonate (0.743 g, 7 mmol). After 10 minutes stirring at room temperature methyliodide (0.44 ml, 7 mmol) was added and stirring continued under nitrogen at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue dissolved in EtOAc (100 ml) and washed with brine (100 ml). The organic extract was dried (MgSO4) filtered and evaporated to afford the title compound as a tan oil (85% pure) (2.98 g, quant.), m/z 329.2[MH+].
Reaction SMILES: C[O:2][C:3](=[O:20])[C@@H:4]([NH:10][C:11]([N:13]1[CH2:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12])[CH2:5][C:6]([F:9])([F:8])[CH3:7].[OH-].[Li+]>O1CCCC1.CO.O>[F:9][C:6]([F:8])([CH3:7])[CH2:5][C@H:4]([NH:10][C:11]([N:13]1[CH2:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12])[C:3]([OH:20])=[O:2]
Reactant: COC(=O)[C@H](CC(C)(F)F)NC(=O)N1CCCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(F)(F)C[C@H](NC(=O)N1CCCOCC1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.6 %

Procedure:
(S)-4,4-Difluoro-2-[(perhydro-1,4-oxazepine-4-carbonyl)-amino]-pentanoic acid methyl ester (0.38 g, 1.29 mmol) is dissolved in tetrahydrofuran/methanol (15 mL/10 mL) and lithium hydroxide (35 mg, 1.40 mmol) dissolved in water (5 mL) added. The reaction is stirred at RT for 18 h, and then the methanol/tetrahydrofuran is removed in vacuo. The residue is acidified with 6M hydrochloric acid (0.25 mL) and extracted with dichloromethane (3×20 mL), dried (Na2SO4), and concentrated to yield (S)-4,4-Difluoro-2-[(perhydro-1,4-oxazepine-4-carbonyl)-amino]-pentanoic acid as a solid (0.36 g, 99%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[O:19][N:18]=[C:17]([CH3:20])[CH:16]=3)[N:4]2[N:3]=1.CC1C=C(C2N3N=C(OCC4C=CC=CN=4)C4C(C3=NN=2)=CC=CC=4)ON=1.Cl[CH2:49][C:50]1[CH:55]=[N:54][CH:53]=[CH:52][N:51]=1>>[CH3:20][C:17]1[CH:16]=[C:15]([C:14]2[N:4]3[N:3]=[C:2]([O:1][CH2:49][C:50]4[CH:55]=[N:54][CH:53]=[CH:52][N:51]=4)[C:11]4[C:6]([C:5]3=[N:12][N:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=4)[O:19][N:18]=1
Reactant: ClCc1cnccn1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(O)nn23)on1
Agent: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccccn4)nn23)on1
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4cnccn4)nn23)on1

Procedure:
The title-compound was prepared from 6-hydroxy-3-(3-methylisoxazol-5-yl)-1,2,4-triazolo[3,4-a]phthalazine (generated from the product of Example 120 part a using the conditions described for the preparation of Intermediate 2) and 2-chloromethylpyrazine (prepared as described in Example 15 part a) using the procedure described in Example part b. 1H NMR (360 MHz, CDCl3) δ 2.48 (3H, s, CH3), 5.83 (2H, s, CH2), 7.03 (1H, s, Ar—H), 7.87 (1H, m, Ar—H), 8.01 (1H, m, Ar—H), 8.32 (1H, d, J=7.8 Hz, Ar—H), 8.62-8.68 (2H, m, 2 of Ar—H), 8.72 (1H, d, J=7.8 Hz, Ar—H), 8.99 (1H, s, Ar—H); MS (ES+) m/e 360 [MH]+; Anal. Found C, 60.24; H, 3.44; N, 27.03. C18H13N7O2 requires C, 60.16; H, 3.63; N, 27.28%.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:12])[CH:8]=2)[CH:3]=1.CC(C)([O-])C.[Na+].[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(Cl)(Cl)Cl>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[F:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH:11]=[CH:10]2
Reactant: C1CNCCN1
Reactant: Fc1ccc2cc(Br)ccc2c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Fc1ccc2cc(N3CCNCC3)ccc2c1
Reaction time: 8 h
Yield: 73.4 %

Procedure:
To a solution of 2-bromo-6-fluoronaphthalene (1 g, 4.44 mmol) in 30 ml of toluene was added sodium tert-butoxide (0.854 g, 8.89 mmol, 2.0 eq), piperazine (0.764 g, 8.87 mmol, 2.0 eq), BINAP (28 mg, 0.045 mmol, 1 mol %) and Pd2(dba)3.CHCl3 (92 mg, 0.089 mmol, 2 mol %) at 70° C. in an oil bath under an inert atmosphere of nitrogen. The resulting solution was stirred overnight and then concentrated under vacuum. The crude material was purified by silica gel chromatography using 10-20% methanol in dichloromethane to elute. The product-containing fractions were combined and concentrated under vacuum to afford 1-(6-fluoronaphthalen-2-yl)piperazine as a light yellow solid (0.75 g, 73%). (ES, m/z): [M+H]+ 231.1; 1H NMR (300 MHz, CDCl3): δ 7.67-7.73 (m, 2H), 7.29-7.38 (m, 2H), 7.18-7.23 (m, 1H), 7.14 (d, J=1.8 Hz, 1H), 3.24 (dd, J=3.6, 3.9 Hz, 4H), 3.12 (dd, J=3.6, 3.9 Hz, 4H).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[C:11]([O:15][C:16](=[O:19])[NH:17][NH2:18])([CH3:14])([CH3:13])[CH3:12]>C1COCC1>[C:11]([O:15][C:16]([NH:17][N:18]=[C:7]1[CH2:8][CH2:9][N:4]([CH:1]2[CH2:3][CH2:2]2)[CH2:5][CH2:6]1)=[O:19])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C1CCN(C2CC2)CC1
Reactant: CC(C)(C)OC(=O)NN
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN=C1CCN(C2CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-cyclopropyl-4-piperidon (10.0 g. 71.8 mmol) and tert-butylcarbazate (9.50 g, 71.8 mmol) in 25 mL THF is stirred for 3 h at RT and then concentrated in vacuo. Yield: 19.2 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15](Cl)=[O:16])=[CH:10]3)[C:6]=2[CH:18]=1.[NH3:19]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]([NH2:19])=[O:16])=[CH:10]3)[C:6]=2[CH:18]=1
Reactant: N
Reactant: O=C(Cl)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Solvent: C1CCOC1
Product: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Temperature: 8 °C
Reaction time: 5 h
Yield: 69 %

Procedure:
Into a 20 L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 9-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carbonyl chloride (460 g, 1.40 mol, 1.00 equiv) in tetrahydrofuran (4.5 L), followed by the addition ammonia (0° C.) (9 L) in one portion. The resulting solution was stirred at 0=8° C. for 5 h. The reaction progress was monitored by LCMS. The precipitates were collected by filtration, washed with 5×500 mL of water and 3×500 mL of EA, and dried in a vacuum oven to afford 300 g (69%) of 9-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide as an off-white solid. LC-MS: 308 [M+H]+1H-NMR (300 MHz, DMSO, ppm): δ 4.48 (4H, s), 6.99-7.02 (1H, d), 7.16 (1H, s), 7.43-7.47 (1H, m), 7.59 (1H, s), 7.80 (1H, s), 8.62-8.63 (1H, d).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH2:13][C:14](Cl)=[N:15][OH:16])[CH:10]=[CH:11][CH:12]=1.O1CCCC1.[C:23]([C:25]1[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[CH:29][CH:30]=1)#[CH:24].C(N(CC)CC)C>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[CH2:13][C:14]1[CH:24]=[C:23]([C:25]2[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[CH:29][CH:30]=2)[O:16][N:15]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1cccc(-c2ccccn2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1ccc(-c2cc(Cc3cccc(-c4ccccn4)c3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (3-(pyridin-2-yl)-phenyl)-acetohydroximoyl chloride (50 mg) described in Manufacturing Example 84-1-3 and tetrahydrofuran (2 mL) were added 3-ethynyl-pyridin-2,6-diamine (6.0 mg, 0.045 mmol) described in Manufacturing Example 13-1-3 and triethylamine (38 μL, 0.27 mmol), which was stirred for 2 hours at room temperature. Water was added to the reaction mixture at the same temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound in a crude product. Then, the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (3.7 mg, 14%) as a ditrifluoroacetic acid salt.
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][C@@H:7]1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[O:5].[CH3:27][Mg]Br.C[O-].[Na+]>CO>[CH2:12]([N:9]1[CH2:10][CH2:11][C@H:6]([C:4](=[O:5])[CH3:27])[C@@H:7]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CON(C)C(=O)[C@@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Reactant: C[Mg]Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of 1-[(3SR,4SR)-1-benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethanone (example 5 (c)) the title compound was prepared from (3S,4R)-1-benzyl-3-(4-chloro-phenyl)-piperidine-4-carboxylic acid methoxy-methyl-amide and methylmagnesium bromide with subsequent epimerisation with NaOMe in methanol. The title compound was obtained as off-white solid. MS (m/e): 328.2 [(M+H)+].
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=3[CH:8]([C:18]3[C:19](=O)[NH:20][C:21](=[O:35])[N:22]([CH2:24][C:25]4[O:26][CH:27]=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:29]=4)[CH:23]=3)[C:6]=2[N:7]=1)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:46])=CC=1>O1CCOCC1>[CH2:1]([C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=3[CH:8]([C:18]3[C:19](=[S:46])[NH:20][C:21](=[O:35])[N:22]([CH2:24][C:25]4[O:26][CH:27]=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:29]=4)[CH:23]=3)[C:6]=2[N:7]=1)[CH3:2]
Reactant: CCOC(=O)c1coc(Cn2cc(C3c4ccc(C)cc4C=Cc4oc(CC)nc43)c(=O)[nH]c2=O)n1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CCOC(=O)c1coc(Cn2cc(C3c4ccc(C)cc4C=Cc4oc(CC)nc43)c(=S)[nH]c2=O)n1

Procedure:
A mixture of the product of step (i) (1.26 g) and Lawesson's reagent (1.56 g) in 1,4-dioxane (30 ml) was heated at reflux for 16 hours. The solvent was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and saturated brine. The organic phase was collected, dried (MgSO4) and solvent evaporated under reduced pressure. Purification was by chromatography eluting with 50% ethyl acetate in toluene.
Reaction SMILES: [CH3:1][C@H:2]([NH2:11])[C@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[N:17]=[CH:16]2.C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)CCC>[Cu]I>[N:24]1[CH:25]=[CH:26][CH:27]=[C:22]([N:18]2[C:19]3[C:15](=[CH:14][C:13]([O:10][C@H:3]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=4)[C@H:2]([CH3:1])[NH2:11])=[CH:21][CH:20]=3)[CH:16]=[N:17]2)[CH:23]=1
Reactant: Ic1ccc2c(cnn2-c2cccnc2)c1
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCC#N
Product: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2cccnc2)c1)c1ccccc1
Yield: 27 %

Procedure:
(1R,2S)-Norephedrine (500 mg, 3.31 mmol), 5-iodo-1-(3-pyridyl)-1H-indazole (1.08 g, 33.37 mmol), cesiumcarbonate (2.15 g, 6.61 mmol), copper (I)-iodide (314.9 mg, 1.65 mmol) and butyronitrile (2 mL) are stirred in a glass pressure tube at 120° C. for 20 h. The reaction mixture is filtered via a glass microfibre filter, the solvent evaporated and the residue purified by chromatography (silicagel, eluents: dichloromethane/methanol). 307.8 mg (27%) of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=C/N(C)C)=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.C1C[O:19]CC1>P([O-])([O-])([O-])=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:19])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1
Reactant: C1CCOC1
Reactant: CN(C)/C=C/c1ccc(Br)cc1[N+](=O)[O-]
Agent: O=P([O-])([O-])[O-]
Product: O=Cc1ccc(Br)cc1[N+](=O)[O-]
Yield: 28 %

Procedure:
To a solution of crude (E)-2-(4-bromo-2-nitrophenyl)-N,N-dimethylethenamine (35.5 g, 131 mmol) in THF (300 mL) and pH 7.2 phosphate buffer (300 mL) was added NaIO4 (56.0 g, 262 mmol). The solids were removed and the filter cake was washed with EtOAc (200 mL). The filtrate was washed with brine (2×100 mL), dried and concentrated. The concentrate was purified via flash chromatography (5% EtOAc/hexanes to 10% EtOAc/hexanes) to provide 4-bromo-2-nitrobenzaldehyde (8.41 g, 28% yield).